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Sample records for syndrome mouse model

  1. Mouse models of myelodysplastic syndromes

    PubMed Central

    Beachy, Sarah H.; Aplan, Peter D.

    2010-01-01

    Synopsis Three general approaches have been used in an attempt to model myelodysplastic syndrome (MDS) in mice, including treatment with mutagens or carcinogens, xenotransplantation of human MDS cells, and genetic engineering of mouse hematopoietic cells. Xenotransplantation of cells from MDS patients has proved difficult, possibly due to the innate characteristics of the MDS clone and microenvironmental influences, including adverse effects of a host immune response. Genetic engineering of hematopoietic cells or mice has been accomplished by in vitro transfer of genes to mouse hematopoietic cells with subsequent transplantation into an irradiated host, or by modification of the mouse germline to generate mice with altered expression of genes of interest. A number of genes have been studied using these approaches, including RUNX1, Evi1, Npm1, SALL4B, NUP98-HOXD13, BCL2/NRAS, Arid4a, Polg and Dido. This review discusses the phenotypes observed in available mouse models for MDS with a concentration on a model that leads to aberrant expression of conserved homeobox (HOX) genes that are important regulators of normal hematopoiesis. Utilizing these models of MDS should allow a more complete understanding of the disease process and provide a platform for pre-clinical testing of therapeutic approaches. PMID:20359631

  2. Mouse models of primary Sjögren’s syndrome

    PubMed Central

    Park, Young-Seok; Gauna, Adrienne E.; Cha, Seunghee

    2015-01-01

    Sjögren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models. PMID:25777752

  3. Dissecting Alzheimer disease in Down syndrome using mouse models

    PubMed Central

    Choong, Xun Yu; Tosh, Justin L.; Pulford, Laura J.; Fisher, Elizabeth M. C.

    2015-01-01

    Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD. PMID:26528151

  4. Modeling fragile X syndrome in the Fmr1 knockout mouse

    PubMed Central

    Kazdoba, Tatiana M.; Leach, Prescott T.; Silverman, Jill L.; Crawley, Jacqueline N.

    2014-01-01

    Summary Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS. PMID:25606362

  5. Liver aging and pseudocapillarization in a Werner syndrome mouse model.

    PubMed

    Cogger, Victoria C; Svistounov, Dmitri; Warren, Alessandra; Zykova, Svetlana; Melvin, Richard G; Solon-Biet, Samantha M; O'Reilly, Jennifer N; McMahon, Aisling C; Ballard, J William O; De Cabo, Rafa; Le Couteur, David G; Lebel, Michel

    2014-09-01

    Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(∆hel/∆hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(∆hel/∆hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(∆hel/∆hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(∆hel/∆hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(∆hel/∆hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver.

  6. A new mouse model of metabolic syndrome and associated complications

    PubMed Central

    Wang, Yun; Zheng, Yue; Nishina, Patsy M; Naggert, Jürgen K.

    2010-01-01

    Metabolic Syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the CLAMS™ animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LepR, SOCS1 and STAT3 phosphorylation were examined. Cardiac function was assessed by Echo- and Electro Cardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with a LOD score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JNK1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of metabolic syndrome and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy. PMID:19398498

  7. A Mouse Model for Meckel Syndrome Type 3

    PubMed Central

    Cook, Susan A.; Collin, Gayle B.; Bronson, Roderick T.; Naggert, Jürgen K.; Liu, Dong P.; Akeson, Ellen C.; Davisson, Muriel T.

    2009-01-01

    Meckel-Gruber syndrome type 3 (MKS3; OMIM 607361) is a severe autosomal recessive disorder characterized by bilateral polycystic kidney disease. Other malformations associated with MKS3 include cystic changes in the liver, polydactyly, and brain abnormalities (occipital encephalocele, hydrocephalus, and Dandy Walker–type cerebellar anomalies). The disorder is hypothesized to be caused by defects in primary cilia. In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. Here, we describe a spontaneous deletion of the mouse ortholog, Tmem67, which results in polycystic kidney disease and death by 3 wk after birth. Hydrocephalus also occurs in some mutants. We verified the mutated gene by transgenic rescue and characterized the phenotype with microcomputed tomography, histology, scanning electron microscopy, and immunohistochemistry. This mutant provides a mouse model for MKS3 and adds to the growing set of mammalian models essential for studying the role of the primary cilium in kidney function. PMID:19211713

  8. Breathing abnormalities in a female mouse model of Rett syndrome.

    PubMed

    Johnson, Christopher M; Cui, Ningren; Zhong, Weiwei; Oginsky, Max F; Jiang, Chun

    2015-09-01

    Rett syndrome (RTT) is a female neurodevelopmental disease with breathing abnormalities. To understand whether breathing defects occur in the early lives of a group of female Mecp2(+/-) mice, a mouse model of RTT, and what percentage of mice shows RTT-like breathing abnormality, breathing activity was measured by plethysmography in conscious mice. Breathing frequency variation and central apnea in a group of Mecp2(+/-) females displayed a distribution pattern similar to Mecp2(-/Y) males, while the rest resembled the wild-type mice. Similar results were obtained using the k-mean clustering statistics analysis. With two independent methods, about 20% of female Mecp2(+/-) mice showed RTT-like breathing abnormalities that began as early as 3 weeks of age in the Mecp2(+/-) mice, and were suppressed with 3% CO2. The finding that only a small proportion of Mecp2(+/-) mice develops RTT-like breathing abnormalities suggests incomplete allele inactivation in the RTT-model Mecp2(+/-) mice.

  9. Mouse model of Timothy syndrome recapitulates triad of autistic traits.

    PubMed

    Bader, Patrick L; Faizi, Mehrdad; Kim, Leo H; Owen, Scott F; Tadross, Michael R; Alfa, Ronald W; Bett, Glenna C L; Tsien, Richard W; Rasmusson, Randall L; Shamloo, Mehrdad

    2011-09-13

    Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.

  10. Activity-Dependent Changes in MAPK Activation in the Angelman Syndrome Mouse Model

    ERIC Educational Resources Information Center

    Filonova, Irina; Trotter, Justin H.; Banko, Jessica L.; Weeber, Edwin J.

    2014-01-01

    Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal "UBE3A" gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular…

  11. Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome

    PubMed Central

    Simoes de Souza, Fabio M.; Busquet, Nicolas; Blatner, Megan; Maclean, Kenneth N.; Restrepo, Diego

    2011-01-01

    Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities. PMID:22355654

  12. The use of mouse models to understand and improve cognitive deficits in Down syndrome

    PubMed Central

    Das, Ishita; Reeves, Roger H.

    2011-01-01

    Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development. PMID:21816951

  13. Exaggerated NMDA Mediated LTD in a Mouse Model of Down Syndrome and Pharmacological Rescuing by Memantine

    ERIC Educational Resources Information Center

    Scott-McKean, Jonah J.; Costa, Alberto C. S.

    2011-01-01

    The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 [mu]M NMDA for 3 min and 50 [mu]M DHPG for 5 min, respectively. We found that Ts65Dn mice…

  14. Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model.

    PubMed

    Guidi, Sandra; Stagni, Fiorenza; Bianchi, Patrizia; Ciani, Elisabetta; Giacomini, Andrea; De Franceschi, Marianna; Moldrich, Randal; Kurniawan, Nyoman; Mardon, Karine; Giuliani, Alessandro; Calzà, Laura; Bartesaghi, Renata

    2014-02-01

    Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored

  15. Mouse model of Sanfilippo syndrome type B: relation of phenotypic features to background strain.

    PubMed

    Gografe, Sylvia I; Garbuzova-Davis, Svitlana; Willing, Alison E; Haas, Ken; Chamizo, Wilfredo; Sanberg, Paul R

    2003-12-01

    Sanfilippo syndrome type B or mucopolysaccharidosis type III B (MPS IIIB) is a lysosomal storage disorder that is inherited in autosomal recessive manner. It is characterized by systemic heparan sulfate accumulation in lysosomes due to deficiency of the enzyme alpha-N-acetylglucosaminidase (Naglu). Devastating clinical abnormalities with severe central nervous system involvement and somatic disease lead to premature death. A mouse model of Sanfilippo syndrome type B was created by targeted disruption of the gene encoding Naglu, providing a powerful tool for understanding pathogenesis and developing novel therapeutic strategies. However, the JAX GEMM Strain B6.129S6-Naglutm1Efn mouse, although showing biochemical similarities to humans with Sanfilippo syndrome, exhibits aging and behavioral differences. We observed idiosyncrasies, such as skeletal dysmorphism, hydrocephalus, ocular abnormalities, organomegaly, growth retardation, and anomalies of the integument, in our breeding colony of Naglu mutant mice and determined that several of them were at least partially related to the background strain C57BL/6. These background strain abnormalities, therefore, potentially mimic or overlap signs of the induced syndrome in our mice. Our observations may prove useful in studies of Naglu mutant mice. The necessity for distinguishing background anomalies from signs of the modeled disease is apparent. PMID:14727810

  16. Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

    PubMed

    Witton, Jonathan; Padmashri, Ragunathan; Zinyuk, Larissa E; Popov, Victor I; Kraev, Igor; Line, Samantha J; Jensen, Thomas P; Tedoldi, Angelo; Cummings, Damian M; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Bannerman, David M; Randall, Andrew D; Brown, Jonathan T; Edwards, Frances A; Rusakov, Dmitri A; Stewart, Michael G; Jones, Matt W

    2015-09-01

    Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

  17. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome

    PubMed Central

    Bjornsson, Hans T.; Benjamin, Joel S.; Zhang, Li; Weissman, Jacqueline; Gerber, Elizabeth E.; Chen, Yi-Chun; Vaurio, Rebecca G.; Potter, Michelle C.; Hansen, Kasper D.; Dietz, Harry C.

    2015-01-01

    Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d+/βGeo mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d+/βGeo mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome. PMID:25273096

  18. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.

    PubMed

    Bjornsson, Hans T; Benjamin, Joel S; Zhang, Li; Weissman, Jacqueline; Gerber, Elizabeth E; Chen, Yi-Chun; Vaurio, Rebecca G; Potter, Michelle C; Hansen, Kasper D; Dietz, Harry C

    2014-10-01

    Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/βGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome. PMID:25273096

  19. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

    PubMed

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-05-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  20. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome.

    PubMed

    Kelley, Scott T; Skarra, Danalea V; Rivera, Alissa J; Thackray, Varykina G

    2016-01-01

    Women with polycystic ovary syndrome (PCOS) have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome) that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet. PMID:26731268

  1. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome.

    PubMed

    Kelley, Scott T; Skarra, Danalea V; Rivera, Alissa J; Thackray, Varykina G

    2016-01-01

    Women with polycystic ovary syndrome (PCOS) have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome) that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet.

  2. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome

    PubMed Central

    Kelley, Scott T.; Skarra, Danalea V.; Rivera, Alissa J.; Thackray, Varykina G.

    2016-01-01

    Women with polycystic ovary syndrome (PCOS) have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome) that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet. PMID:26731268

  3. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

    PubMed Central

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-01-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  4. Reducing GABAergic inhibition restores cognitive functions in a mouse model of Down syndrome.

    PubMed

    Potier, Marie-Claude; Braudeau, Jérôme; Dauphinot, Luce; Delatour, Benoît

    2014-02-01

    Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and have been tested in a mouse model of Down syndrome. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse agonists of the GABA-benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse agonists selective for the α5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down syndrome mouse model after acute treatment.

  5. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

    PubMed

    Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D; Bell, Aaron J; Chambers, Daniel B; Hinchey, Joseph; Choi, Richard J; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J; Ferrick, Neal J; Terlizzi, Allison M; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A; Zukin, R Suzanne; Woo, Newton H; Tranfaglia, Michael R; Louneva, Natalia; Arnold, Steven E; Siegel, Steven J; Bolduc, Francois V; McDonald, Thomas V; Jongens, Thomas A; McBride, Sean M J

    2015-01-01

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

  6. Facial Image Classification of Mouse Embryos for the Animal Model Study of Fetal Alcohol Syndrome

    PubMed Central

    Fang, Shiaofen; Liu, Ying; Huang, Jeffrey; Vinci-Booher, Sophia; Anthony, Bruce; Zhou, Feng

    2010-01-01

    Fetal Alcohol Syndrome (FAS) is a developmental disorder caused by maternal drinking during pregnancy. Computerize imaging techniques have been applied to study human facial dysmorphology associated with FAS. This paper describes a new facial image analysis method based on a multi-angle image classification technique using micro-video images of mouse embryo. Images taken from several different angles are analyzed separately, and the results are combined for classifications that separate embryos with and without alcohol exposures. Analysis results from animal models provide critical references for the understanding of FAS and potential therapy solutions for human patients. PMID:20502627

  7. Behavioural characteristics of the Prader-Willi syndrome related biallelic Snord116 mouse model.

    PubMed

    Zieba, Jerzy; Low, Jac Kee; Purtell, Louise; Qi, Yue; Campbell, Lesley; Herzog, Herbert; Karl, Tim

    2015-10-01

    Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans and is associated with several behavioural phenotypes such as altered motoric function, reduced activity, and learning disabilities. It can include mood instability and, in some cases, psychotic episodes. Recently, the Snord116 gene has been associated with the development of PWS, however, it's contribution to the behavioural aspects of the disease are unknown. Here we show that male and female mice lacking Snord116 on both alleles exhibit normal motor behaviours and exploration but do display task-dependent alterations to locomotion and anxiety-related behaviours. Sociability is well developed in Snord116 deficient mice as are social recognition memory, spatial working memory, and fear-associated behaviours. No sex-specific effects were found. In conclusion, the biallelic Snord116 deficiency mouse model exhibits particular endophenotypes with some relevance to PWS, suggesting partial face validity for the syndrome. PMID:26259850

  8. Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome.

    PubMed

    Hamlett, Eric D; Boger, Heather A; Ledreux, Aurélie; Kelley, Christy M; Mufson, Elliott J; Falangola, Maria F; Guilfoyle, David N; Nixon, Ralph A; Patterson, David; Duval, Nathan; Granholm, Ann-Charlotte E

    2016-01-01

    Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer's disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review agerelated neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration. PMID:26391050

  9. Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

    PubMed Central

    Hamlett, Eric D.; Boger, Heather A.; Ledreux, Aurélie; Kelley, Christy M.; Mufson, Elliott J.; Falangola, Maria F.; Guilfoyle, David N.; Nixon, Ralph A.; Patterson, David; Duval, Nathan; Granholm, Ann-Charlotte E.

    2016-01-01

    Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer’s disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review age-related neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration. PMID:26391050

  10. Dsprul: A spontaneous mouse mutation in Desmoplakin as a model of Carvajal-Huerta Syndrome

    PubMed Central

    Pratt, C. Herbert; Potter, Christopher S.; Fairfield, Heather; Reinholdt, Laura G.; Bergstrom, David E.; Harris, Belinda S.; Greenstein, Ian; Dadras, Soheil S.; Liang, Bruce T.; Schofield, Paul N.; Sundberg, John P.

    2015-01-01

    Studies of spontaneous mutations in mice have provided valuable disease models and important insights into the mechanisms of human disease. Ruffled (rul) is a new autosomal recessive mutation causing abnormal hair coat in mice. The rul allele arose spontaneously in the RB156Bnr/EiJ inbred mouse strain. In addition to an abnormal coat texture, we found diffuse epidermal blistering, abnormal electrocardiograms (ECGs), and ventricular fibrosis in mutant animals. Using high-throughput sequencing (HTS) we found a frameshift mutation at 38,288,978 bp of chromosome 13 in the desmoplakin gene (Dsp). The predicted mutant protein is truncated at the c-terminus and missing the majority of the plakin repeat domain. The phenotypes found in Dsprul mice closely model a rare human disorder, Carvajal-Huerta Syndrome. Carvajal-Huerta Syndrome (CHS) is a rare cardiocutaneous disorder that presents in humans with woolly hair, palmoplantar keratoderma and ventricular cardiomyopathy. CHS results from an autosomal recessive mutation on the 3′ end of Desmoplakin (DSP) truncating the full length protein. The Dsprul mouse provides a new model to investigate the pathogenesis of CHS, as well as the underlying basic biology of the adhesion molecules coded by the desmosomal genes. PMID:25659760

  11. A chimeric human-mouse model of Sjögren's syndrome.

    PubMed

    Young, Nicholas A; Wu, Lai-Chu; Bruss, Michael; Kaffenberger, Benjamin H; Hampton, Jeffrey; Bolon, Brad; Jarjour, Wael N

    2015-01-01

    Despite recent advances in the understanding of Sjögren's Syndrome (SjS), the pathogenic mechanisms remain elusive and an ideal model for early drug discovery is not yet available. To establish a humanized mouse model of SjS, peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with SjS were transferred into immunodeficient NOD-scid IL-2rγ(null) mouse recipients to produce chimeric mice. While no difference was observed in the distribution of cells, chimeric mice transferred with PBMCs from SjS patients produced enhanced cytokine levels, most significantly IFN-γ and IL-10. Histological examination revealed enhanced inflammatory responses in the lacrimal and salivary glands of SjS chimeras, as measured by digital image analysis and blinded histopathological scoring. Infiltrates were primarily CD4+, with minimal detection of CD8+ T-cells and B-cells. These results demonstrate a novel chimeric mouse model of human SjS that provides a unique in vivo environment to test experimental therapeutics and investigate T-cell disease pathology.

  12. Mouse Models of Down Syndrome as a Tool to Unravel the Causes of Mental Disabilities

    PubMed Central

    Rueda, Noemí; Flórez, Jesús; Martínez-Cué, Carmen

    2012-01-01

    Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition due to alterations in GABAA-mediated transmission and disturbances in the glutamatergic, noradrenergic and cholinergic systems, among others, has also been demonstrated. DS cognitive dysfunction caused by neurodevelopmental alterations is worsened in later life stages by neurodegenerative processes. A number of pharmacological therapies have been shown to partially restore morphological anomalies concomitantly with cognition in these mice. In conclusion, the use of mouse models is enormously effective in the study of the neurobiological substrates of mental disabilities in DS and in the testing of therapies that rescue these alterations. These studies provide the basis for developing clinical trials in DS individuals and sustain the hope that some of these drugs will be useful in rescuing mental disabilities in DS individuals. PMID:22685678

  13. A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment.

    PubMed

    Webster, R G; Cossins, J; Lashley, D; Maxwell, S; Liu, W W; Wickens, J R; Martinez-Martinez, P; de Baets, M; Beeson, D

    2013-10-01

    In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human ε-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a ~1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 ± 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these β2-adrenergic receptor agonists for the treatment of the slow channel syndrome.

  14. Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome.

    PubMed

    Marland, Jamie R K; Smillie, Karen J; Cousin, Michael A

    2016-01-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV) endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy.

  15. Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome

    PubMed Central

    Marland, Jamie R. K.; Smillie, Karen J.; Cousin, Michael A.

    2016-01-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV) endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy. PMID:26808141

  16. Genotype, phenotype, and karyotype correlation in the XO mouse model of Turner Syndrome.

    PubMed

    Probst, Frank J; Cooper, Mitchell Lance; Cheung, Sau Wai; Justice, Monica J

    2008-01-01

    The murine model for Turner Syndrome is the XO mouse. Unlike their human counterparts, XO mice are typically fertile, and their lack of a second sex chromosome can be transmitted from one generation to the next as an X-linked dominant trait with male lethality. The introduction of an X-linked coat-color marker (tabby) has greatly facilitated the maintenance of this useful mouse strain. XO mice can be produced in large numbers, generation after generation, and rapidly identified on the basis of their sex and coat color. Although this breeding scheme appears to be effective at the phenotype level, its utility has never been conclusively proved at the molecular or cytogenetic levels. Here, we clone and sequence the tabby deletion break point and present a multiplex polymerase chain reaction-based assay for the tabby mutation. By combining the results of this assay with whole-chromosome painting data, we demonstrate that genotype, phenotype, and karyotype all show perfect correlation in the publicly available XO breeding stock. This work lays the foundation for the use of this strain to study Turner Syndrome in particular and the X chromosome in general. PMID:18499648

  17. Embryonic Gut Anomalies in a Mouse Model of Retinoic Acid-Induced Caudal Regression Syndrome

    PubMed Central

    Pitera, Jolanta E.; Smith, Virpi V.; Woolf, Adrian S.; Milla, Peter J.

    2001-01-01

    Vitamin A and its derivatives such as retinoic acid (RA) are important signaling molecules for morphogenesis of vertebrate embryos. Little is known, however, about morphogenetic factors controlling the development of the gastrointestinal tract and RA is likely to be involved. In the mouse, teratogenic doses of RA cause truncation of the embryonic caudal body axis that parallel the caudal regression syndrome as described in humans. These changes are often associated with anomalies of the lower digestive tract. Overlapping spatiotemporal expression of retinoic acid receptor-β (RARβ) and cellular retinol-binding protein I, CRBPI, with Hoxb5 and c-ret in the gut mesoderm imply possible cooperation required for proper neuromuscular development. To determine susceptibility and responsiveness of the developing gut and its neuromusculature to exogenous retinoids we used a mouse model of RA-induced caudal regression syndrome. The results showed that stage-specific RA treatment both in vivo and in vitro affected gut looping/rotation morphogenesis and growth of asymmetrical structures such as the cecum together with delayed differentiation of the gut mesoderm and colonization of the postcecal gut by neural crest-derived enteric neuronal precursors. These observations demonstrate that RA has a direct effect on gut morphogenesis and innervation. PMID:11733381

  18. Calea zacatechichi dichloromethane extract exhibits antidiarrheal and antinociceptive effects in mouse models mimicking irritable bowel syndrome.

    PubMed

    Sałaga, M; Kowalczuk, A; Zielinska, M; Błażewicz, A; Fichna, J

    2015-10-01

    Calea zacatechichi Schltdl. (Asteraceae alt. Compositae) is a Mexican plant commonly used in folk medicine to treat respiratory and gastrointestinal (GI) disorders. The objective of this study is to characterize the effect of C. zacatechichi extracts in mouse models mimicking the symptoms of irritable bowel syndrome (IBS). Powdered C. zacatechichi herb (leaves, stems, and flowers) was extracted with methanol. Methanolic extract was filtered and evaporated giving methanolic fraction. The residue was extracted with dichloromethane (DCM). Methanolic and DCM (200 mg/kg, per os) extracts were screened for their effect on GI motility in several in vitro tests, and the antidiarrheal and antinociceptive effects were assessed using mouse models. The influence of the DCM extract on motoric parameters and exploratory behaviors was also assessed. Finally, the composition of C. zacatechichi DCM extract was qualitatively analyzed using liquid chromatography-mass spectrometry (LC-MS) method. C. zacatechichi DCM extract significantly inhibited the contractility of mouse colon in vitro (IC50 = 17 ± 2 μg/ml). Administration of the DCM extract in vivo (200 mg/kg, per os) significantly prolonged the time of whole GI transit (46 ± 1 vs. 117 ± 27 min for control and DCM-treated animals, respectively; P = 0.0023), inhibited hypermotility, and reduced pain in mouse models mimicking functional GI disorders. Our findings suggest that constituents of the C. zacatechichi DCM extract exhibit antidiarrheal and analgesic activity. The extract may thus become an attractive material for isolation of compounds that may be used as a supplementary treatment for pain and diarrhea associated with IBS in the future. PMID:26068703

  19. Polycystic ovary syndrome (PCOS)-like phenotypes in the d-galactose-induced aging mouse model.

    PubMed

    Park, Ji-Hun; Choi, Tae-Saeng

    2012-11-01

    The D-galactose (D-gal)-induced animal model, which is established by consecutive subcutaneous d-gal injections for approximately 6weeks, has been frequently used for aging research. This animal model has been shown to accelerate aging of the brain, kidneys, liver, and blood cells. However, aging of the female reproductive organs in this animal model has not been reported. The aim of this study was to investigate changes in the ovary in the d-gal-induced aging mouse model. First, we evaluated anti-Müllerian hormone (AMH) as a marker of ovarian aging in blood plasma. We speculated there would be lower AMH levels in d-gal-treated mice because ovarian aging would be induced by d-gal, as reported for other tissues. However, the results showed that AMH levels in d-gal-treated mice were approximately four-fold higher than control mice. Abnormally high AMH levels are detected in ovarian cancer and polycystic ovary syndrome (PCOS) patients. Therefore, we examined PCOS-related markers in this mouse model. Total testosterone levels were high and abnormal estrous cycles were induced in d-gal-treated mice. These changes, including AMH levels, in d-gal-treated mice were inhibited by aminoguanidine treatment, an advanced glycation end product reducer. In addition, ovarian cysts were observed in some d-gal-treated mice. These results indicate that with respect to female reproduction, d-gal-treated mice are suitable for PCOS studies, rather than aging studies.

  20. Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1

    PubMed Central

    Sedman, Tuuli; Rünkorg, Kertu; Krass, Maarja; Luuk, Hendrik; Plaas, Mario; Vasar, Eero; Volke, Vallo

    2016-01-01

    Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 μg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes. PMID:27069934

  1. Tau Reduction Prevents Disease in a Mouse Model of Dravet Syndrome

    PubMed Central

    Gheyara, Ania L; Ponnusamy, Ravikumar; Djukic, Biljana; Craft, Ryan J; Ho, Kaitlyn; Guo, Weikun; Finucane, Mariel M; Sanchez, Pascal E; Mucke, Lennart

    2014-01-01

    Objective Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies. Methods We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Nav1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays. Results Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. Interpretation Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies. Ann Neurol 2014;76:443–456 PMID:25042160

  2. A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling

    PubMed Central

    Weatherbee, Scott D.; Niswander, Lee A.; Anderson, Kathryn V.

    2009-01-01

    Meckel syndrome (MKS) is a rare autosomal recessive disease causing perinatal lethality associated with a complex syndrome that includes occipital meningoencephalocele, hepatic biliary ductal plate malformation, postaxial polydactyly and polycystic kidneys. The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. However, shRNA knockdown studies in cell culture have reported conflicting results on the role of Mks1 in ciliogenesis. Here we show that loss of function of mouse Mks1 results in an accurate model of human MKS, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development and the kidney that mirror the human syndrome. In contrast to cell culture studies, loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects, although both tissues show an expansion of the domain of response to Shh signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage and long bones are likely to be the result of the disruption of Hh signaling, and the basis of defects in the liver and kidney require further analysis. Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1. PMID:19776033

  3. A mouse model of conduction system patterning abnormalities in heterotaxy syndrome.

    PubMed

    Czosek, Richard J; Haaning, Allison; Ware, Stephanie M

    2010-10-01

    Duplication or absence of parts of the specialized cardiac conduction system in patients with heterotaxy syndrome causes significant clinical disease, but the mechanistic basis by which embryonic disruption of left-right patterning alters conduction system patterning in these patients is not well understood. We sought to determine whether a mouse model of X-linked human heterotaxy recapitulates conduction system abnormalities identified in patients with heterotaxy. Cardiac structure and conduction system patterning were evaluated in Zic3 null embryos from e9.5 to e16.5 using genetic and molecular methods. Severe structural abnormalities involving atrial, ventricular, and conotruncal development were associated with a spectrum of disorganized and ambiguous arrangements throughout the conduction system, including the appearance of duplicated structures. The severity and location of conduction system abnormalities correlated with the severity and location of associated structural heart disease and were identifiable at the earliest stages examined. The Zic3 mouse model provides a novel tool to dissect the mechanistic underpinnings of conduction system patterning and dysfunction and its relationship to cardiovascular malformations, making it a promising model to improve understanding and risk assessment in the clinical arena.

  4. Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome.

    PubMed

    Liu, Zhong-Hua; Smith, Carolyn Beebe

    2009-04-17

    Anxiety is a common symptom in fragile X patients. However, an anxiety-prone phenotype in mouse models of fragile X syndrome is not clear. In most studies of fmr1 knockout mice, decreased anxiety-like responses in exploratory-based models are found, but mice also exhibit abnormal social interactions. We hypothesize the coexistence of elevated social anxiety and reduced nonsocial anxiety in fmr1 knockout mice. In the present study, we applied an automated three-chambered social approach method and the elevated zero maze test to further investigate social interactions and general anxiety, respectively. Results indicate lower levels of both social approach behavior and response to social novelty in fmr1 knockout mice compared with wild-type littermates in the social interaction test. In the elevated zero maze, fmr1 knockout mice spent a greater percent time in open quadrants than wild-type mice, suggesting reduced nonsocial anxiety. These findings support the hypothesis that social and nonsocial anxiety can be dissociated and that in the fragile X mouse model, behavior consistent with hyper-social anxiety coexists with hypo-nonsocial anxiety.

  5. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

    PubMed Central

    2014-01-01

    Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. PMID:25136376

  6. Mouse and hamster mutants as models for Waardenburg syndromes in humans.

    PubMed Central

    Asher, J H; Friedman, T B

    1990-01-01

    Four different Waardenburg syndromes have been defined based upon observed phenotypes. These syndromes are responsible for approximately 2% of subjects with profound congenital hearing loss. At present, Waardenburg syndromes have not been mapped to particular human chromosomes. One or more of the mouse mutant alleles, Ph (patch), s (piebald), Sp (splotch), and Mior (microphthalmia-Oak Ridge) and the hamster mutation Wh (anophthalmic white) may be homologous to mutations causing Waardenburg syndromes. In heterozygotes, phenotypic effects of these four mouse mutations and the hamster mutation are similar to the phenotypes produced by different Waardenburg syndrome mutations. The chromosomal locations and syntenic relationships associated with three of the four mouse mutant genes have been used to predict human chromosomal locations for Waardenburg syndromes: (1) on chromosome 2q near FN1 (fibronectin 1), (2) on chromosome 3p near the proto-oncogene RAF1 or 3q near RHO (rhodopsin), and (3) on chromosome 4p near the proto-oncogene KIT. Waardenburg syndromes show extensive intrafamilial phenotypic variability. Results of our studies with the hamster mutation Wh suggest that this variability may be explained in part by modifier genes segregating within families. Images PMID:2246770

  7. Hearing loss in a mouse model of 22q11.2 Deletion Syndrome.

    PubMed

    Fuchs, Jennifer C; Zinnamon, Fhatarah A; Taylor, Ruth R; Ivins, Sarah; Scambler, Peter J; Forge, Andrew; Tucker, Abigail S; Linden, Jennifer F

    2013-01-01

    22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM. PMID:24244619

  8. Hearing loss in a mouse model of 22q11.2 Deletion Syndrome.

    PubMed

    Fuchs, Jennifer C; Zinnamon, Fhatarah A; Taylor, Ruth R; Ivins, Sarah; Scambler, Peter J; Forge, Andrew; Tucker, Abigail S; Linden, Jennifer F

    2013-01-01

    22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM.

  9. Hearing Loss in a Mouse Model of 22q11.2 Deletion Syndrome

    PubMed Central

    Fuchs, Jennifer C.; Zinnamon, Fhatarah A.; Taylor, Ruth R.; Ivins, Sarah; Scambler, Peter J.; Forge, Andrew; Tucker, Abigail S.; Linden, Jennifer F.

    2013-01-01

    22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM. PMID:24244619

  10. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model.

    PubMed

    Kurabayashi, Nobuhiro; Nguyen, Minh Dang; Sanada, Kamon

    2015-11-01

    Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS. PMID:26373433

  11. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model.

    PubMed

    Kurabayashi, Nobuhiro; Nguyen, Minh Dang; Sanada, Kamon

    2015-11-01

    Down syndrome (DS) arises from triplication of genes on human chromosome 21 and is associated with anomalies in brain development such as reduced production of neurons and increased generation of astrocytes. Here, we show that differentiation of cortical progenitor cells into astrocytes is promoted by DYRK1A, a Ser/Thr kinase encoded on human chromosome 21. In the Ts1Cje mouse model of DS, increased dosage of DYRK1A augments the propensity of progenitors to differentiate into astrocytes. This tendency is associated with enhanced astrogliogenesis in the developing neocortex. We also find that overexpression of DYRK1A upregulates the activity of the astrogliogenic transcription factor STAT in wild-type progenitors. Ts1Cje progenitors exhibit elevated STAT activity, and depletion of DYRK1A in these cells reverses the deregulation of STAT. In sum, our findings indicate that potentiation of the DYRK1A-STAT pathway in progenitors contributes to aberrant astrogliogenesis in DS.

  12. Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome

    PubMed Central

    Popov, V.I.; Kraev, I.; Line, S.J.; Jensen, T.P.; Tedoldi, A.; Cummings, D.M.; Tybulewicz, V.L.J.; Fisher, E.M.C.; Bannerman, D.M.; Randall, A.D.; Brown, J.T.; Edwards, F.A.; Rusakov, D.A.; Stewart, M.G.; Jones, M.W.

    2015-01-01

    Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome (DS), yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here, we report dysfunctional connectivity between dentate gyrus (DG) and CA3 networks in the transchromosomic Tc1 mouse model of DS, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at DG-CA3 excitatory synapses culminate in impaired coding of novel spatial information in CA3 and CA1 and disrupted behaviour in vivo. These results highlight the vulnerability of DG-CA3 networks to aberrant human chromosome 21 gene expression, and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in DS. PMID:26237367

  13. Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome.

    PubMed

    Reynolds, Louise E; Watson, Alan R; Baker, Marianne; Jones, Tania A; D'Amico, Gabriela; Robinson, Stephen D; Joffre, Carine; Garrido-Urbani, Sarah; Rodriguez-Manzaneque, Juan Carlos; Martino-Echarri, Estefanía; Aurrand-Lions, Michel; Sheer, Denise; Dagna-Bricarelli, Franca; Nizetic, Dean; McCabe, Christopher J; Turnell, Andrew S; Kermorgant, Stephanie; Imhof, Beat A; Adams, Ralf; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Hart, Ian R; Hodivala-Dilke, Kairbaan M

    2010-06-10

    Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients. PMID:20535211

  14. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.

    PubMed

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-09-01

    Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice. PMID

  15. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model

    PubMed Central

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Orešič, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-01-01

    SUMMARY Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27Kip1 expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice

  16. Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Das, Devsmita; Medina, Brian; Baktir, Mehmet Akif; Mojabi, Fatemeh S; Fahimi, Atoossa; Ponnusamy, Ravikumar; Salehi, Ahmad

    2015-09-14

    In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice.

  17. Altered auditory processing in a mouse model of fragile X syndrome.

    PubMed

    Rotschafer, Sarah; Razak, Khaleel

    2013-04-19

    This study provides the first description of auditory cortical processing in a mouse model of Fragile X Syndrome (FXS). FXS is a genetic cause of intellectual impairment and is an autism spectrum disorder. Human studies with auditory evoked potentials indicate that FXS is associated with abnormal auditory processing. The Fmr1 knock-out (KO) mouse is a useful model for studying FXS. The KO mice show acoustic hypersensitivity and propensity for audiogenic seizures, suggesting altered auditory responses. However, the nature of changes at the neuronal level is not known. Here we conducted in vivo single unit extracellular electrophysiology in the auditory cortex of urethane/xylazine-anesthetized Fmr1 KO mice in response to tones and frequency modulated (FM) sweeps. Using tones as stimuli, we report expanded frequency tuning, enhanced response magnitude, and more variable first spike latencies in Fmr1 KO mice compared to wild-type controls. FM sweep stimuli revealed altered sensitivity to the rate of frequency change indicating abnormal spectrotemporal processing. There was no difference in FM sweep direction selectivity. Consistent with studies of the somatosensory cortex, these data point to hyper-responsiveness of auditory neurons as a key processing abnormality in FXS. Auditory neural responses can serve as outcome measures in preclinical trials of therapeutics for FXS as well as serve as physiological probes to study their mechanisms of action. PMID:23458504

  18. Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Das, Devsmita; Medina, Brian; Baktir, Mehmet Akif; Mojabi, Fatemeh S; Fahimi, Atoossa; Ponnusamy, Ravikumar; Salehi, Ahmad

    2015-09-14

    In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice. PMID:26240993

  19. Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome.

    PubMed

    Liu, Xiaoxi; Tamada, Kota; Kishimoto, Rui; Okubo, Hiroko; Ise, Satoko; Ohta, Hisashi; Ruf, Sandra; Nakatani, Jin; Kohno, Nobuoki; Spitz, François; Takumi, Toru

    2015-09-01

    Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11-q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader-Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late-onset obesity and hypersensitivity to a high-fat diet. These phenotypes are likely to be the results of genetic perturbations since the energy expenditures and food intakes of patDp/+ mice do not significantly differ from those of wild-type mice. Intriguingly, we found that an enlargement of adipose cells precedes the onset of obesity in patDp/+ mice. To understand the underlying molecular networks responsible for this pre-obese phenotype, we performed transcriptome profiling of white adipose tissue from patDp/+ and wild-type mice using microarray. We identified 230 genes as differentially expressed genes. Sfrp5 - a gene whose expression is positively correlated with adipocyte size, was found to be up-regulated, and Fndc5, a potent inducer of brown adipogenesis was identified to be the top down-regulated gene. Subsequent pathway analysis highlighted a set of 35 molecules involved in energy production, lipid metabolism, and small molecule biochemistry as the top candidate biological network responsible for the pre-obese phenotype of patDp/+. The microarray data were deposited in NCBI Gene Expression Omnibus database with accession number GSE58191. Ultimately, our dataset provides novel insights into the molecular mechanism of obesity and demonstrated that patDp/+ is a valuable mouse model for obesity research. PMID:26484295

  20. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    PubMed

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc. PMID:27317352

  1. An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.

    PubMed

    Zhang, Shuang; Johnson, Christopher M; Cui, Ningren; Xing, Hao; Zhong, Weiwei; Wu, Yang; Jiang, Chun

    2016-10-01

    Rett syndrome (RTT) is a neurodevelopmental disorder affecting multiple functions, including the norepinephrine (NE) system. In the CNS, NE is produced mostly by neurons in the locus coeruleus (LC), where defects in intrinsic neuronal properties, NE biosynthetic enzymes, neuronal CO2 sensitivity, and synaptic currents have been reported in mouse models of RTT. LC neurons in methyl-CpG-binding protein 2 gene (Mecp2) null mice show a high rate of spontaneous firing, although whether such hyperexcitability might increase or decrease the NE release from synapses is unknown. To activate the NEergic axonal terminals selectively, we generated an optogenetic mouse model of RTT in which NEergic neuronal excitability can be manipulated with light. Using commercially available mouse breeders, we produced a new strain of double-transgenic mice with Mecp2 knockout and channelrhodopsin (ChR) knockin in catecholaminergic neurons. Several RTT-like phenotypes were found in the tyrosine hydroxylase (TH)-ChR-Mecp2(-/Y) mice, including hypoactivity, low body weight, hindlimb clasping, and breathing disorders. In brain slices, optostimulation produced depolarization and an increase in the firing rate of LC neurons from TH-ChR control mice. In TH-ChR control mice, optostimulation of presynaptic NEergic neurons augmented the firing rate of hypoglossal neurons (HNs), which was blocked by the α-adrenoceptor antagonist phentolamine. Such optostimulation of NEergic terminals had almost no effect on HNs from two or three TH-ChR-Mecp2(-/Y) mice, indicating that excessive excitation of presynaptic neurons does not benefit NEergic modulation in mice with Mecp2 disruption. These results also demonstrate the feasibility of generating double-transgenic mice for studies of RTT with commercially available mice, which are inexpensive, labor/time efficient, and promising for cell-specific stimulation. © 2016 Wiley Periodicals, Inc.

  2. Tumour angiogenesis is reduced in the Tc1 mouse model of Down Syndrome

    PubMed Central

    Reynolds, Louise E.; Watson, Alan R.; Baker, Marianne; Jones, Tania A.; D’Amico, Gabriela; Robinson, Stephen D.; Joffre, Carine; Garrido-Urbani, Sarah; Rodriguez-Manzaneque, Juan Carlos; Martino-Echarri, Estefanía; Aurrand-Lions, Michel; Sheer, Denise; Dagna-Bricarelli, Franca; Nizetic, Dean; McCabe, Christopher J.; Turnell, Andrew S.; Kermorgant, Stephanie; Imhof, Beat A.; Adams, Ralf; Fisher, Elizabeth M.C.; Tybulewicz, Victor L. J.; Hart, Ian R.; Hodivala-Dilke, Kairbaan M.

    2012-01-01

    Down Syndrome (DS) is a genetic disorder caused by full or partial trisomy of chromosome 21. It occurs in approximately 1/750 live births and presents with many clinical phenotypes including a reduced incidence of solid tumours1,2. Recent work using the Ts65Dn model of DS, that has orthologs of approximately 50% of the genes on human chromosome 21 (Hsa21), has suggested that three copies of the ETS23 or Down Syndrome candidate region 1 (DSCR1) genes4 (a previously known suppressor of angiogenesis5,6) is sufficient to inhibit tumour growth. We have used the Tc1 transchromosomic mouse model of DS9 to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses approximately 81% of Hsa21 genes but not the human DSCR1 region (Supplementary Fig. 1). We transplanted B16F0 and Lewis Lung Carcinoma (LLC) tumour cells into Tc1 mice and showed that growth of these tumours was reduced substantially when compared to wild-type littermate controls. Furthermore, tumour angiogenesis was repressed significantly in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS17,8 and ERG9) and novel endothelial cell-specific genes10, never shown before to be involved in angiogenesis (JAM-B11 and PTTG1IP) that, when overexpressed, are responsible for the inhibition of angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis providing an explanation for the reduced tumour growth in DS. Furthermore, we anticipate that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will likely allow for the identification of other endothelial-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients. PMID:20535211

  3. Using Mouse Models to Explore Genotype-Phenotype Relationship in Down Syndrome

    ERIC Educational Resources Information Center

    Salehi, Ahmad; Faizi, Mehrdad; Belichenko, Pavel V.; Mobley, William C.

    2007-01-01

    Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of…

  4. Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome

    PubMed Central

    Goodliffe, Joseph W.; Olmos-Serrano, Jose Luis; Aziz, Nadine M.; Pennings, Jeroen L.A.; Guedj, Faycal; Bianchi, Diana W.

    2016-01-01

    Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral

  5. Genetic Enhancement of Limb Defects in a Mouse Model of Cornelia de Lange Syndrome

    PubMed Central

    LOPEZ-BURKS, MARTHA E.; SANTOS, ROSAYSELA; KAWAUCHI, SHIMAKO; CALOF, ANNE L.; LANDER, ARTHUR D.

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl+/− mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl+/− mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl+/− mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. PMID:27120109

  6. Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome.

    PubMed

    Kedlaya, Rajendra; Veera, Shreya; Horan, Daniel J; Moss, Rachel E; Ayturk, Ugur M; Jacobsen, Christina M; Bowen, Margot E; Paszty, Chris; Warman, Matthew L; Robling, Alexander G

    2013-11-13

    Osteoporosis pseudoglioma syndrome (OPPG) is a rare genetic disease that produces debilitating effects in the skeleton. OPPG is caused by mutations in LRP5, a WNT co-receptor that mediates osteoblast activity. WNT signaling through LRP5, and also through the closely related receptor LRP6, is inhibited by the protein sclerostin (SOST). It is unclear whether OPPG patients might benefit from the anabolic action of sclerostin neutralization therapy (an approach currently being pursued in clinical trials for postmenopausal osteoporosis) in light of their LRP5 deficiency and consequent osteoblast impairment. To assess whether loss of sclerostin is anabolic in OPPG, we measured bone properties in a mouse model of OPPG (Lrp5(-/-)), a mouse model of sclerosteosis (Sost(-/-)), and in mice with both genes knocked out (Lrp5(-/-);Sost(-/-)). Lrp5(-/-);Sost(-/-) mice have larger, denser, and stronger bones than do Lrp5(-/-) mice, indicating that SOST deficiency can improve bone properties via pathways that do not require LRP5. Next, we determined whether the anabolic effects of sclerostin depletion in Lrp5(-/-) mice are retained in adult mice by treating 17-week-old Lrp5(-/-) mice with a sclerostin antibody for 3 weeks. Lrp5(+/+) and Lrp5(-/-) mice each exhibited osteoanabolic responses to antibody therapy, as indicated by increased bone mineral density, content, and formation rates. Collectively, our data show that inhibiting sclerostin can improve bone mass whether LRP5 is present or not. In the absence of LRP5, the anabolic effects of SOST depletion can occur via other receptors (such as LRP4/6). Regardless of the mechanism, our results suggest that humans with OPPG might benefit from sclerostin neutralization therapies.

  7. Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome.

    PubMed

    Lopez-Burks, Martha E; Santos, Rosaysela; Kawauchi, Shimako; Calof, Anne L; Lander, Arthur D

    2016-06-01

    Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl(+/-) mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl(+/-) mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl(+/-) mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. © 2016 Wiley Periodicals, Inc.

  8. Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome.

    PubMed

    Lopez-Burks, Martha E; Santos, Rosaysela; Kawauchi, Shimako; Calof, Anne L; Lander, Arthur D

    2016-06-01

    Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl(+/-) mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl(+/-) mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl(+/-) mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. © 2016 Wiley Periodicals, Inc. PMID:27120109

  9. Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome

    PubMed Central

    Korade, Zeljka; Xu, Libin; Mirnics, Karoly; Porter, Ned A.

    2013-01-01

    7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3β-hydroxysterol-Δ7-reductase (DHCR7). We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 oxysterols have been identified as products of oxidation of 7-DHC in solution. As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7-KO mouse model of SLOS, including oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively. In addition to a previously described oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), we provide evidence for the chemical structures of three new oxysterols in the brain and/or liver tissue of Dhcr7-KO mice, two of which were quantified. We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7-KO mice relative to matching WT mice. While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7-DHC-derived oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress. PMID:22718275

  10. Effect of human milk as a treatment for dry eye syndrome in a mouse model

    PubMed Central

    Diego, Jose L.; Bidikov, Luke; Pedler, Michelle G.; Kennedy, Jeffrey B.; Quiroz-Mercado, Hugo; Gregory, Darren G.; Petrash, J. Mark

    2016-01-01

    Purpose Dry eye syndrome (DES) affects millions of people worldwide. Homeopathic remedies to treat a wide variety of ocular diseases have previously been documented in the literature, but little systematic work has been performed to validate the remedies’ efficacy using accepted laboratory models of disease. The purpose of this study was to evaluate the efficacy of human milk and nopal cactus (prickly pear), two widely used homeopathic remedies, as agents to reduce pathological markers of DES. Methods The previously described benzalkonium chloride (BAK) dry eye mouse model was used to study the efficacy of human milk and nopal cactus (prickly pear). BAK (0.2%) was applied to the mouse ocular surface twice daily to induce dry eye pathology. Fluorescein staining was used to verify that the animals had characteristic signs of DES. After induction of DES, the animals were treated with human milk (whole and fat-reduced), nopal, nopal extract derivatives, or cyclosporine four times daily for 7 days. Punctate staining and preservation of corneal epithelial thickness, measured histologically at the end of treatment, were used as indices of therapeutic efficacy. Results Treatment with BAK reduced the mean corneal epithelial thickness from 36.77±0.64 μm in the control mice to 21.29±3.2 μm. Reduction in corneal epithelial thickness was largely prevented by administration of whole milk (33.2±2.5 μm) or fat-reduced milk (36.1±1.58 μm), outcomes that were similar to treatment with cyclosporine (38.52±2.47 μm), a standard in current dry eye therapy. In contrast, crude or filtered nopal extracts were ineffective at preventing BAK-induced loss of corneal epithelial thickness (24.76±1.78 μm and 27.99±2.75 μm, respectively), as were solvents used in the extraction of nopal materials (26.53±1.46 μm for ethyl acetate, 21.59±5.87 μm for methanol). Epithelial damage, as reflected in the punctate scores, decreased over 4 days of treatment with whole and fat

  11. Effect of human milk as a treatment for dry eye syndrome in a mouse model

    PubMed Central

    Diego, Jose L.; Bidikov, Luke; Pedler, Michelle G.; Kennedy, Jeffrey B.; Quiroz-Mercado, Hugo; Gregory, Darren G.; Petrash, J. Mark

    2016-01-01

    Purpose Dry eye syndrome (DES) affects millions of people worldwide. Homeopathic remedies to treat a wide variety of ocular diseases have previously been documented in the literature, but little systematic work has been performed to validate the remedies’ efficacy using accepted laboratory models of disease. The purpose of this study was to evaluate the efficacy of human milk and nopal cactus (prickly pear), two widely used homeopathic remedies, as agents to reduce pathological markers of DES. Methods The previously described benzalkonium chloride (BAK) dry eye mouse model was used to study the efficacy of human milk and nopal cactus (prickly pear). BAK (0.2%) was applied to the mouse ocular surface twice daily to induce dry eye pathology. Fluorescein staining was used to verify that the animals had characteristic signs of DES. After induction of DES, the animals were treated with human milk (whole and fat-reduced), nopal, nopal extract derivatives, or cyclosporine four times daily for 7 days. Punctate staining and preservation of corneal epithelial thickness, measured histologically at the end of treatment, were used as indices of therapeutic efficacy. Results Treatment with BAK reduced the mean corneal epithelial thickness from 36.77±0.64 μm in the control mice to 21.29±3.2 μm. Reduction in corneal epithelial thickness was largely prevented by administration of whole milk (33.2±2.5 μm) or fat-reduced milk (36.1±1.58 μm), outcomes that were similar to treatment with cyclosporine (38.52±2.47 μm), a standard in current dry eye therapy. In contrast, crude or filtered nopal extracts were ineffective at preventing BAK-induced loss of corneal epithelial thickness (24.76±1.78 μm and 27.99±2.75 μm, respectively), as were solvents used in the extraction of nopal materials (26.53±1.46 μm for ethyl acetate, 21.59±5.87 μm for methanol). Epithelial damage, as reflected in the punctate scores, decreased over 4 days of treatment with whole and fat

  12. Digastric Muscle Phenotypes of the Ts65Dn Mouse Model of Down Syndrome

    PubMed Central

    Connor, Nadine P.

    2016-01-01

    Down syndrome is frequently associated with complex difficulties in oromotor development, feeding, and swallowing. However, the muscle phenotypes underlying these deficits are unclear. We tested the hypotheses that the Ts65Dn mouse model of DS has significantly altered myosin heavy chain (MyHC) isoform profiles of the muscles involved in feeding and swallowing, as well as reductions in the speed of these movements during behavioral assays. SDS-PAGE, immunofluorescence, and qRT-PCR were used to assess MyHC isoform expression in pertinent muscles, and functional feeding and swallowing performance were quantified through videofluoroscopy and mastication assays. We found that both the anterior digastric (ADG) and posterior digastric (PDG) muscles in 11-day old and 5–6 week old Ts65Dn groups showed significantly lower MyHC 2b protein levels than in age-matched euploid control groups. In videofluoroscopic and videotape assays used to quantify swallowing and mastication performance, 5–6 week old Ts65Dn and euploid controls showed similar swallow rates, inter-swallow intervals, and mastication rates. In analysis of adults, 10–11 week old Ts65Dn mice revealed significantly less MyHC 2b mRNA expression in the posterior digastric, but not the anterior digastric muscle as compared with euploid controls. Analysis of MyHC 2b protein levels across an adult age range (10–53 weeks of age) revealed lower levels of MyHC 2b protein in the PDG of Ts65Dn than in euploids, but similar levels of MyHC 2b in the ADG. Cumulatively, these results indicate biochemical differences in some, but not all, muscles involved in swallowing and jaw movement in Ts65Dn mice that manifest early in post-natal development, and persist into adulthood. These findings suggest potential utility of this model for future investigations of the mechanisms of oromotor difficulties associated with Down syndrome. PMID:27336944

  13. A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.

    PubMed

    Alagramam, Kumar N; Gopal, Suhasini R; Geng, Ruishuang; Chen, Daniel H-C; Nemet, Ina; Lee, Richard; Tian, Guilian; Miyagi, Masaru; Malagu, Karine F; Lock, Christopher J; Esmieu, William R K; Owens, Andrew P; Lindsay, Nicola A; Ouwehand, Krista; Albertus, Faywell; Fischer, David F; Bürli, Roland W; MacLeod, Angus M; Harte, William E; Palczewski, Krzysztof; Imanishi, Yoshikazu

    2016-06-01

    Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders. PMID:27110679

  14. A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.

    PubMed

    Alagramam, Kumar N; Gopal, Suhasini R; Geng, Ruishuang; Chen, Daniel H-C; Nemet, Ina; Lee, Richard; Tian, Guilian; Miyagi, Masaru; Malagu, Karine F; Lock, Christopher J; Esmieu, William R K; Owens, Andrew P; Lindsay, Nicola A; Ouwehand, Krista; Albertus, Faywell; Fischer, David F; Bürli, Roland W; MacLeod, Angus M; Harte, William E; Palczewski, Krzysztof; Imanishi, Yoshikazu

    2016-06-01

    Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

  15. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models.

  16. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  17. Endogenous glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse model of haemolytic uraemic syndrome

    PubMed Central

    GÓMEZ, S A; FERNÁNDEZ, G C; VANZULLI, S; DRAN, G; RUBEL, C; BERKI, T; ISTURIZ, M A; PALERMO, M S

    2003-01-01

    The concept that during an immune challenge the release of glucocorticoids (GC) provides feedback inhibition on evolving immune responses has been drawn primarily from studies of autoimmune and/or inflammatory processes in animal models. The epidemic form of haemolytic uraemic syndrome (HUS) occurs secondary to infection with Gram-negative bacteria that produce Shiga toxin (Stx). Although Stx binding to the specific receptors present on renal tissue is the primary pathogenic mechanism, inflammatory or immune interactions are necessary for the development of the complete form of HUS. The aim of this study was to investigate the influence of endogenous GC on Stx-toxicity in a mouse model. Stx2 was injected into GC-deprived mice and survival rate, renal damage and serum urea levels were evaluated. Plasma corticosterone and cytosolic GC receptor (GR) concentration were also determined at multiple intervals post-Stx2 treatment. Higher sensitivity to Stx2 was observed in mice lacking endogenous GC, evidenced by an increase in mortality rates, circulating urea levels and renal histological damage. Moreover, Stx2 injection was associated with a transient but significant rise in corticosterone secretion. Interestingly, 24 h after Stx inoculation significant increases in total GR were detected in circulating neutrophils. These results indicate that interactions between the neuroendocrine and immune systems can modulate the level of damage significantly during a bacterial infection. PMID:12562380

  18. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models

    PubMed Central

    Souchet, Benoit; Guedj, Fayçal; Penke-Verdier, Zsuza; Daubigney, Fabrice; Duchon, Arnaud; Herault, Yann; Bizot, Jean-Charles; Janel, Nathalie; Créau, Nicole; Delatour, Benoit; Delabar, Jean M.

    2015-01-01

    Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models. PMID:26539088

  19. Widespread cerebellar transcriptome changes in Ts65Dn Down syndrome mouse model after lifelong running.

    PubMed

    Walus, Marius; Kida, Elizabeth; Rabe, Ausma; Albertini, Giorgio; Golabek, Adam A

    2016-01-01

    Our previous study showed an improvement in locomotor deficits after voluntary lifelong running in Ts65Dn mice, an animal model for Down syndrome (DS). In the present study, we employed mouse microarrays printed with 55,681 probes in an attempt to identify molecular changes in the cerebellar transcriptome that might contribute to the observed behavioral benefits of voluntary long-term running in Ts65Dn mice. Euploid mice were processed in parallel for comparative purposes in some analyses. We found that running significantly changed the expression of 4,315 genes in the cerebellum of Ts65Dn mice, over five times more than in euploid animals, up-regulating 1,991 and down-regulating 2,324 genes. Functional analysis of these genes revealed a significant enrichment of 92 terms in the biological process category, including regulation of biosynthesis and metabolism, protein modification, phosphate metabolism, synaptic transmission, development, regulation of cell death/apoptosis, protein transport, development, neurogenesis and neuron differentiation. The KEGG pathway database identified 18 pathways that are up-regulated and two that are down-regulated by running that were associated with learning, memory, cell signaling, proteolysis, regeneration, cell cycle, proliferation, growth, migration, and survival. Of six mRNA protein products we tested by immunoblotting, four showed significant running-associated changes in their levels, the most prominent in glutaminergic receptor metabotropic 1, and two showed changes that were close to significant. Thus, unexpectedly, our data point to the high molecular plasticity of Ts65Dn mouse cerebellum, which translated into humans with DS, suggests that the motor deficits of individuals with DS could markedly benefit from prolonged exercise.

  20. Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

    PubMed Central

    Meechan, Daniel W.; Maynard, Thomas M.; Fernandez, Alejandra; Karpinski, Beverly A.; Rothblat, Lawrence A.; LaMantia, Anthony S.

    2015-01-01

    Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic “model” syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that “modeling a model”, in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development. PMID:25866365

  1. Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.

    PubMed

    Vermeij, Wilbert P; Hoeijmakers, Jan H J; Pothof, Joris

    2016-01-01

    Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology.

  2. Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.

    PubMed

    Vermeij, Wilbert P; Hoeijmakers, Jan H J; Pothof, Joris

    2016-01-01

    Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology. PMID:26514200

  3. Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome

    PubMed Central

    Nilsson, Simon RO.; Fejgin, Kim; Gastambide, Francois; Vogt, Miriam A.; Kent, Brianne A.; Nielsen, Vibeke; Nielsen, Jacob; Gass, Peter; Robbins, Trevor W.; Saksida, Lisa M.; Stensbøl, Tine B.; Tricklebank, Mark D.; Didriksen, Michael; Bussey, Timothy J.

    2016-01-01

    A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus – within the current protocols – the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional “hits” being required for phenotypic expression. PMID:27507786

  4. Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

    PubMed

    Nilsson, Simon Ro; Fejgin, Kim; Gastambide, Francois; Vogt, Miriam A; Kent, Brianne A; Nielsen, Vibeke; Nielsen, Jacob; Gass, Peter; Robbins, Trevor W; Saksida, Lisa M; Stensbøl, Tine B; Tricklebank, Mark D; Didriksen, Michael; Bussey, Timothy J

    2016-10-01

    A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

  5. Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome.

    PubMed

    Kaminen-Ahola, Nina; Ahola, Arttu; Flatscher-Bader, Traute; Wilkins, Sarah J; Anderson, Greg J; Whitelaw, Emma; Chong, Suyinn

    2010-10-01

    Growth restriction, craniofacial dysmorphology, and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal or postnatal, but the underlying mechanisms remain unknown.We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome (e.g., craniofacial changes and growth restriction in adolescent mice). In this study, we characterize in detail the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and by extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of nonfostered, ethanol-exposed and control mice at postnatal day 28.We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This finding suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiologic result of ethanol exposure in utero. We also find that, despite some catch-up growth after 5 weeks of age, the effect extends into adulthood, which is consistent with longitudinal studies in humans.Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis, and lipid metabolism.

  6. Sleep-like behavior and 24-h rhythm disruption in the Tc1 mouse model of Down syndrome.

    PubMed

    Heise, I; Fisher, S P; Banks, G T; Wells, S; Peirson, S N; Foster, R G; Nolan, P M

    2015-02-01

    Down syndrome is a common disorder associated with intellectual disability in humans. Among a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24-h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans-species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterized in Tc1 mice. Using both circadian wheel-running analysis and video-based sleep scoring, we showed that these mice exhibited fragmented patterns of sleep-like behaviour during the light phase of a 12:12-h light/dark (LD) cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night-time was less effective in inducing sleep-like behaviour in Tc1 animals than in wild-type controls. In wheel-running analysis, free running in constant light (LL) or constant darkness (DD) showed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in LD and in DD. Our data confirm that Tc1 mice express sleep-related phenotypes that are comparable with those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes, while circadian period under constant lighting conditions is essentially unaffected.

  7. Sleep-like behavior and 24-h rhythm disruption in the Tc1 mouse model of Down syndrome

    PubMed Central

    Heise, I; Fisher, S P; Banks, G T; Wells, S; Peirson, S N; Foster, R G; Nolan, P M

    2015-01-01

    Down syndrome is a common disorder associated with intellectual disability in humans. Among a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24-h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans-species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterized in Tc1 mice. Using both circadian wheel-running analysis and video-based sleep scoring, we showed that these mice exhibited fragmented patterns of sleep-like behaviour during the light phase of a 12:12-h light/dark (LD) cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night-time was less effective in inducing sleep-like behaviour in Tc1 animals than in wild-type controls. In wheel-running analysis, free running in constant light (LL) or constant darkness (DD) showed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in LD and in DD. Our data confirm that Tc1 mice express sleep-related phenotypes that are comparable with those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes, while circadian period under constant lighting conditions is essentially unaffected. PMID:25558895

  8. Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).

    PubMed

    Drum, Benjamin M L; Dixon, Rose E; Yuan, Can; Cheng, Edward P; Santana, Luis F

    2014-01-01

    Ca(2+) flux through l-type CaV1.2 channels shapes the waveform of the ventricular action potential (AP) and is essential for excitation-contraction (EC) coupling. Timothy syndrome (TS) is a disease caused by a gain-of-function mutation in the CaV1.2 channel (CaV1.2-TS) that decreases inactivation of the channel, which increases Ca(2+) influx, prolongs APs, and causes lethal arrhythmias. Although many details of the CaV1.2-TS channels are known, the cellular mechanisms by which they induce arrhythmogenic changes in intracellular Ca(2+) remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca(2+) "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca(2+)]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) spark activity, larger amplitude [Ca(2+)]i transients, and augmented frequency of Ca(2+) waves. The large SR Ca(2+) release in TS myocytes had a profound effect on the kinetics of CaV1.2 current in these cells, increasing the rate of inactivation to a high, persistent level. This limited the amount of influx during EC coupling in TS myocytes. The relationship between the level of expression of CaV1.2-TS channels and the probability of Ca(2+) wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca(2+)]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca(2+)]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca(2+) release. PMID:24215710

  9. Vascular Dysfunction in a Mouse Model of Rett Syndrome and Effects of Curcumin Treatment

    PubMed Central

    Panighini, Anna; Duranti, Emiliano; Santini, Ferruccio; Maffei, Margherita; Pizzorusso, Tommaso; Funel, Niccola; Taddei, Stefano; Bernardini, Nunzia; Ippolito, Chiara; Virdis, Agostino; Costa, Mario

    2013-01-01

    Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG–binding protein) are present in around 80% of patients with Rett Syndrome, a common cause of intellectual disability in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients, is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used the MeCP2 null mouse model B6.129SF1-MeCP2tm1Jae for functional and pharmacological studies. Functional experiments were performed on isolated resistance mesenteric vessels, mounted on a pressurized myograph. Vessels from female MeCP2+/− mice show a reduced endothelium-dependent relaxation, due to a reduced Nitric Oxide (NO) availability secondary to an increased Reactive Oxygen Species (ROS) generation. Such functional aspects are associated with an intravascular increase in superoxide anion production, and a decreased vascular eNOS expression. These alterations are reversed by curcumin administration (5% (w/w) dietary curcumin for 21 days), which restores endothelial NO availability, decreases intravascular ROS production and normalizes vascular eNOS gene expression. In conclusion our findings highlight alterations in the vascular/endothelial system in the absence of a correct function of MeCP2, and uncover related cellular/molecular mechanisms that are rescued by an anti-oxidant treatment. PMID:23705018

  10. Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome.

    PubMed

    Yang, Annan; Currier, Duane; Poitras, Jennifer L; Reeves, Roger H

    2016-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of human chromosome 21 (Hsa21). People with DS display multiple clinical traits as a result of the dosage imbalance of several hundred genes. While many outcomes of trisomy are deleterious, epidemiological studies have shown a significant risk reduction for most solid tumors in DS. Reduced tumor incidence has also been demonstrated in functional studies using trisomic DS mouse models. Therefore, it was interesting to find that Ts1Rhr trisomic mice developed more papillomas than did their euploid littermates in a DMBA-TPA chemical carcinogenesis paradigm. Papillomas in Ts1Rhr mice also proliferated faster. The increased proliferation was likely caused by a stronger response of trisomy to TPA induction. Treatment with TPA caused hyperkeratosis to a greater degree in Ts1Rhr mice than in euploid, reminiscent of hyperkeratosis seen in people with DS. Cultured trisomic keratinocytes also showed increased TPA-induced proliferation compared to euploid controls. These outcomes suggest that altered gene expression in trisomy could elevate a proliferation signalling pathway. Gene expression analysis of cultured keratinocytes revealed upregulation of several trisomic and disomic genes may contribute to this hyperproliferation. The contributions of these genes to hyper-proliferation were further validated in a siRNA knockdown experiment. The unexpected findings reported here add a new aspect to our understanding of tumorigenesis with clinical implications for DS and demonstrates the complexity of the tumor repression phenotype in this frequent condition. PMID:26752700

  11. Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome.

    PubMed

    Yang, Annan; Currier, Duane; Poitras, Jennifer L; Reeves, Roger H

    2016-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of human chromosome 21 (Hsa21). People with DS display multiple clinical traits as a result of the dosage imbalance of several hundred genes. While many outcomes of trisomy are deleterious, epidemiological studies have shown a significant risk reduction for most solid tumors in DS. Reduced tumor incidence has also been demonstrated in functional studies using trisomic DS mouse models. Therefore, it was interesting to find that Ts1Rhr trisomic mice developed more papillomas than did their euploid littermates in a DMBA-TPA chemical carcinogenesis paradigm. Papillomas in Ts1Rhr mice also proliferated faster. The increased proliferation was likely caused by a stronger response of trisomy to TPA induction. Treatment with TPA caused hyperkeratosis to a greater degree in Ts1Rhr mice than in euploid, reminiscent of hyperkeratosis seen in people with DS. Cultured trisomic keratinocytes also showed increased TPA-induced proliferation compared to euploid controls. These outcomes suggest that altered gene expression in trisomy could elevate a proliferation signalling pathway. Gene expression analysis of cultured keratinocytes revealed upregulation of several trisomic and disomic genes may contribute to this hyperproliferation. The contributions of these genes to hyper-proliferation were further validated in a siRNA knockdown experiment. The unexpected findings reported here add a new aspect to our understanding of tumorigenesis with clinical implications for DS and demonstrates the complexity of the tumor repression phenotype in this frequent condition.

  12. Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Best, Tyler K; Cramer, Nathan P; Chakrabarti, Lina; Haydar, Tarik F; Galdzicki, Zygmunt

    2012-02-01

    GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABA(B)/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABA(B) and GABA(A) mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABA(B)/GABA(A) ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABA(B)/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABA(B) and GABA(A) inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.

  13. Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current.

    PubMed

    Best, Tyler K; Siarey, Richard J; Galdzicki, Zygmunt

    2007-01-01

    Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein-coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here we report that this overexpression leads to a significant increase ( approximately 2-fold) in GABA(B)-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggests unimpaired mechanisms of interaction between GIRK channel and GABA(B) receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.

  14. Cardiovascular Development and Survival During Gestation in the TS65DN Mouse Model for Down Syndrome

    PubMed Central

    Lorandeau, Candice G.; Hakkinen, Lauren A.; Moore, Clara S.

    2011-01-01

    The Ts65Dn mouse model for Down syndrome (DS) exhibits many phenotypes seen in human DS. Previous research has revealed a reduced rate of transmission of the T65Dn marker chromosome in neonates. To analyze potential fetal loss, litters from trisomic females at 10.5dpc through 14.5dpc were genotyped. No significant differences from the expected Mendelian ratio were found in transmission of T65Dn at any stage. Cardiovascular defects found in trisomic neonates are associated with formation of pharyngeal arch arteries. Vessel tracing was used to identify anomalies in 10.5dpc, 11.5dpc, and 13.5dpc embryos. Comparison of trisomic versus euploid embryos injected with India ink revealed delay and abnormality in cardiovascular development in trisomic embryos at each stage. Through the analysis of transmission rate and cardiovascular development in embryonic mice, we learn more about prenatal mortality and the origins of cardiac abnormality in the Ts65Dn mice to assist in understanding cardiovascular malformation associated with DS. PMID:21157920

  15. Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome

    PubMed Central

    Yang, Annan; Currier, Duane; Poitras, Jennifer L.; Reeves, Roger H.

    2016-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of human chromosome 21 (Hsa21). People with DS display multiple clinical traits as a result of the dosage imbalance of several hundred genes. While many outcomes of trisomy are deleterious, epidemiological studies have shown a significant risk reduction for most solid tumors in DS. Reduced tumor incidence has also been demonstrated in functional studies using trisomic DS mouse models. Therefore, it was interesting to find that Ts1Rhr trisomic mice developed more papillomas than did their euploid littermates in a DMBA-TPA chemical carcinogenesis paradigm. Papillomas in Ts1Rhr mice also proliferated faster. The increased proliferation was likely caused by a stronger response of trisomy to TPA induction. Treatment with TPA caused hyperkeratosis to a greater degree in Ts1Rhr mice than in euploid, reminiscent of hyperkeratosis seen in people with DS. Cultured trisomic keratinocytes also showed increased TPA-induced proliferation compared to euploid controls. These outcomes suggest that altered gene expression in trisomy could elevate a proliferation signalling pathway. Gene expression analysis of cultured keratinocytes revealed upregulation of several trisomic and disomic genes may contribute to this hyperproliferation. The contributions of these genes to hyper-proliferation were further validated in a siRNA knockdown experiment. The unexpected findings reported here add a new aspect to our understanding of tumorigenesis with clinical implications for DS and demonstrates the complexity of the tumor repression phenotype in this frequent condition. PMID:26752700

  16. Impairments in motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome.

    PubMed

    Galante, Micaela; Jani, Harsha; Vanes, Lesley; Daniel, Hervé; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Bliss, Timothy V P; Morice, Elise

    2009-04-15

    Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of human chromosome 21 (Hsa21). Recently, O'Doherty et al. [An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309 (2005) 2033-2037] generated a trans-species aneuploid mouse line (Tc1) that carries an almost complete Hsa21. The Tc1 mouse is the most complete animal model for DS currently available. Tc1 mice show many features that relate to human DS, including alterations in memory, synaptic plasticity, cerebellar neuronal number, heart development and mandible size. Because motor deficits are one of the most frequently occurring features of DS, we have undertaken a detailed analysis of motor behaviour in cerebellum-dependent learning tasks that require high motor coordination and balance. In addition, basic electrophysiological properties of cerebellar circuitry and synaptic plasticity have been investigated. Our results reveal that, compared with controls, Tc1 mice exhibit a higher spontaneous locomotor activity, a reduced ability to habituate to their environments, a different gait and major deficits on several measures of motor coordination and balance in the rota rod and static rod tests. Moreover, cerebellar long-term depression is essentially normal in Tc1 mice, with only a slight difference in time course. Our observations provide further evidence that support the validity of the Tc1 mouse as a model for DS, which will help us to provide insights into the causal factors responsible for motor deficits observed in persons with DS.

  17. DYRK1A BAC transgenic mouse: a new model of thyroid dysgenesis in Down syndrome.

    PubMed

    Kariyawasam, Dulanjalee; Rachdi, Latif; Carré, Aurore; Martin, Mercè; Houlier, Marine; Janel, Nathalie; Delabar, Jean-Maurice; Scharfmann, Raphaël; Polak, Michel

    2015-03-01

    The most common thyroid abnormality among Down syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onward, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by bacterial artificial chromosome engineering (mBACTgDyrk1A), have 3 copies of the Dyrk1A gene. The objective is to determine whether this transgenic Dyrk1A (Dyrk1A(+/++)) mouse is an adequate murine model for the study of thyroid dysgenesis in DS. Embryonic thyroid development from embryonic day 13.5 (E13.5) to E17.5 was analyzed in wild-type (WT) and Dyrk1A(+/++) mice by immunofluorescence with anti-Nkx2-1, anti-thyroglobulin, and anti-T4 antibodies, markers of early thyroid development, hormonogenesis, and final differentiation, respectively. The expression of transcription factors Nkx2-1, Pax8, and Foxe1 involved in thyroidogenesis were studied by quantitative RT-PCR at the same embryonic stages. We then compared the adult phenotype at 8 to 12 weeks in Dyrk1A(+/++) and WT mice for T4 and TSH levels, thyroidal weight, and histological analysis. Regarding thyroidal development, at E15.5, Dyrk1A(+/++) thyroid lobes are double the size of WT thyroids (P = .01), but the thyroglobulin stained surface in Dyrk1A(+/++) thyroids is less than a third as large at E17.5 (P = .04) and their differentiated follicular surface half the size (P = .004). We also observed a significant increase in Nkx2-1, Foxe1, and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A(+/++) embryonic thyroids. Dyrk1A(+/++) young adult mice have significantly lower plasma T4 (2.4 ng/mL versus WT, 3.7 ng/mL; P = 0.019) and nonsignificantly higher plasma TSH (114 mUI/L versus WT, 73mUI/L; P = .09). In addition, their thyroids are significantly heavier (P = .04) and exhibit large disorganized regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid

  18. Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model.

    PubMed

    Ossetrova, Natalia I; Ney, Patrick H; Condliffe, Donald P; Krasnopolsky, Katya; Hieber, Kevin P

    2016-08-01

    Radiation accidents or terrorist attacks can result in serious consequences for the civilian population and for military personnel responding to such emergencies. The early medical management situation requires quantitative indications for early initiation of cytokine therapy in individuals exposed to life-threatening radiation doses and effective triage tools for first responders in mass-casualty radiological incidents. Previously established animal (Mus musculus, Macaca mulatta) total-body irradiation (γ-exposure) models have evaluated a panel of radiation-responsive proteins that, together with peripheral blood cell counts, create a multiparametic dose-predictive algorithm with a threshold for detection of ~1 Gy from 1 to 7 d after exposure as well as demonstrate the acute radiation syndrome severity score systems created similar to the Medical Treatment Protocols for Radiation Accident Victims developed by Fliedner and colleagues. The authors present a further demonstration of the acute radiation sickness severity score system in a mouse (CD2F1, males) TBI model (1-14 Gy, Co γ-rays at 0.6 Gy min) based on multiple biodosimetric endpoints. This includes the acute radiation sickness severity Observational Grading System, survival rate, weight changes, temperature, peripheral blood cell counts and radiation-responsive protein expression profile: Flt-3 ligand, interleukin 6, granulocyte-colony stimulating factor, thrombopoietin, erythropoietin, and serum amyloid A. Results show that use of the multiple-parameter severity score system facilitates identification of animals requiring enhanced monitoring after irradiation and that proteomics are a complementary approach to conventional biodosimetry for early assessment of radiation exposure, enhancing accuracy and discrimination index for acute radiation sickness response categories and early prediction of outcome. PMID:27356057

  19. Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model.

    PubMed

    Ossetrova, Natalia I; Ney, Patrick H; Condliffe, Donald P; Krasnopolsky, Katya; Hieber, Kevin P

    2016-08-01

    Radiation accidents or terrorist attacks can result in serious consequences for the civilian population and for military personnel responding to such emergencies. The early medical management situation requires quantitative indications for early initiation of cytokine therapy in individuals exposed to life-threatening radiation doses and effective triage tools for first responders in mass-casualty radiological incidents. Previously established animal (Mus musculus, Macaca mulatta) total-body irradiation (γ-exposure) models have evaluated a panel of radiation-responsive proteins that, together with peripheral blood cell counts, create a multiparametic dose-predictive algorithm with a threshold for detection of ~1 Gy from 1 to 7 d after exposure as well as demonstrate the acute radiation syndrome severity score systems created similar to the Medical Treatment Protocols for Radiation Accident Victims developed by Fliedner and colleagues. The authors present a further demonstration of the acute radiation sickness severity score system in a mouse (CD2F1, males) TBI model (1-14 Gy, Co γ-rays at 0.6 Gy min) based on multiple biodosimetric endpoints. This includes the acute radiation sickness severity Observational Grading System, survival rate, weight changes, temperature, peripheral blood cell counts and radiation-responsive protein expression profile: Flt-3 ligand, interleukin 6, granulocyte-colony stimulating factor, thrombopoietin, erythropoietin, and serum amyloid A. Results show that use of the multiple-parameter severity score system facilitates identification of animals requiring enhanced monitoring after irradiation and that proteomics are a complementary approach to conventional biodosimetry for early assessment of radiation exposure, enhancing accuracy and discrimination index for acute radiation sickness response categories and early prediction of outcome.

  20. Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models.

    PubMed

    Caldwell, A S L; Middleton, L J; Jimenez, M; Desai, R; McMahon, A C; Allan, C M; Handelsman, D J; Walters, K A

    2014-08-01

    Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age, causing a range of reproductive, metabolic and endocrine defects including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, and an increased risk of type 2 diabetes and cardiovascular disease. Hyperandrogenism is the most consistent feature of PCOS, but its etiology remains unknown, and ethical and logistic constraints limit definitive experimentation in humans to determine mechanisms involved. In this study, we provide the first comprehensive characterization of reproductive, endocrine, and metabolic PCOS traits in 4 distinct murine models of hyperandrogenism, comprising prenatal dihydrotestosterone (DHT, potent nonaromatizable androgen) treatment during days 16-18 of gestation, or long-term treatment (90 days from 21 days of age) with DHT, dehydroepiandrosterone (DHEA), or letrozole (aromatase inhibitor). Prenatal DHT-treated mature mice exhibited irregular estrous cycles, oligo-ovulation, reduced preantral follicle health, hepatic steatosis, and adipocyte hypertrophy, but lacked overall changes in body-fat composition. Long-term DHT treatment induced polycystic ovaries displaying unhealthy antral follicles (degenerate oocyte and/or > 10% pyknotic granulosa cells), as well as anovulation and acyclicity in mature (16-week-old) females. Long-term DHT also increased body and fat pad weights and induced adipocyte hypertrophy and hypercholesterolemia. Long-term letrozole-treated mice exhibited absent or irregular cycles, oligo-ovulation, polycystic ovaries containing hemorrhagic cysts atypical of PCOS, and displayed no metabolic features of PCOS. Long-term dehydroepiandrosterone treatment produced no PCOS features in mature mice. Our findings reveal that long-term DHT treatment replicated a breadth of ovarian, endocrine, and metabolic features of human PCOS and provides the best mouse model for experimental studies of PCOS pathogenesis.

  1. Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

    PubMed Central

    Beurlet, Stephanie; Chomienne, Christine; Padua, Rose Ann

    2013-01-01

    Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. PMID:23065517

  2. Behavioral and Genetic Dissection of a Mouse Model for Advanced Sleep Phase Syndrome

    PubMed Central

    Jiang, Peng; Striz, Martin; Wisor, Jonathan P.; O'Hara, Bruce F.

    2011-01-01

    Study Objective: The adaptive value of the endogenous circadian clock arises from its ability to synchronize (i.e., entrain) to external light-dark (LD) cycles at an appropriate phase. Studies have suggested that advanced circadian phase alignment might result from shortening of the period length of the clock. Here we explore mechanisms that contribute to an early activity phase in CAST/EiJ (CAST) mice. Methods: We investigated circadian rhythms of wheel-running activity in C57BL/6J (B6), CAST and 2 strains of B6.CAST congenic mice, which carry CAST segments introgressed in a B6 genome. Results: When entrained, all CAST mice initiate daily activity several hours earlier than normal mice. This difference could not be explained by alterations in the endogenous period, as activity onset did not correlate with period length. However, the photic phase-shifting responses in these mice were phase-lagged by 3 hours relative to their activity. Attenuated light masking responses were also found in CAST mice, which allow for activity normally inhibited by light. A previously identified quantitative trait locus (QTL), Era1, which contributes to the early activity trait, was confirmed and refined here using two B6.CAST congenic strains. Surprisingly, these B6.CAST mice exhibited longer rather than shorter endogenous periods, further demonstrating that the advanced phase in these mice is not due to alterations in period. Conclusions: CAST mice have an advanced activity phase similar to human advanced sleep phase syndrome. This advanced phase is not due to its shorter period length or smaller light-induced phase shifts, but appears to be related to both light masking and altered coupling of the circadian pacemaker with various outputs. Lastly, a QTL influencing this trait was confirmed and narrowed using congenic mice as a first step toward gene identification. Citation: Jiang P; Striz M; Wisor JP; O'Hara BF. Behavioral and genetic dissection of a mouse model for advanced sleep

  3. Sleep Impairment and Reduced Interneuron Excitability in a Mouse Model of Dravet Syndrome

    PubMed Central

    Kalume, Franck; Oakley, John C.; Westenbroek, Ruth E.; Gile, Jennifer; de la Iglesia, Horacio O.; Scheuer, Todd; Catterall, William A.

    2015-01-01

    Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our genetic mouse model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice. PMID:25766678

  4. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome.

    PubMed

    Kalume, Franck; Oakley, John C; Westenbroek, Ruth E; Gile, Jennifer; de la Iglesia, Horacio O; Scheuer, Todd; Catterall, William A

    2015-05-01

    Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our mouse genetic model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice. PMID:25766678

  5. Biomechanical properties of bone in a mouse model of Rett syndrome

    PubMed Central

    Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, K. Elizabeth; Isaksson, Hanna; Mathavan, Neashan; Cobb, Stuart R.

    2015-01-01

    Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ mice in which Mecp2 is silenced in ~ 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. PMID:25445449

  6. Biomechanical properties of bone in a mouse model of Rett syndrome.

    PubMed

    Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, K Elizabeth; Isaksson, Hanna; Mathavan, Neashan; Cobb, Stuart R

    2015-02-01

    Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies.

  7. Effectiveness of trimebutine maleate on modulating intestinal hypercontractility in a mouse model of postinfectious irritable bowel syndrome.

    PubMed

    Long, Yanqin; Liu, Ying; Tong, Jingjing; Qian, Wei; Hou, Xiaohua

    2010-06-25

    Trimebutine maleate, which modulates the calcium and potassium channels, relieves abdominal pain in patients with irritable bowel syndrome. However, its effect on postinfectious irritable bowel syndrome is not clarified. The aim of this study was to investigate the effectiveness of trimebutine maleate on modulating colonic hypercontractility in a mouse model of postinfectious irritable bowel syndrome. Mice infected up to 8 weeks with T. spiralis underwent abdominal withdrawal reflex to colorectal distention to evaluate the visceral sensitivity at different time points. Tissues were examined for histopathology scores. Colonic longitudinal muscle strips were prepared in the organ bath under basal condition or to be stimulated by acetylcholine and potassium chloride, and consecutive concentrations of trimebutine maleate were added to the bath to record the strip responses. Significant inflammation was observed in the intestines of the mice infected 2 weeks, and it resolved in 8 weeks after infection. Visceral hyperalgesia and colonic muscle hypercontractility emerged after infection, and trimebutine maleate could effectively reduce the colonic hyperreactivity. Hypercontractility of the colonic muscle stimulated by acetylcholine and high K(+) could be inhibited by trimebutine maleate in solution with Ca(2+), but not in Ca(2+) free solution. Compared with 8-week postinfectious irritable bowel syndrome group, 2-week acute infected strips were much more sensitive to the stimulators and the drug trimebutine maleate. Trimebutine maleate was effective in reducing the colonic muscle hypercontractility of postinfectious irritable bowel syndrome mice. The findings may provide evidence for trimebutine maleate to treat postinfectious irritable bowel syndrome patients effectively. PMID:20371236

  8. Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome.

    PubMed

    Goodliffe, Joseph W; Olmos-Serrano, Jose Luis; Aziz, Nadine M; Pennings, Jeroen L A; Guedj, Faycal; Bianchi, Diana W; Haydar, Tarik F

    2016-03-01

    Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. PMID:26961948

  9. Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome.

    PubMed

    Goodliffe, Joseph W; Olmos-Serrano, Jose Luis; Aziz, Nadine M; Pennings, Jeroen L A; Guedj, Faycal; Bianchi, Diana W; Haydar, Tarik F

    2016-03-01

    Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16.

  10. Postnatal brain and skull growth in an Apert syndrome mouse model

    PubMed Central

    Hill, Cheryl A.; Martínez-Abadías, Neus; Motch, Susan M.; Austin, Jordan R.; Wang, Yingli; Jabs, Ethylin Wang; Richtsmeier, Joan T.; Aldridge, Kristina

    2012-01-01

    Craniofacial and neural tissues develop in concert throughout pre- and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for Apert syndrome using the Fgfr2+/P253R mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2+/P253R mice and unaffected littermates at P0 (N=28) and P2 (N=23). 3D coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2+/P253R mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other. PMID:23495236

  11. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

    PubMed Central

    Gomis-González, Maria; Busquets-Garcia, Arnau; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés

    2016-01-01

    Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS. PMID:27589806

  12. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

    PubMed

    Gomis-González, Maria; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés

    2016-01-01

    Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS. PMID:27589806

  13. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

    PubMed

    Gomis-González, Maria; Busquets-Garcia, Arnau; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés

    2016-08-31

    Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS.

  14. The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.

    PubMed

    Guedj, Faycal; Pennings, Jeroen L A; Ferres, Millie A; Graham, Leah C; Wick, Heather C; Miczek, Klaus A; Slonim, Donna K; Bianchi, Diana W

    2015-09-01

    Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition.

  15. The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.

    PubMed

    Guedj, Faycal; Pennings, Jeroen L A; Ferres, Millie A; Graham, Leah C; Wick, Heather C; Miczek, Klaus A; Slonim, Donna K; Bianchi, Diana W

    2015-09-01

    Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition. PMID:25975229

  16. Deficits in Tactile Learning in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Arnett, Megan T.; Herman, David H.; McGee, Aaron W.

    2014-01-01

    The fragile X mental retardation 1 mutant mouse (Fmr1 KO) recapitulates several of the neurologic deficits associated with Fragile X syndrome (FXS). As tactile hypersensitivity is a hallmark of FXS, we examined the sensory representation of individual whiskers in somatosensory barrel cortex of Fmr1 KO and wild-type (WT) mice and compared their performance in a whisker-dependent learning paradigm, the gap cross assay. Fmr1 KO mice exhibited elevated responses to stimulation of individual whiskers as measured by optical imaging of intrinsic signals. In the gap cross task, initial performance of Fmr1 KO mice was indistinguishable from WT controls. However, while WT mice improved significantly with experience at all gap distances, Fmr1 KO mice displayed significant and specific deficits in improvement at longer distances which rely solely on tactile information from whiskers. Thus, Fmr1 KO mice possess altered cortical responses to sensory input that correlates with a deficit in tactile learning. PMID:25296296

  17. Resveratrol improves salivary dysfunction in a non-obese diabetic (NOD) mouse model of Sjögren’s syndrome

    PubMed Central

    Inoue, Hiroko; Kishimoto, Atsuhiro; Ushikoshi-Nakayama, Ryoko; Hasaka, Ayaka; Takahashi, Ayako; Ryo, Koufuchi; Muramatsu, Takashi; Ide, Fumio; Mishima, Kenji; Saito, Ichiro

    2016-01-01

    Resveratrol is a natural polyphenol produced by plants in response to environmental stress. This compound has been shown to have pharmacological effects against a wide range of diseases including neurological, hepatic, cardiovascular and autoimmune conditions. The non-obese diabetic (NOD) mouse, in which loss of lacrimal and salivary gland function occurs, has been studied as an animal model for Sjögren’s syndrome. In this study, we confirmed that administration of resveratrol results in increased secretion of saliva in NOD mice. Although resveratrol enhanced Sirt1 activity, inflammatory cell infiltration was not affected. Moreover, expression of the anti-inflammatory cytokine IL-10 in salivary glands was enhanced in the resveratrol-administered group. Thus, we confirmed a novel therapeutic effect for resveratrol on salivary dysfunction in Sjögren’s syndrome. PMID:27698537

  18. Resveratrol improves salivary dysfunction in a non-obese diabetic (NOD) mouse model of Sjögren’s syndrome

    PubMed Central

    Inoue, Hiroko; Kishimoto, Atsuhiro; Ushikoshi-Nakayama, Ryoko; Hasaka, Ayaka; Takahashi, Ayako; Ryo, Koufuchi; Muramatsu, Takashi; Ide, Fumio; Mishima, Kenji; Saito, Ichiro

    2016-01-01

    Resveratrol is a natural polyphenol produced by plants in response to environmental stress. This compound has been shown to have pharmacological effects against a wide range of diseases including neurological, hepatic, cardiovascular and autoimmune conditions. The non-obese diabetic (NOD) mouse, in which loss of lacrimal and salivary gland function occurs, has been studied as an animal model for Sjögren’s syndrome. In this study, we confirmed that administration of resveratrol results in increased secretion of saliva in NOD mice. Although resveratrol enhanced Sirt1 activity, inflammatory cell infiltration was not affected. Moreover, expression of the anti-inflammatory cytokine IL-10 in salivary glands was enhanced in the resveratrol-administered group. Thus, we confirmed a novel therapeutic effect for resveratrol on salivary dysfunction in Sjögren’s syndrome.

  19. Repeated sense of hunger leads to the development of visceral obesity and metabolic syndrome in a mouse model.

    PubMed

    Han, Jong-Min; Kim, Hyeong-Geug; Lee, Jin-Seok; Choi, Min-Kyung; Kim, Young-Ae; Son, Chang-Gue

    2014-01-01

    Obesity-related disorders, especially metabolic syndrome, contribute to 2.8 million deaths each year worldwide, with significantly increasing morbidity. Eating at regular times and proper food quantity are crucial for maintaining a healthy status. However, many people in developed countries do not follow a regular eating schedule due to a busy lifestyle. Herein, we show that a repeated sense of hunger leads to a high risk of developing visceral obesity and metabolic syndrome in a mouse model (both 3-week and 6-week-old age, 10 mice in each group). The ad libitum (AL) group (normal eating pattern) and the food restriction (FR) group (alternate-day partially food restriction by given only 1/3 of average amount) were compared after 8-week experimental period. The total food consumption in the FR group was lower than in the AL group, however, the FR group showed a metabolic syndrome-like condition with significant fat accumulation in adipose tissues. Consequently, the repeated sense of hunger induced the typical characteristics of metabolic syndrome in an animal model; a distinct visceral obesity, hyperlipidemia, hyperglycemia and hepatic steatosis. Furthermore, we found that specifically leptin, a major metabolic hormone, played a major role in the development of these pathological disorders. Our study indicated the importance of regular eating habits besides controlling calorie intake.

  20. Aging and Intellectual Disability: Insights from Mouse Models of Down Syndrome

    ERIC Educational Resources Information Center

    Ruparelia, Aarti; Pearn, Matthew L.; Mobley, William C.

    2013-01-01

    Down syndrome (DS) is one of many causes of intellectual disability (ID), others including but not limited to, fetal alcohol syndrome, Fragile X syndrome, Rett syndrome, Williams syndrome, hypoxia, and infection. Down syndrome is characterized by a number of neurobiological problems resulting in learning and memory deficits and early onset…

  1. A defect in early myogenesis causes Otitis media in two mouse models of 22q11.2 Deletion Syndrome

    PubMed Central

    Fuchs, Jennifer C.; Linden, Jennifer F.; Baldini, Antonio; Tucker, Abigail S.

    2015-01-01

    Otitis media (OM), the inflammation of the middle ear, is the most common disease and cause for surgery in infants worldwide. Chronic Otitis media with effusion (OME) often leads to conductive hearing loss and is a common feature of a number of craniofacial syndromes, such as 22q11.2 Deletion Syndrome (22q11.2DS). OM is more common in children because the more horizontal position of the Eustachian tube (ET) in infants limits or delays clearance of middle ear effusions. Some mouse models with OM have shown alterations in the morphology and angle of the ET. Here, we present a novel mechanism in which OM is caused not by a defect in the ET itself but in the muscles that control its function. Our results show that in two mouse models of 22q11.2DS (Df1/+ and Tbx1+/−) presenting with bi- or unilateral OME, the fourth pharyngeal arch-derived levator veli palatini muscles were hypoplastic, which was associated with an earlier altered pattern of MyoD expression. Importantly, in mice with unilateral OME, the side with the inflammation was associated with significantly smaller muscles than the contralateral unaffected ear. Functional tests examining ET patency confirmed a reduced clearing ability in the heterozygous mice. Our findings are also of clinical relevance as targeting hypoplastic muscles might present a novel preventative measure for reducing the high rates of OM in 22q11.2DS patients. PMID:25452432

  2. Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration

    PubMed Central

    Mustafi, Debarshi; Kevany, Brian M.; Genoud, Christel; Okano, Kiichiro; Cideciyan, Artur V.; Sumaroka, Alexander; Roman, Alejandro J.; Jacobson, Samuel G.; Engel, Andreas; Adams, Mark D.; Palczewski, Krzysztof

    2011-01-01

    Enhanced S-cone syndrome (ESCS), featuring an excess number of S cones, manifests as a progressive retinal degeneration that leads to blindness. Here, through optical imaging, we identified an abnormal interface between photoreceptors and the retinal pigment epithelium (RPE) in 9 patients with ESCS. The neural retina leucine zipper transcription factor-knockout (Nrl−/−) mouse model demonstrates many phenotypic features of human ESCS, including unstable S-cone-positive photoreceptors. Using massively parallel RNA sequencing, we identified 6203 differentially expressed transcripts between wild-type (Wt) and Nrl−/− mouse retinas, with 6 highly significant differentially expressed genes of the Pax, Notch, and Wnt canonical pathways. Changes were also obvious in expression of 30 genes involved in the visual cycle and 3 key genes in photoreceptor phagocytosis. Novel high-resolution (100 nm) imaging and reconstruction of Nrl−/− retinas revealed an abnormal packing of photoreceptors that contributed to buildup of photoreceptor deposits. Furthermore, lack of phagosomes in the RPE layer of Nrl−/− retina revealed impairment in phagocytosis. Cultured RPE cells from Wt and Nrl−/− mice illustrated that the phagocytotic defect was attributable to the aberrant interface between ESCS photoreceptors and the RPE. Overcoming the retinal phagocytosis defect could arrest the progressive degenerative component of this disease.—Mustafi, D., Kevany, B. M., Genoud, C., Okano, K., Cideciyan, A. V., Sumaroka, A., Roman, A. J., Jacobson, S. G. Engel, A., Adams, M. D., Palczewski, K. Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration. PMID:21659555

  3. Astrocyte Transcriptome from the Mecp2(308)-Truncated Mouse Model of Rett Syndrome.

    PubMed

    Delépine, Chloé; Nectoux, Juliette; Letourneur, Franck; Baud, Véronique; Chelly, Jamel; Billuart, Pierre; Bienvenu, Thierry

    2015-12-01

    Mutations in the gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) are responsible for the neurodevelopmental disorder Rett syndrome which is one of the most frequent sources of intellectual disability in women. Recent studies showed that loss of Mecp2 in astrocytes contributes to Rett-like symptoms and restoration of Mecp2 can rescue some of these defects. The goal of this work is to compare gene expression profiles of wild-type and mutant astrocytes from Mecp2(308/y) mice (B6.129S-MeCP2/J) by using Affymetrix mouse 2.0 microarrays. Results were confirmed by quantitative real-time RT-PCR and by Western blot analysis. Gene set enrichment analysis utilizing Ingenuity Pathways was employed to identify pathways disrupted by Mecp2 deficiency. A total of 2152 genes were statistically differentially expressed between wild-type and mutated samples, including 1784 coding transcripts. However, only 257 showed fold changes >1.2. We confirmed our data by replicative studies in independent primary cultures of cortical astrocytes from Mecp2-deficient mice. Interestingly, two genes known to encode secreted proteins, chromogranin B and lipocalin-2, showed significant dysregulation. These proteins secreted from Mecp2-deficient glia may exert negative non-cell autonomous effects on neuronal properties, including dendritic morphology. Moreover, transcriptional profiling revealed altered Nr2f2 expression which may explain down- and upregulation of several target genes in astrocytes such as Ccl2, Lcn2 and Chgb. Unraveling Nr2f2 involvement in Mecp2-deficient astrocytes could pave the way for a better understanding of Rett syndrome pathophysiology and offers new therapeutic perspectives.

  4. The Ptch1DL mouse: a new model to study lambdoid craniosynostosis and basal cell nevus syndrome associated skeletal defects

    PubMed Central

    Feng, Weiguo; Choi, Irene; Clouthier, David E.; Niswander, Lee; Williams, Trevor

    2013-01-01

    Mouse models provide valuable opportunities for probing the underlying pathology of human birth defects. Employing an ENU-based screen for recessive mutations affecting craniofacial anatomy we isolated a mouse strain, Dogface-like (DL), with abnormal skull and snout morphology. Examination of the skull indicated that these mice developed craniosynostosis of the lambdoid suture. Further analysis revealed skeletal defects related to the pathology of basal cell nevus syndrome (BCNS) including defects in development of the limbs, scapula, ribcage, secondary palate, cranial base, and cranial vault. In humans, BCNS is often associated with mutations in the Hedgehog receptor PTCH1 and genetic mapping in DL identified a point mutation at a splice donor site in Ptch1. Using genetic complementation analysis we determined that DL is a hypomorphic allele of Ptch1, leading to increased Hedgehog signaling. Two aberrant transcripts are generated by the mutated Ptch1DL gene, which would be predicted to reduce significantly the levels of functional Patched1 protein. This new Ptch1 allele broadens the mouse genetic reagents available to study the Hedgehog pathway and provides a valuable means to study the underlying skeletal abnormalities in BCNS. In addition, these results strengthen the connection between elevated Hedgehog signaling and craniosynostosis. PMID:23897749

  5. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

    PubMed

    Li, Ronghui; Dong, Qiping; Yuan, Xinni; Zeng, Xin; Gao, Yu; Chiao, Cassandra; Li, Hongda; Zhao, Xinyu; Keles, Sunduz; Wang, Zefeng; Chang, Qiang

    2016-06-01

    Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies. PMID:27352031

  6. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome

    PubMed Central

    Li, Ronghui; Dong, Qiping; Yuan, Xinni; Zeng, Xin; Gao, Yu; Li, Hongda; Keles, Sunduz; Wang, Zefeng; Chang, Qiang

    2016-01-01

    Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies. PMID:27352031

  7. Selecting the "right" mouse model for metabolic syndrome and type 2 diabetes research.

    PubMed

    Leiter, Edward H

    2009-01-01

    This is not a "Methods" chapter in the traditional sense. Rather, it is an essay designed to help address one of the most frequently asked questions by investigators about to embark on a study requiring an animal model of diabetes - what is the "right" model for the reader's specific research application. Because genetic heterogeneity and the requirement for complex gene-environment interaction characterize the various mouse models of Type 2 diabetes as well as the human disease manifestations, the readers may come to share the author's conclusion that more than one model is required if the investigator is interested in knowing how broadly effective a given compound with putative therapeutic efficacy might be.

  8. Mild Electrical Stimulation and Heat Shock Ameliorates Progressive Proteinuria and Renal Inflammation in Mouse Model of Alport Syndrome

    PubMed Central

    Fukuda, Ryosuke; Morino-Koga, Saori; Suico, Mary Ann; Koyama, Kosuke; Sato, Takashi; Shuto, Tsuyoshi; Kai, Hirofumi

    2012-01-01

    Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro-inflammatory cytokines interleukin-6, tumor necrosis factor-α and interleukin-1β were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH2-terminal kinase 1/2 (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome. PMID:22937108

  9. Quantitative Profiling of Brain Lipid Raft Proteome in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Kalinowska, Magdalena; Castillo, Catherine; Francesconi, Anna

    2015-01-01

    Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders. PMID:25849048

  10. Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome.

    PubMed

    Sagelius, H; Rosengardten, Y; Schmidt, E; Sonnabend, C; Rozell, B; Eriksson, M

    2008-12-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare progeroid syndrome caused by mutations in the LMNA gene. Currently there is no treatment available for HGPS, but promising results from several studies using farnesyl transferase inhibitors (FTIs) on cells and animal models of HGPS have been published and a clinical trial using FTIs has been started in patients with HGPS. However, the published data from animal models treated with FTIs come from studies where the treatment was started before pronounced disease development. This study used an inducible transgenic animal model of HGPS with abnormalities of the skin and teeth. After phenotype development, the transgenic expression was turned off and a rapid improvement of the phenotype was noted, within 4 weeks of transgenic suppression. After 13 weeks, the skin was almost indistinguishable from wild-type skin. This study shows that in these tissues, expression of the progeria mutation does not cause irreversible damage and that reversal of disease phenotype is possible, which gives promise for a treatment for this disease.

  11. Preservation of Long-Term Memory and Synaptic Plasticity Despite Short-Term Impairments in the Tc1 Mouse Model of Down Syndrome

    ERIC Educational Resources Information Center

    Morice, Elise; Andreae, Laura C.; Cooke, Sam F.; Vanes, Lesley; Fisher, Elizabeth M. C.; Tybulewicz, Victor L. J.; Bliss, Timothy V. P.

    2008-01-01

    Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a…

  12. Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

  13. Treatment with neuropeptides attenuates c-fos expression in a mouse model of fetal alcohol syndrome.

    PubMed

    Incerti, Maddalena; Vink, Joy; Roberson, Robin; Abebe, Daniel; Spong, Catherine Y

    2010-10-01

    Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation and is characterized by neurodevelopmental anomalies. C-FOS is a cellular marker of transcriptional activity in the stress-signal pathway. Previously, we showed the treatment with NAP (NAPVSIPQ) + SAL (SALLRSIPA) reversed the learning deficit after prenatal alcohol exposure in FAS. Our objective was to evaluate if the mechanism of actions of NAP + SAL involves the stress-signal pathway differentiating C-FOS expression in mouse brains after prenatal alcohol exposure. C57Bl6/J mice were treated with alcohol (0.03 mL/g) or placebo on gestational day 8. On postnatal day 40, in utero alcohol-exposed males were treated via gavage with 40 μg D-NAP and 40 μg D-SAL ( N = 6) or placebo ( N = 4); controls were gavaged with placebo daily ( N = 12). After learning evaluation, hippocampus, cerebellum, and cortex were isolated. Calibrator-normalized relative real-time polymerase chain reaction and Western blot analysis were performed. Statistics included analysis of variance and post hoc Fisher analysis. Adult treatment with NAP + SAL restored the down-regulation of C-FOS in the hippocampus after prenatal alcohol exposure ( P < 0.05), but not in the cerebellum. There was no difference in C-FOS expression in the cortex. Adult treatment with NAP + SAL restored the down-regulation of C-FOS expression in hippocampus attenuating the alcohol-induced alteration of the stress-signal pathway.

  14. Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome*

    PubMed Central

    Acehan, Devrim; Vaz, Frederic; Houtkooper, Riekelt H.; James, Jeanne; Moore, Vicky; Tokunaga, Chonan; Kulik, Willem; Wansapura, Janaka; Toth, Matthew J.; Strauss, Arnold; Khuchua, Zaza

    2011-01-01

    Barth syndrome is an X-linked genetic disorder caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia. Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling. Although tafazzin function has been studied in non-mammalian model organisms, mammalian genetic loss of function approaches have not been used. We examined the consequences of tafazzin knockdown on sarcomeric mitochondria and cardiac function in mice. Tafazzin knockdown resulted in a dramatic decrease of tetralinoleoyl cardiolipin in cardiac and skeletal muscles and accumulation of monolysocardiolipins and cardiolipin molecular species with aberrant acyl groups. Electron microscopy revealed pathological changes in mitochondria, myofibrils, and mitochondrion-associated membranes in skeletal and cardiac muscles. Echocardiography and magnetic resonance imaging revealed severe cardiac abnormalities, including left ventricular dilation, left ventricular mass reduction, and depression of fractional shortening and ejection fraction in tafazzin-deficient mice. Tafazzin knockdown mice provide the first mammalian model system for Barth syndrome in which the pathophysiological relationships between altered content of mitochondrial phospholipids, ultrastructural abnormalities, myocardial and mitochondrial dysfunction, and clinical outcome can be completely investigated. PMID:21068380

  15. Abnormal Expression of Synaptic Proteins and Neurotrophin-3 in the Down Syndrome Mouse Model Ts65Dn

    PubMed Central

    Pollonini, Gabriella; Gao, Virginia; Rabe, Ausma; Palminiello, Sonia; Albertini, Giorgio; Alberini, Cristina M.

    2008-01-01

    Down Syndrome (DS) results from triplication of the whole or distal part of human chromosome 21. DS subjects suffer from deficits in learning and memory and cognitive functions in general, and, starting from early development, their brains show dendritic and spine structural alterations and cell loss. These defects concern many cortical brain regions as well as the hippocampus, which is known to play a critical role in memory and cognition. Most of these abnormalities are reproduced in the mouse model Ts65Dn, which is partially trisomic for the mouse chromosome 16 that is homologous to a portion of human chromosome 21. Thus, Ts65Dn is widely utilized as an animal model of DS. To better understand the molecular defects underlying the cognitive and particularly the memory impairments of DS, we investigated whether the expression of several molecules known to play critical roles in long-term synaptic plasticity and long-term memory in a variety of species is dysregulated in either the neonatal brain or adult hippocampus of Ts65Dn mice. We found abnormal expression of the synaptic proteins synaptophysin, MAP2 and CDK5 and of the neurotrophin NT-3. Both the neonatal brain and adult hippocampus revealed significant abnormalities. These results suggest that a dysregulation in the expression of neurotrophins as well as proteins involved in synaptic development and plasticity may play a potential role in the neural pathology of DS in humans. PMID:18703118

  16. Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model.

    PubMed

    Stringer, Megan; Abeysekera, Irushi; Dria, Karl J; Roper, Randall J; Goodlett, Charles R

    2015-11-01

    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function.

  17. Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model.

    PubMed

    Stringer, Megan; Abeysekera, Irushi; Dria, Karl J; Roper, Randall J; Goodlett, Charles R

    2015-11-01

    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function. PMID:26363314

  18. The osteopontin transgenic mouse is a new model for Sjögren's syndrome.

    PubMed

    Husain-Krautter, Sehba; Kramer, Jill M; Li, Wentian; Guo, Benchang; Rothstein, Thomas L

    2015-03-01

    Osteopontin (Opn) is a cytokine involved in both physiological and pathological processes, and is elevated in many autoimmune diseases. Sjögren's syndrome (SS) is an autoimmune disease with a strong female predilection characterized by lymphocytic infiltration of exocrine glands. We hypothesized that Opn contributes to SS pathogenesis. We examined an established SS model and found increased Opn locally and systemically. Next, we examined Opn transgenic (Opn Tg) mice for evidence of SS. Opn Tg animals exhibited lymphocytic infiltration of salivary and lacrimal glands, and Opn co-localized with the infiltrates. Moreover, saliva production was reduced, and SS autoantibodies were observed in the serum of these mice. Finally, female Opn Tg mice showed more severe disease compared to males. Taken together, these data support a role for Opn in SS pathogenesis. We identify a new model of spontaneous SS that recapitulates the human disease in terms of sex predilection, histopathology, salivary deficits, and autoantibodies. PMID:25572532

  19. The Osteopontin Transgenic Mouse is a New Model for Sjögren’s Syndrome

    PubMed Central

    Husain-Krautter, Sehba; Kramer, Jill M.; Li, Wentian; Guo, Benchang; Rothstein, Thomas L.

    2015-01-01

    Osteopontin (Opn) is a cytokine involved in both physiological and pathological processes, and is elevated in many autoimmune diseases. Sjögren’s syndrome (SS) is an autoimmune disease with a strong female predilection characterized by lymphocytic infiltration of exocrine glands. We hypothesized Opn contributes to SS pathogenesis. We examined an established SS model, and found increased Opn locally and systemically. Next, we examined Opn transgenic (Opn Tg) mice for evidence of SS. Opn Tg animals exhibited lymphocytic infiltration of salivary and lacrimal glands, and Opn co-localized with the infiltrates. Moreover, saliva production was reduced, and SS autoantibodies were observed in the serum of these mice. Finally, female Opn Tg mice showed more severe disease compared to males. Taken together, these data support a role for Opn in SS pathogenesis. We identify a new model of spontaneous SS that recapitulates the human disease in terms of sex predilection, histopathology, salivary deficits, and autoantibodies. PMID:25572532

  20. Effects of toxic shock syndrome Staphylococcus aureus, endotoxin and tampons in a mouse model.

    PubMed

    Tierno, P M; Malloy, V; Matias, J R; Hanna, B A

    1987-03-01

    Synthetic tampons and toxic shock syndrome toxin-one (TSST-1)-producing strains of Staphylococcus aureus have been linked to an increased incidence of toxic shock syndrome (TSS). While recent reports attempt to define the tampon connection as the creation of an optimal environment for the production of TSST-1, the role of other factors in disease expression in an animal model remain under investigation. To understand the role of tampons and bacteria, pools of Swiss mice were inoculated with permutations of effluents from TSS strains of S. aureus and Escherichia coli grown inside tampons. Depending on tampon brand, when all 3 factors were combined mortality ranged from 20-100%. In controls inoculated with single effluents, or effluents from growth in the presence of cotton, no deaths were observed. Likewise, when hairless mice were inoculated with exotoxin, endotoxin, and tampon leachables, mortality was 100%. In the absence of any 1 component, mortality ranged from 0-40%. Lethal toxicity can be the result of enhancement, since animal death in apparent shock was observed in all pools containing the 3 components, and in all pools containing effluents of TSS S. aureus and E. coli grown in the presence of synthetic tampons, but not in their absence. A retrospective analysis of fatal vs non-fatal TSS in humans supports the hypothesis of enhancement.

  1. Rapid generation of a mouse model for Middle East respiratory syndrome

    PubMed Central

    Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine; Agnihothram, Sudhakar S.; Fett, Craig; Zhao, Jingxian; Gale, Michael J.; Baric, Ralph S.; Enjuanes, Luis; Gallagher, Tom; McCray, Paul B.; Perlman, Stanley

    2014-01-01

    In this era of continued emergence of zoonotic virus infections, the rapid development of rodent models represents a critical barrier to public health preparedness, including the testing of antivirus therapy and vaccines. The Middle East respiratory syndrome coronavirus (MERS-CoV) was recently identified as the causative agent of a severe pneumonia. Given the ability of coronavirus to rapidly adapt to new hosts, a major public health concern is that MERS-CoV will further adapt to replication in humans, triggering a pandemic. No small-animal model for this infection is currently available, but studies suggest that virus entry factors can confer virus susceptibility. Here, we show that mice were sensitized to MERS-CoV infection by prior transduction with adenoviral vectors expressing the human host-cell receptor dipeptidyl peptidase 4. Mice developed a pneumonia characterized by extensive inflammatory-cell infiltration with virus clearance occurring 6–8 d after infection. Clinical disease and histopathological changes were more severe in the absence of type-I IFN signaling whereas the T-cell response was required for virus clearance. Using these mice, we demonstrated the efficacy of a therapeutic intervention (poly I:C) and a potential vaccine [Venezuelan equine encephalitis replicon particles expressing MERS-CoV spike protein]. We also found little protective cross-reactivity between MERS-CoV and the severe acute respiratory syndrome-CoV. Our results demonstrate that this system will be useful for MERS-CoV studies and for the rapid development of relevant animal models for emerging respiratory viral infections. PMID:24599590

  2. Dysregulated TGF-β signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome.

    PubMed

    Dewan, Ashvin K; Tomlinson, Ryan E; Mitchell, Stuart; Goh, Brian C; Yung, Rachel M; Kumar, Sarvesh; Tan, Eric W; Faugere, Marie-Claude; Dietz, Harry C; Clemens, Thomas L; Sponseller, Paul D

    2015-10-01

    Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor-β (TGF-β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-β type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF-β1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-β1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-β-related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF-β receptor signaling in bone.

  3. Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits.

    PubMed

    Roy, Snigdha; Watkins, Nick; Heck, Detlef

    2012-01-01

    Fragile X syndrome (FXS) is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1) gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP). Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO) mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs) when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT) littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.

  4. Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse.

    PubMed

    Tsuchiya, Yoshiki; Minami, Yoichi; Umemura, Yasuhiro; Watanabe, Hitomi; Ono, Daisuke; Nakamura, Wataru; Takahashi, Tomoyuki; Honma, Sato; Kondoh, Gen; Matsuishi, Toyojiro; Yagita, Kazuhiro

    2015-12-01

    Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.

  5. Fully-Automated μMRI Morphometric Phenotyping of the Tc1 Mouse Model of Down Syndrome

    PubMed Central

    Modat, Marc; Cardoso, M. Jorge; Ma, Da; Holmes, Holly E.; Yu, Yichao; O’Callaghan, James; Cleary, Jon O.; Sinclair, Ben; Wiseman, Frances K.; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Lythgoe, Mark F.; Ourselin, Sébastien

    2016-01-01

    We describe a fully automated pipeline for the morphometric phenotyping of mouse brains from μMRI data, and show its application to the Tc1 mouse model of Down syndrome, to identify new morphological phenotypes in the brain of this first transchromosomic animal carrying human chromosome 21. We incorporate an accessible approach for simultaneously scanning multiple ex vivo brains, requiring only a 3D-printed brain holder, and novel image processing steps for their separation and orientation. We employ clinically established multi-atlas techniques–superior to single-atlas methods–together with publicly-available atlas databases for automatic skull-stripping and tissue segmentation, providing high-quality, subject-specific tissue maps. We follow these steps with group-wise registration, structural parcellation and both Voxel- and Tensor-Based Morphometry–advantageous for their ability to highlight morphological differences without the laborious delineation of regions of interest. We show the application of freely available open-source software developed for clinical MRI analysis to mouse brain data: NiftySeg for segmentation and NiftyReg for registration, and discuss atlases and parameters suitable for the preclinical paradigm. We used this pipeline to compare 29 Tc1 brains with 26 wild-type littermate controls, imaged ex vivo at 9.4T. We show an unexpected increase in Tc1 total intracranial volume and, controlling for this, local volume and grey matter density reductions in the Tc1 brain compared to the wild-types, most prominently in the cerebellum, in agreement with human DS and previous histological findings. PMID:27658297

  6. Perigestational dietary folic acid deficiency protects against medulloblastoma formation in a mouse model of nevoid basal cell carcinoma syndrome.

    PubMed

    Been, Raha A; Ross, Julie A; Nagel, Christian W; Hooten, Anthony J; Langer, Erica K; DeCoursin, Krista J; Marek, Courtney A; Janik, Callie L; Linden, Michael A; Reed, Robyn C; Schutten, Melissa M; Largaespada, David A; Johnson, Kimberly J

    2013-01-01

    Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the perigestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n = 126) were randomized to 1 of 3 diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) 1 mo prior to mating with Ptch1 (+/-) C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio = 0.47; 95% confidence interval 0.27-0.80) at 1 yr. No significant difference in incidence was observed between the control and high FA groups. Low maternal perigestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes. PMID:23909730

  7. Specific age-related molecular alterations in the cerebellum of Down syndrome mouse models.

    PubMed

    Créau, Nicole; Cabet, Eva; Daubigney, Fabrice; Souchet, Benoit; Bennaï, Soumia; Delabar, Jean

    2016-09-01

    Down syndrome, or trisomy 21, has been modeled with various trisomic and transgenic mice to help understand the consequences of an altered gene dosage in brain development and function. Though Down syndrome has been associated with premature aging, little is known about the molecular and cellular alterations that target brain function. To help identify alterations at specific ages, we analyzed the cerebellum of Ts1Cje mice, trisomic for 77 HSA21 orthologs, at three ages-young (4 months), middle-age (12 months), and old (17 months)-compared to age-matched controls. Quantification of neuronal and glial markers (n=11) revealed increases in GFAP, with an age effect, and S100B, with age and genotype effects. The genotype effect on S100B with age was unexpected as Ts1Cje has only two copies of the S100b gene. Interestingly, the different increase in GFAP observed between Ts1Cje (trisomic segment includes Pcp4 gene) and controls was magnified in TgPCP4 mice (1 extra copy of the human PCP4 gene) at the same age. S100B increase was not found in the TgPCP4 confirming a difference of regulation with aging for GFAP and S100B and excluding the calcium signaling regulator, Pcp4, as a potential candidate for increase of S100B in the Ts1Cje. To understand these differences, comparison of GFAP and S100B immunostainings at young and middle-age were performed. Immunohistochemical detection of differences in GFAP and S100B localization with aging implicate S100B+ oligodendrocytes as a new phenotypic target in this specific aging process. PMID:27297494

  8. Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo

    PubMed Central

    Nagaoka, Akira; Takehara, Hiroaki; Hayashi-Takagi, Akiko; Noguchi, Jun; Ishii, Kazuhiko; Shirai, Fukutoshi; Yagishita, Sho; Akagi, Takanori; Ichiki, Takanori; Kasai, Haruo

    2016-01-01

    Dendritic spine generation and elimination play an important role in learning and memory, the dynamics of which have been examined within the neocortex in vivo. Spine turnover has also been detected in the absence of specific learning tasks, and is frequently exaggerated in animal models of autistic spectrum disorder (ASD). The present study aimed to examine whether the baseline rate of spine turnover was activity-dependent. This was achieved using a microfluidic brain interface and open-dura surgery, with the goal of abolishing neuronal Ca2+ signaling in the visual cortex of wild-type mice and rodent models of fragile X syndrome (Fmr1 knockout [KO]). In wild-type and Fmr1 KO mice, the majority of baseline turnover was found to be activity-independent. Accordingly, the application of matrix metalloproteinase-9 inhibitors selectively restored the abnormal spine dynamics observed in Fmr1 KO mice, without affecting the intrinsic dynamics of spine turnover in wild-type mice. Such findings indicate that the baseline turnover of dendritic spines is mediated by activity-independent intrinsic dynamics. Furthermore, these results suggest that the targeting of abnormal intrinsic dynamics might pose a novel therapy for ASD. PMID:27221801

  9. Using Mouse and Zebrafish Models to Understand the Etiology of Developmental Defects in Cornelia de Lange Syndrome

    PubMed Central

    KAWAUCHI, SHIMAKO; SANTOS, ROSAYSELA; MUTO, AKIHIKO; LOPEZ-BURKS, MARTHA E.; SCHILLING, THOMAS F.; LANDER, ARTHUR D.; CALOF, ANNE L.

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin-associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl+/− mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a “transcriptomopathy,” that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. PMID:27120001

  10. Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome

    PubMed Central

    Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou; Czirr, Eva; Stan, Trisha; Sahbaie, Peyman; Wyss-Coray, Tony; Kingery, Wade S.; Clark, J. David

    2014-01-01

    Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (µMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, µMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in µMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS. PMID:25218828

  11. Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome.

    PubMed

    Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou; Czirr, Eva; Stan, Trisha; Sahbaie, Peyman; Wyss-Coray, Tony; Kingery, Wade S; Clark, J David

    2014-11-01

    Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (μMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, μMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in μMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS.

  12. Early environmental therapy rescues brain development in a mouse model of Down syndrome.

    PubMed

    Begenisic, Tatjana; Sansevero, Gabriele; Baroncelli, Laura; Cioni, Giovanni; Sale, Alessandro

    2015-10-01

    Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS. PMID:26244989

  13. Early environmental therapy rescues brain development in a mouse model of Down syndrome.

    PubMed

    Begenisic, Tatjana; Sansevero, Gabriele; Baroncelli, Laura; Cioni, Giovanni; Sale, Alessandro

    2015-10-01

    Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS.

  14. Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome.

    PubMed

    Daily, Jennifer L; Nash, Kevin; Jinwal, Umesh; Golde, Todd; Rogers, Justin; Peters, Melinda M; Burdine, Rebecca D; Dickey, Chad; Banko, Jessica L; Weeber, Edwin J

    2011-01-01

    Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr(286) and Thr(305/306), resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.

  15. Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype.

    PubMed

    Klemmer, Patricia; Meredith, Rhiannon M; Holmgren, Carl D; Klychnikov, Oleg I; Stahl-Zeng, Jianru; Loos, Maarten; van der Schors, Roel C; Wortel, Joke; de Wit, Heidi; Spijker, Sabine; Rotaru, Diana C; Mansvelder, Huibert D; Smit, August B; Li, Ka Wan

    2011-07-22

    Fragile X syndrome (FXS), the most common form of hereditary mental retardation, is caused by a loss-of-function mutation of the Fmr1 gene, which encodes fragile X mental retardation protein (FMRP). FMRP affects dendritic protein synthesis, thereby causing synaptic abnormalities. Here, we used a quantitative proteomics approach in an FXS mouse model to reveal changes in levels of hippocampal synapse proteins. Sixteen independent pools of Fmr1 knock-out mice and wild type mice were analyzed using two sets of 8-plex iTRAQ experiments. Of 205 proteins quantified with at least three distinct peptides in both iTRAQ series, the abundance of 23 proteins differed between Fmr1 knock-out and wild type synapses with a false discovery rate (q-value) <5%. Significant differences were confirmed by quantitative immunoblotting. A group of proteins that are known to be involved in cell differentiation and neurite outgrowth was regulated; they included Basp1 and Gap43, known PKC substrates, and Cend1. Basp1 and Gap43 are predominantly expressed in growth cones and presynaptic terminals. In line with this, ultrastructural analysis in developing hippocampal FXS synapses revealed smaller active zones with corresponding postsynaptic densities and smaller pools of clustered vesicles, indicative of immature presynaptic maturation. A second group of proteins involved in synaptic vesicle release was up-regulated in the FXS mouse model. In accordance, paired-pulse and short-term facilitation were significantly affected in these hippocampal synapses. Together, the altered regulation of presynaptically expressed proteins, immature synaptic ultrastructure, and compromised short-term plasticity points to presynaptic changes underlying glutamatergic transmission in FXS at this stage of development.

  16. Calorie seeking, but not hedonic response, contributes to hyperphagia in a mouse model for Prader-Willi syndrome.

    PubMed

    Davies, Jennifer R; Humby, Trevor; Dwyer, Dominic M; Garfield, Alastair S; Furby, Hannah; Wilkinson, Lawrence S; Wells, Timothy; Isles, Anthony R

    2015-08-01

    Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13, the most recognised feature of which is hyperphagia. This is thought to arise as a consequence of abnormalities in both the physiological drive for food and the rewarding properties of food. Although a number of mouse models for PWS exist, the underlying variables dictating maladaptive feeding remain unknown. Here, feeding behaviour in a mouse model in which the imprinting centre (IC) of the syntenic PWS interval has been deleted (PWS(ICdel) mice) is characterised. It is demonstrated that PWS(ICdel) mice show hyperghrelinaemia and increased consumption of food both following overnight fasting and when made more palatable with sucrose. However, hyperphagia in PWS(ICdel) mice was not accompanied by any changes in reactivity to the hedonic properties of palatable food (sucrose or saccharin), as measured by lick-cluster size. Nevertheless, overall consumption by PWS(ICdel) mice for non-caloric saccharin in the licking test was significantly reduced. Combined with converging findings from a continuous reinforcement schedule, these data indicate that PWS(ICdel) mice show a marked heightened sensitivity to the calorific value of food. Overall, these data indicate that any impact of the rewarding properties of food on the hyperphagia seen in PWS(ICdel) mice is driven primarily by calorie content and is unlikely to involve hedonic processes. This has important implications for understanding the neural systems underlying the feeding phenotype of PWS and the contribution of imprinted genes to abnormal feeding behaviour more generally. PMID:26040449

  17. The NF-κB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome

    PubMed Central

    Nishimura, Misato; Nii, Tokiko; Trimova, Gulzhan; Miura, Shuhei; Umezawa, Kazuo; Ushiyama, Akira; Kubota, Tetsuo

    2013-01-01

    Background: β2-glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing the expression of tissue factor, inflammatory cytokines, and chemokines, most of which are dependent upon the NF-κB pathway. Therefore, the NF-κB is regarded as a promising target for the development of a novel therapeutic strategy. However, progress has been limited owing to the fact that there are no widely-used in vivo models, or highly specific inhibitors. Objective:This study aimed to test the effects of an NF-κB-specific inhibitor, DHMEQ, in preventing thrombus formation using an original mouse model of APS. Materials and Methods: Specificity of a monoclonal aPL WB-6 was examined by ELISA. WB-6 was injected into normal BALB/c mice with or without DHMEQ treatment. A pulse laser was radiated to a cutaneous vein in the window of a dorsal skinfold chamber attached to the mouse and thrombus formation was observed and recorded under a microscope. Results: WB-6 bound preferentially to the caldiolipin (CL)-β2GPI complex rather than to CL alone, or β2GPI alone. WB-6, but not isotype-matched control antibody, induced a prothrombotic state in the mice by inducing tissue factor expression upon circulating monocytes, resulting in thrombus formation at the site of laser-induced endothelial injury. This diathesis was almost completely ameliorated by DHMEQ treatment. Conclusions: Inhibition of the NF-κB pathway is a promising strategy for the development of a novel treatment for APS. PMID:24475437

  18. Interaction Between Emotion and Memory: Importance of Mammillary Bodies Damage in a Mouse Model of the Alcoholic Korsakoff Syndrome

    PubMed Central

    Béracochéa, Daniel

    2005-01-01

    Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency attributed to diencephalie damage and/or to medial temporal or cortical related dysfunction. The etiology of KS remains unclear. Most animal models of KS involve thiaminedeficient diets associated with pyrithiamine treatment. Here we present a mouse model of CAC-induced KS. We demonstrate that CAC-generated retrieval memory deficits in working/ episodic memory tasks, together with a reduction of fear reactivity, result from damage to the mammillary bodies (MB). Experimental lesions of MB in non-alcoholic mice produced the same memory and emotional impairments. Drugs having anxiogenic-like properties counteract such impairments produced by CAC or by MB lesions. We suggest (a) that MB are the essential components of a brain network underlying emotional processes, which would be critically important in the retrieval processes involved in working/ episodic memory tasks, and (b) that failure to maintain emotional arousal due to MB damage can be a main factor of CAC-induced memory deficits. Overall, our animal model fits well with general neuropsychological and anatomic impairments observed in KS. PMID:16444899

  19. Interaction between emotion and memory: importance of mammillary bodies damage in a mouse model of the alcoholic Korsakoff syndrome.

    PubMed

    Béracochéa, Daniel

    2005-01-01

    Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency attributed to diencephalic damage and/or to medial temporal or cortical related dysfunction. The etiology of KS remains unclear. Most animal models of KS involve thiamine-deficient diets associated with pyrithiamine treatment. Here we present a mouse model of CAC-induced KS. We demonstrate that CAC-generated retrieval memory deficits in working/ episodic memory tasks, together with a reduction of fear reactivity, result from damage to the mammillary bodies (MB). Experimental lesions of MB in non-alcoholic mice produced the same memory and emotional impairments. Drugs having anxiogenic-like properties counteract such impairments produced by CAC or by MB lesions. We suggest (a) that MB are the essential components of a brain network underlying emotional processes, which would be critically important in the retrieval processes involved in working/ episodic memory tasks, and (b) that failure to maintain emotional arousal due to MB damage can be a main factor of CAC-induced memory deficits. Overall, our animal model fits well with general neuropsychological and anatomic impairments observed in KS.

  20. Altered Intrathalamic GABAA Neurotransmission in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome

    PubMed Central

    Zhou, Chengwen; Ding, Li; Deel, M. Elizabeth; Ferrick, Elizabeth A.; Emeson, Ronald B.; Gallagher, Martin J.

    2014-01-01

    We previously demonstrated that heterozygous deletion of Gabra1, the mouse homolog of the human absence epilepsy gene that encodes the GABAA receptor (GABAAR) α1 subunit, causes absence seizures. We showed that cortex partially compensates for this deletion by increasing the cell surface expression of residual α1 subunit and by increasing α3 subunit expression. Absence seizures also involve two thalamic nuclei: the ventrobasal (VB) nucleus, which expresses only the α1 and α4 subtypes of GABAAR α subunits, and the reticular (nRT) nucleus, which expresses only the α3 subunit subtype. Here, we found that, unlike cortex, VB exhibited significantly reduced total and synaptic α1 subunit expression. In addition, heterozygous α1 subunit deletion substantially reduced miniature inhibitory postsynaptic current (mIPSC) peak amplitudes and frequency in VB. However, there was no change in expression of the extrasynaptic α4 or δ subunits in VB and, unlike other models of absence epilepsy, no change in tonic GABAAR currents. Although heterozygous α1 subunit knockout increased α3 subunit expression in medial thalamic nuclei, it did not alter α3 subunit expression in nRT. However, it did enlarge the presynaptic vesicular inhibitory amino acid transporter puncta and lengthen the time constant of mIPSC decay in nRT. We conclude that increased tonic GABAA currents are not necessary for absence seizures. In addition, heterozygous loss of α1 subunit disinhibits VB by substantially reducing phasic GABAergic currents and surprisingly, it also increases nRT inhibition by prolonging phasic currents. The increased inhibition in nRT likely represents a partial compensation that helps reduce absence seizures. PMID:25447232

  1. Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

    PubMed Central

    Clayton, Stephen; Prigmore, Elena; Langley, Elizabeth; Yang, Fengtang; Maguire, Sean; Fu, Beiyuan; Rajan, Diana; Sheppard, Olivia; Scott, Carol; Hauser, Heidi; Stephens, Philip J.; Stebbings, Lucy A.; Ng, Bee Ling; Fitzgerald, Tomas; Quail, Michael A.; Banerjee, Ruby; Rothkamm, Kai; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Carter, Nigel P.

    2013-01-01

    Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439. PMID:23596509

  2. Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?

    PubMed

    Vogel, P; Gelfman, C M; Issa, T; Payne, B J; Hansen, G M; Read, R W; Jones, C; Pitcher, M R; Ding, Z-M; DaCosta, C M; Shadoan, M K; Vance, R B; Powell, D R

    2015-05-01

    Mice deficient in TMEM218 (Tmem218(-/-) ) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218(-/-) mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218(-/-) mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218(-/-) mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

  3. Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome

    PubMed Central

    Fortress, Ashley M.; Hamlett, Eric D.; Vazey, Elena M.; Aston-Jones, Gary; Cass, Wayne A.; Boger, Heather A.

    2015-01-01

    Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrug l-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia. PMID:25632113

  4. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity.

    PubMed

    Kondo, Mari A; Gray, Laura J; Pelka, Gregory J; Leang, Sook-Kwan; Christodoulou, John; Tam, Patrick P L; Hannan, Anthony J

    2016-02-01

    Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2(+/-) mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2(+/-) mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder.

  5. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)

    PubMed Central

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-01-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence. PMID:27446562

  6. Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome

    PubMed Central

    Yu, Hongwei; Wessels, Andy; Chen, Jianliang; Phelps, Aimee L; Oatis, John; Tint, G Stephen; Patel, Shailendra B

    2004-01-01

    Background Normal post-squalene cholesterol biosynthesis is important for mammalian embryonic development. Neonatal mice lacking functional dehydrocholesterol Δ7-reductase (Dhcr7), a model for the human disease of Smith-Lemli-Opitz syndrome, die within 24 hours of birth. Although they have a number of biochemical and structural abnormalities, one cause of death is from apparent respiratory failure due to developmental pulmonary abnormalities. Results In this study, we characterized further the role of cholesterol deficiency in lung development of these mice. Significant growth retardation, beginning at E14.5~E16.5, was observed in Dhcr7-/- embryos. Normal lobation but smaller lungs with a significant decrease in lung-to-body weight ratio was noted in Dhcr7-/- embryos, compared to controls. Lung branching morphogenesis was comparable between Dhcr7-/- and controls at early stages, but delayed saccular development was visible in all Dhcr7-/- embryos from E17.5 onwards. Impaired pre-alveolar development of varying severity, inhibited cell proliferation, delayed differentiation of type I alveolar epithelial cells (AECs) and delayed vascular development were all evident in knockout lungs. Differentiation of type II AECs was apparently normal as judged by surfactant protein (SP) mRNAs and SP-C immunostaining. A significant amount of cholesterol was detectable in knockout lungs, implicating some maternal transfer of cholesterol. No significant differences of the spatial-temporal localization of sonic hedgehog (Shh) or its downstream targets by immunohistochemistry were detected between knockout and wild-type lungs and Shh autoprocessing occurred normally in tissues from Dhcr7-/- embryos. Conclusion Our data indicated that cholesterol deficiency caused by Dhcr7 null was associated with a distinct lung saccular hypoplasia, characterized by failure to terminally differentiate alveolar sacs, a delayed differentiation of type I AECs and an immature vascular network at late

  7. First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome.

    PubMed

    Chen, Frieda; Guo, Ruolin; Itoh, Shousaku; Moreno, Luisa; Rosenthal, Esther; Zappitelli, Tanya; Zirngibl, Ralph A; Flenniken, Ann; Cole, William; Grynpas, Marc; Osborne, Lucy R; Vogel, Wolfgang; Adamson, Lee; Rossant, Janet; Aubin, Jane E

    2014-06-01

    By using a genome-wide N-ethyl-N-nitrosourea (ENU)-induced dominant mutagenesis screen in mice, a founder with low bone mineral density (BMD) was identified. Mapping and sequencing revealed a T to C transition in a splice donor of the collagen alpha1 type I (Col1a1) gene, resulting in the skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain of Col1a1. Col1a1(Jrt) /+ mice were smaller in size, had lower BMD associated with decreased bone volume/tissue volume (BV/TV) and reduced trabecular number, and furthermore exhibited mechanically weak, brittle, fracture-prone bones, a hallmark of osteogenesis imperfecta (OI). Several markers of osteoblast differentiation were upregulated in mutant bone, and histomorphometry showed that the proportion of trabecular bone surfaces covered by activated osteoblasts (Ob.S/BS and N.Ob/BS) was elevated, but bone surfaces undergoing resorption (Oc.S/BS and N.Oc/BS) were not. The number of bone marrow stromal osteoprogenitors (CFU-ALP) was unaffected, but mineralization was decreased in cultures from young Col1a1(Jrt) /+ versus +/+ mice. Total collagen and type I collagen content of matrices deposited by Col1a1(Jrt) /+ dermal fibroblasts in culture was ∼40% and 30%, respectively, that of +/+ cells, suggesting that mutant collagen chains exerted a dominant negative effect on type I collagen biosynthesis. Mutant collagen fibrils were also markedly smaller in diameter than +/+ fibrils in bone, tendon, and extracellular matrices deposited by dermal fibroblasts in vitro. Col1a1(Jrt) /+ mice also exhibited traits associated with Ehlers-Danlos syndrome (EDS): Their skin had reduced tensile properties, tail tendon appeared more frayed, and a third of the young adult mice had noticeable curvature of the spine. Col1a1(Jrt) /+ is the first reported model of combined OI/EDS and will be useful for exploring aspects of OI and EDS pathophysiology and treatment.

  8. Environmental enrichment reveals effects of genotype on hippocampal spine morphologies in the mouse model of Fragile X Syndrome.

    PubMed

    Lauterborn, Julie C; Jafari, Matiar; Babayan, Alex H; Gall, Christine M

    2015-02-01

    Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS.

  9. Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome.

    PubMed

    Martínez-Cué, Carmen; Martínez, Paula; Rueda, Noemí; Vidal, Rebeca; García, Susana; Vidal, Verónica; Corrales, Andrea; Montero, Juan A; Pazos, Ángel; Flórez, Jesús; Gasser, Rodolfo; Thomas, Andrew W; Honer, Michael; Knoflach, Frédéric; Trejo, Jose Luis; Wettstein, Joseph G; Hernández, Maria-Clemencia

    2013-02-27

    Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS. PMID:23447605

  10. Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.

    PubMed

    Capurro, Mariana I; Li, Fuchuan; Filmus, Jorge

    2009-08-01

    Loss-of-function mutations of Glypican 3 (Gpc3) cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and developmental overgrowth is observed in Gpc3-null mice, a mouse model for SGBS. We recently reported that GPC3 inhibits Hedgehog (Hh) signalling by inducing its endocytosis and degradation. Here, we show that the developmental overgrowth observed in Gpc3-null mice is, at least in part, a consequence of the hyperactivation of the Hh pathway. We bred Gpc3-null mice with mice that are Hh signalling-deficient owing to the lack of Indian Hh (Ihh), one of the three mammalian Hhs. We found that the Gpc3-null mice showed a 29.9% overgrowth in an Ihh wild-type background, whereas an Ihh-null background partly rescues the overgrowth caused by the lack of Gpc3 as the double mutants were 19.8% bigger than the Ihh-null mice. Consistent with the role of GPC3 in Hh endocytosis and degradation, the Gpc3-null mice show increased levels of Ihh protein and signalling, but similar levels of Ihh messenger RNA.

  11. Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

    PubMed Central

    Mandel-Brehm, Caleigh; Salogiannis, John; Dhamne, Sameer C.; Rotenberg, Alexander; Greenberg, Michael E.

    2015-01-01

    Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder. PMID:25848016

  12. Lithium restores neurogenesis in the subventricular zone of the Ts65Dn mouse, a model for Down syndrome.

    PubMed

    Bianchi, Patrizia; Ciani, Elisabetta; Contestabile, Andrea; Guidi, Sandra; Bartesaghi, Renata

    2010-01-01

    Down syndrome (DS), a high-incidence genetic pathology, involves brain hypoplasia and mental retardation. Emerging evidence suggests that reduced neurogenesis may be a major determinant of brain underdevelopment in DS. To establish whether it is possible to improve neurogenesis in DS, Ts65Dn mice--the most widely used model for DS--and euploid mice were treated with control or lithium chow for 1 month. During the last 3 days animals received one daily injection of 5-bromo-2-deoxyuridine (BrdU)--a marker of proliferating cells--and were sacrificed 24 h after the last injection. Neurogenesis was examined in the subventricular zone (SVZ), a region that retains a neurogenic potential across life. We found that Ts65Dn mice had less (-40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment. Treatment with lithium increased the number of Brdu+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ cells became similar to that of untreated euploid mice. Our study shows that lithium is able to restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with mood stabilizers as a potential tool to improve neurogenesis in patients with DS.

  13. Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression.

    PubMed

    Mandel-Brehm, Caleigh; Salogiannis, John; Dhamne, Sameer C; Rotenberg, Alexander; Greenberg, Michael E

    2015-04-21

    Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder. PMID:25848016

  14. PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress

    PubMed Central

    Müller, C. Catharina; Nguyen, Tam H.; Ahlemeyer, Barbara; Meshram, Mallika; Santrampurwala, Nishreen; Cao, Siyu; Sharp, Peter; Fietz, Pamela B.; Baumgart-Vogt, Eveline; Crane, Denis I.

    2011-01-01

    SUMMARY Delayed cerebellar development is a hallmark of Zellweger syndrome (ZS), a severe neonatal neurodegenerative disorder. ZS is caused by mutations in PEX genes, such as PEX13, which encodes a protein required for import of proteins into the peroxisome. The molecular basis of ZS pathogenesis is not known. We have created a conditional mouse mutant with brain-restricted deficiency of PEX13 that exhibits cerebellar morphological defects. PEX13 brain mutants survive into the postnatal period, with the majority dying by 35 days, and with survival inversely related to litter size and weaning body weight. The impact on peroxisomal metabolism in the mutant brain is mixed: plasmalogen content is reduced, but very-long-chain fatty acids are normal. PEX13 brain mutants exhibit defects in reflex and motor development that correlate with impaired cerebellar fissure and cortical layer formation, granule cell migration and Purkinje cell layer development. Astrogliosis and microgliosis are prominent features of the mutant cerebellum. At the molecular level, cultured cerebellar neurons from E19 PEX13-null mice exhibit elevated levels of reactive oxygen species and mitochondrial superoxide dismutase-2 (MnSOD), and show enhanced apoptosis together with mitochondrial dysfunction. PEX13 brain mutants show increased levels of MnSOD in cerebellum. Our findings suggest that PEX13 deficiency leads to mitochondria-mediated oxidative stress, neuronal cell death and impairment of cerebellar development. Thus, PEX13-deficient mice provide a valuable animal model for investigating the molecular basis and treatment of ZS cerebellar pathology. PMID:20959636

  15. Cholesterol Biosynthesis from Birth to Adulthood in a Mouse Model for 7-dehydrosterol reductase deficiency (Smith-Lemli-Opitz Syndrome)

    PubMed Central

    Marcos, Josep; Shackleton, Cedric H.L.; Buddhikot, Madhavee M.; Porter, Forbes D.; Watson, Gordon L.

    2007-01-01

    Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis, which is catalyzed by 7-dehydrocholesterol reductase (DHCR7). The disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. Pathogenesis of SLOS is complex due to multiple roles of cholesterol and may be further complicated by unknown effects of aberrant metabolites that arise when 7-dehydrocholesterol (7-DHC), the substrate for DHCR7, accumulates. A viable mouse model for SLOS has recently been developed, and here we characterize cholesterol metabolism in this model with emphasis on changes during the first few weeks of postnatal development. Cholesterol and 7-DHC were measured in “SLOS” mice and compared with measurements in normal mice. SLOS mice had measurable levels of 7-DHC at all ages tested (up to one year), while 7-DHC was below the threshold for detection in normal mice. In perinatal to weaning age SLOS mice, cholesterol and 7-DHC levels changed dramatically. Changes in brain and liver were independent; in brain cholesterol increased several fold while 7-DHC remained relatively constant, but in liver cholesterol first increased then decreased again while 7-DHC first decreased then increased. In older SLOS animals the ratio of 7-DHC/cholesterol, which is an index of biochemical severity, tended to approach, but not reach, normal. While these mice provide the best available genetic animal model for the study of SLOS pathogenesis and treatment, they probably will be most useful at early ages when the metabolic effects of the mutations are most dramatic. To correlate any experimental treatment with improved sterol metabolism will require age-matched controls. Finally, determining the mechanism by which these “SLOS” mice tend to normalize may provide insight into the future development of therapy. PMID:17714750

  16. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

    PubMed

    Arbogast, Thomas; Ouagazzal, Abdel-Mouttalib; Chevalier, Claire; Kopanitsa, Maksym; Afinowi, Nurudeen; Migliavacca, Eugenia; Cowling, Belinda S; Birling, Marie-Christine; Champy, Marie-France; Reymond, Alexandre; Herault, Yann

    2016-02-01

    The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. PMID:26872257

  17. An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome.

    PubMed

    Belichenko, Pavel V; Madani, Rime; Rey-Bellet, Lorianne; Pihlgren, Maria; Becker, Ann; Plassard, Adeline; Vuillermot, Stephanie; Giriens, Valérie; Nosheny, Rachel L; Kleschevnikov, Alexander M; Valletta, Janice S; Bengtsson, Sara K S; Linke, Gordon R; Maloney, Michael T; Hickman, David T; Reis, Pedro; Granet, Anne; Mlaki, Dorin; Lopez-Deber, Maria Pilar; Do, Long; Singhal, Nishant; Masliah, Eliezer; Pearn, Matthew L; Pfeifer, Andrea; Muhs, Andreas; Mobley, William C

    2016-01-01

    In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD). At present, no treatment targets Aβ-related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1-15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS. PMID:27023444

  18. An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome

    PubMed Central

    Rey-Bellet, Lorianne; Pihlgren, Maria; Becker, Ann; Plassard, Adeline; Vuillermot, Stephanie; Giriens, Valérie; Nosheny, Rachel L.; Kleschevnikov, Alexander M.; Valletta, Janice S.; Bengtsson, Sara K. S.; Linke, Gordon R.; Maloney, Michael T.; Hickman, David T.; Reis, Pedro; Granet, Anne; Mlaki, Dorin; Lopez-Deber, Maria Pilar; Do, Long; Singhal, Nishant; Masliah, Eliezer; Pearn, Matthew L.; Pfeifer, Andrea; Muhs, Andreas; Mobley, William C.

    2016-01-01

    In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS. PMID:27023444

  19. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes

    PubMed Central

    Arbogast, Thomas; Ouagazzal, Abdel-Mouttalib; Chevalier, Claire; Kopanitsa, Maksym; Afinowi, Nurudeen; Migliavacca, Eugenia; Cowling, Belinda S.; Birling, Marie-Christine; Champy, Marie-France; Reymond, Alexandre; Herault, Yann

    2016-01-01

    The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. PMID:26872257

  20. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation

    PubMed Central

    Sakai, Daisuke; Dixon, Jill; Achilleos, Annita; Dixon, Michael; Trainor, Paul A.

    2016-01-01

    Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype–phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1+/− mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies. PMID:26792133

  1. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation.

    PubMed

    Sakai, Daisuke; Dixon, Jill; Achilleos, Annita; Dixon, Michael; Trainor, Paul A

    2016-01-21

    Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype-phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1(+/-) mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies.

  2. Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome.

    PubMed

    Oginsky, Max F; Cui, Ningren; Zhong, Weiwei; Johnson, Christopher M; Jiang, Chun

    2014-09-15

    Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis. Here we show evidence for potential compensatory modulation of LC neurons by post- and presynaptic ACh inputs. We found that the postsynaptic currents of nicotinic ACh receptors (nAChR) were smaller in amplitude and longer in decay time in the Mecp2-null mice than in the wild type. Single-cell PCR analysis showed a decrease in the expression of α3-, α4-, α7-, and β3-subunits and an increase in the α5- and α6-subunits in the mutant mice. The α5-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABAA-ergic inhibitory postsynaptic currents in LC neurons was enhanced in Mecp2-null mice. In contrast, the nAChR manipulation of glutamatergic input to LC neurons was unaffected in both groups of mice. Our current-clamp studies showed that the modulation of LC neurons by ACh input was reduced moderately in Mecp2-null mice, despite the major decrease in nAChR currents, suggesting possible compensatory processes may take place, thus reducing the defects to a lesser extent in LC neurons.

  3. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model

    PubMed Central

    Rangasamy, Sampathkumar; Olfers, Shannon; Gerald, Brittany; Hilbert, Alex; Svejda, Sean; Narayanan, Vinodh

    2016-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model ( Mecp2 A140V “knock-in” mutant) expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant ( Mecp2 A140V/y) and wild type ( Mecp2 +/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele) and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2   mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”). PMID:27781091

  4. 7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome

    PubMed Central

    Gou-Fàbregas, Myriam; Macià, Anna; Anerillas, Carlos; Vaquero, Marta; Jové, Mariona; Jain, Sanjay; Ribera, Joan; Encinas, Mario

    2016-01-01

    Smith-Lemli-Opitz syndrome (SLOS) is a rare disorder of cholesterol synthesis. Affected individuals exhibit growth failure, intellectual disability and a broad spectrum of developmental malformations. Among them, renal agenesis or hypoplasia, decreased innervation of the gut, and ptosis are consistent with impaired Ret signaling. Ret is a receptor tyrosine kinase that achieves full activity when recruited to lipid rafts. Mice mutant for Ret are born with no kidneys and enteric neurons, and display sympathetic nervous system defects causing ptosis. Since cholesterol is a critical component of lipid rafts, here we tested the hypothesis of whether the cause of the above malformations found in SLOS is defective Ret signaling owing to improper lipid raft composition or function. No defects consistent with decreased Ret signaling were found in newborn Dhcr7−/− mice, or in Dhcr7−/− mice lacking one copy of Ret. Although kidneys from Dhcr7−/− mice showed a mild branching defect in vitro, GDNF was able to support survival and downstream signaling of sympathetic neurons. Consistently, GFRα1 correctly partitioned to lipid rafts in brain tissue. Finally, replacement experiments demonstrated that 7-DHC efficiently supports Ret signaling in vitro. Taken together, our findings do not support a role of Ret signaling in the pathogenesis of SLOS. PMID:27334845

  5. 7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome.

    PubMed

    Gou-Fàbregas, Myriam; Macià, Anna; Anerillas, Carlos; Vaquero, Marta; Jové, Mariona; Jain, Sanjay; Ribera, Joan; Encinas, Mario

    2016-06-23

    Smith-Lemli-Opitz syndrome (SLOS) is a rare disorder of cholesterol synthesis. Affected individuals exhibit growth failure, intellectual disability and a broad spectrum of developmental malformations. Among them, renal agenesis or hypoplasia, decreased innervation of the gut, and ptosis are consistent with impaired Ret signaling. Ret is a receptor tyrosine kinase that achieves full activity when recruited to lipid rafts. Mice mutant for Ret are born with no kidneys and enteric neurons, and display sympathetic nervous system defects causing ptosis. Since cholesterol is a critical component of lipid rafts, here we tested the hypothesis of whether the cause of the above malformations found in SLOS is defective Ret signaling owing to improper lipid raft composition or function. No defects consistent with decreased Ret signaling were found in newborn Dhcr7(-/-) mice, or in Dhcr7(-/-) mice lacking one copy of Ret. Although kidneys from Dhcr7(-/-) mice showed a mild branching defect in vitro, GDNF was able to support survival and downstream signaling of sympathetic neurons. Consistently, GFRα1 correctly partitioned to lipid rafts in brain tissue. Finally, replacement experiments demonstrated that 7-DHC efficiently supports Ret signaling in vitro. Taken together, our findings do not support a role of Ret signaling in the pathogenesis of SLOS.

  6. R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Qin, Mei; Huang, Tianjian; Kader, Michael; Krych, Leland; Xia, Zengyan; Burlin, Thomas; Zeidler, Zachary; Zhao, Tingrui

    2015-01-01

    Background: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates. Methods: To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-14C]leucine method in vehicle- and R-baclofen–treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis. Results: Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug. Conclusions: Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS. PMID:25820841

  7. Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome.

    PubMed

    Dickson, Price E; Corkill, Beau; McKimm, Eric; Miller, Mellessa M; Calton, Michele A; Goldowitz, Daniel; Blaha, Charles D; Mittleman, Guy

    2013-09-01

    Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load.

  8. Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman Syndrome are dependent on maternal and dietary influences

    PubMed Central

    Grier, Mark D.; Carson, Robert P.; Lagrange, Andre H.

    2015-01-01

    Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype. PMID:26028516

  9. Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome.

    PubMed

    Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

    2015-03-13

    Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases.

  10. Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.

    PubMed

    Grier, Mark D; Carson, Robert P; Lagrange, Andre H

    2015-09-15

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype. PMID:26028516

  11. Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

    2015-01-01

    Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases. PMID:25348604

  12. Long-term running alleviates some behavioral and molecular abnormalities in Down syndrome mouse model Ts65Dn.

    PubMed

    Kida, Elizabeth; Rabe, Ausma; Walus, Marius; Albertini, Giorgio; Golabek, Adam A

    2013-02-01

    Running may affect the mood, behavior and neurochemistry of running animals. In the present study, we investigated whether voluntary daily running, sustained over several months, might improve cognition and motor function and modify the brain levels of selected proteins (SOD1, DYRK1A, MAP2, APP and synaptophysin) in Ts65Dn mice, a mouse model for Down syndrome (DS). Ts65Dn and age-matched wild-type mice, all females, had free access to a running wheel either from the time of weaning (post-weaning cohort) or from around 7 months of age (adult cohort). Sedentary female mice were housed in similar cages, without running wheels. Behavioral testing and evaluation of motor performance showed that running improved cognitive function and motor skills in Ts65Dn mice. However, while a dramatic improvement in the locomotor functions and learning of motor skills was observed in Ts65Dn mice from both post-weaning and adult cohorts, improved object memory was seen only in Ts65Dn mice that had free access to the wheel from weaning. The total levels of APP and MAP2ab were reduced and the levels of SOD1 were increased in the runners from the post-weaning cohort, while only the levels of MAP2ab and α-cleaved C-terminal fragments of APP were reduced in the adult group in comparison with sedentary trisomic mice. Hence, our study demonstrates that Ts65Dn females benefit from sustained voluntary physical exercise, more prominently if running starts early in life, providing further support to the idea that a properly designed physical exercise program could be a valuable adjuvant to future pharmacotherapy for DS. PMID:23201095

  13. Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11) deletion syndrome

    PubMed Central

    Karpinski, Beverly A.; Maynard, Thomas M.; Fralish, Matthew S.; Nuwayhid, Samer; Zohn, Irene E.; Moody, Sally A.; LaMantia, Anthony-S.

    2014-01-01

    ABSTRACT We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS. PMID:24357327

  14. Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman Syndrome

    PubMed Central

    Baudry, Michel; Kramar, Eniko; Xu, Xiaobo; Zadran, Homera; Moreno, Stephanie; Lynch, Gary; Gall, Christine; Bi, Xiaoning

    2012-01-01

    Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: ‘AS mice’) of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50% in vehicle-treated AS mice but were comparable to values for littermate controls in the ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment. PMID:22525571

  15. Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model

    PubMed Central

    Jabba, Sairam V; Oelke, Alisha; Singh, Ruchira; Maganti, Rajanikanth J; Fleming, Sherry; Wall, Susan M; Everett, Lorraine A; Green, Eric D; Wangemann, Philine

    2006-01-01

    Background Pendred syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Methods Slc26a4-/- and age-matched control (Slc26a4+/+ or Slc26a4+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Results Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68, a marker for macrophages. Marginal cells in Slc26a4-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs, C3 and Cd45 was found in stria vascularis of P15 Slc26a4+/- and Slc26a4-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a, Il6, Il12a, Nos2 and Nos3 were found at P15, after weaning or in adults. The

  16. Cardiac metabolic pathways affected in the mouse model of barth syndrome.

    PubMed

    Huang, Yan; Powers, Corey; Madala, Satish K; Greis, Kenneth D; Haffey, Wendy D; Towbin, Jeffrey A; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W; Khuchua, Zaza

    2015-01-01

    Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

  17. p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

    PubMed Central

    Caprio, Cinzia; Baldini, Antonio

    2014-01-01

    T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbx1. We found that Gbx2 expression is down-regulated in Tbx1+/− embryos and is restored to normal levels in Tbx1+/−;Trp53+/− embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1+/−;Trp53+/− embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically. PMID:25197075

  18. Cardiac Metabolic Pathways Affected in the Mouse Model of Barth Syndrome

    PubMed Central

    Huang, Yan; Powers, Corey; Madala, Satish K.; Greis, Kenneth D.; Haffey, Wendy D.; Towbin, Jeffrey A.; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W.; Khuchua, Zaza

    2015-01-01

    Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS. PMID:26030409

  19. A Mouse Model for MeCP2 Duplication Syndrome: MeCP2 Overexpression Impairs Learning and Memory and Synaptic Transmission

    PubMed Central

    Na, Elisa S.; Nelson, Erika D.; Adachi, Megumi; Autry, Anita E.; Mahgoub, Melissa A.; Kavalali, Ege T.; Monteggia, Lisa M.

    2013-01-01

    Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss of function and gain of function alterations in Methyl-CpG Binding Protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole cell voltage clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature excitatory postsynaptic currents with no change in miniature inhibitory postsynaptic currents indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder. PMID:22378884

  20. Memory and Learning--Using Mouse to Model Neurobiological and Behavioural Aspects of Down Syndrome and Assess Pharmacotherapeutics

    ERIC Educational Resources Information Center

    Gardiner, Katheleen

    2009-01-01

    Mouse models are a standard tool in the study of many human diseases, providing insights into the normal functions of a gene, how these are altered in disease and how they contribute to a disease process, as well as information on drug action, efficacy and side effects. Our knowledge of human genes, their genetics, functions, interactions and…

  1. Dosage of the Abcg1-U2af1 region modifies locomotor and cognitive deficits observed in the Tc1 mouse model of Down syndrome.

    PubMed

    Marechal, Damien; Lopes Pereira, Patricia; Duchon, Arnaud; Herault, Yann

    2015-01-01

    Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features.

  2. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome.

    PubMed

    Moore, Aleisha M; Prescott, Melanie; Campbell, Rebecca E

    2013-02-01

    Gonadal steroid hormone feedback is impaired in polycystic ovarian syndrome (PCOS), a common endocrine disorder characterized by hyperandrogenism and an associated increase in LH pulse frequency. Using a prenatal androgen (PNA)-treated mouse model of PCOS, we aimed to investigate negative and positive feedback effects of estrogens on the hypothalamic-pituitary axis regulation of LH. PNA-treated mice exhibited severely disrupted estrous cycles, hyperandrogenism, significantly reduced fertility, and altered ovarian morphology. To assess the negative feedback effects of estrogens, LH was measured before and after ovariectomy and after estradiol (E2) administration. Compared with controls, PNA-treated mice exhibited a blunted postcastration rise in LH (P < .001) and an absence of LH suppression after E2 administration. To assess E2-positive feedback, control and PNA-treated GnRH-green fluorescent protein transgenic mice were subjected to a standard ovariectomy with E2-replacement regimen, and both plasma and perfusion-fixed brains were collected at the time of the expected GnRH/LH surge. Immunocytochemistry and confocal imaging of cFos and green fluorescent protein were used to assess GnRH neuron activation and spine density. In the surged group, both control and PNA-treated mice had significantly increased LH and cFos activation in GnRH neurons (P < .05) compared with nonsurged animals. Spine density was quantified in cFos-positive and -negative GnRH neurons to examine whether there was an increase in spine density in cFos-expressing GnRH neurons of surged mice as expected. A significant increase in spine density in cFos-expressing GnRH neurons was evident in control animals; however, no significant increase was observed in the PNA-treated mice because spine density was elevated across all GnRH neurons. These data support that PNA treatment results in a PCOS-like phenotype that includes impaired E2-negative feedback. Additionally, although E2-positive feedback

  3. Comprehensive Behavioral Phenotyping of Ts65Dn Mouse Model of Down Syndrome: Activation of β1-Adrenergic Receptor by Xamoterol as a Potential Cognitive Enhancer

    PubMed Central

    Faizi, Mehrdad; Bader, Patrick L.; Tun, Christine; Encarnacion, Angelo; Kleschevnikov, Alexander; Belichenko, Pavel; Saw, Nay; Priestley, Matthew; Tsien, Richard W; Mobley, William C; Shamloo, Mehrdad

    2012-01-01

    Down Syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a β1-adrenergic receptor (β1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective β1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down Syndrome display cognitive deficits which is mediated by imbalance in noradrenergic

  4. A novel mouse model for Sézary syndrome using xenotransplantation of Sézary cells into immunodeficient RAG2(-/-) γc(-/-) mice.

    PubMed

    van der Fits, Leslie; Rebel, Heggert G; Out-Luiting, Jacoba J; Pouw, Stephan M; Smit, Fiona; Vermeer, Kim G; van Zijl, Lisanne; Tensen, Cornelis P; Weijer, Kees; Vermeer, Maarten H

    2012-09-01

    Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma with CD4+ tumor cells localized in the skin, lymph nodes and peripheral blood. Characteristic molecular aberrancies in SS have been identified; however, paucity of functional models severely hampered the translation of these observations into pathogenic mechanisms, and subsequent validation of novel therapeutic targets. We therefore developed a mouse model for SS using intrahepatic injection of SS cells in newborn immunodeficient RAG2(-/-) γc(-/-) mice that are completely devoid of T-, B- and NK-cell activity. Injection of the SS cell line SeAx led to long-term and reproducible systemic repopulation of the mice. Injection of mice with the SS cell line HuT-78 led to the death of the mice owing to massive growth of internal tumors. Four weeks after injection of primary SS cells, human CD3+ T cells could be tracked back in the liver, peripheral blood, lymph nodes, spleen and skin of the mice, although the engraftment rate varied when using cells from different patients. In conclusion, we demonstrate that injection of SS cell lines or primary cells in newborn RAG2(-/-) γc(-/-) mice results in long-term systemic repopulation of the mice, thereby providing a novel mouse model for Sézary syndrome.

  5. The mechanism of mTOR (mammalian target of rapamycin) in a mouse model of polycystic ovary syndrome (PCOS)

    PubMed Central

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder affecting 5-10% of women in reproductive age that is characterized by hyperandrogenism, oligo- or anovulation and infertility. However the pathophysiology of PCOS still remains unknown. The mammalian target of rapamycin (mTOR) is a central component that regulates various processes including cell growth, proliferation, metabolism, and angiogenesis. mTOR signaling cascade has recently been examined in ovarian follicles where it regulates granulosa cell proliferation and differentiation. mTOR functions as two complexes, mTOR complex 1 and 2. Therefore, we hypothesized that mTORC1 and/or 2 may have important role in proliferation of theca and granulosa cells in PCOS. In the present study, we sought to determine the mTOR signaling pathway in PCOS mouse ovary. We designed 3 groups: Control (C, no treatment), PCOS (P, The injection of DHEA (6 mg/100 g BW in 0.1 ml of sesame oil) (s.c) for 20 consecutive days), Vehicle (V, daily (s.c) sesame oil alone injection). Our results showed that mTORC1 and mTORC2-mediated signaling may play a role in PCOS mouse ovary. These findings provide evidence that mTORC1 and mTORC2 may have responsibility in increased ovarian follicular cell proliferation and growth in PCOS. Consequently, these results suggest that the mTOR signaling pathways (mTORC1 and mTORC 2) may create new clinical strategies to optimize developmental competence of PCOS should target correction of the entire follicle growth, oocyte development process and anovulatory infertility in PCOS. PMID:23185989

  6. The Ptch1(DL) mouse: a new model to study lambdoid craniosynostosis and basal cell nevus syndrome-associated skeletal defects.

    PubMed

    Feng, Weiguo; Choi, Irene; Clouthier, David E; Niswander, Lee; Williams, Trevor

    2013-10-01

    Mouse models provide valuable opportunities for probing the underlying pathology of human birth defects. By using an N-ethyl-N-nitrosourea-based screen for recessive mutations affecting craniofacial anatomy, we isolated a mouse strain, Dogface-like (DL), with abnormal skull and snout morphology. Examination of the skull indicated that these mice developed craniosynostosis of the lambdoid suture. Further analysis revealed skeletal defects related to the pathology of basal cell nevus syndrome (BCNS) including defects in development of the limbs, scapula, ribcage, secondary palate, cranial base, and cranial vault. In humans, BCNS is often associated with mutations in the Hedgehog receptor PTCH1 and genetic mapping in DL identified a point mutation at a splice donor site in Ptch1. By using genetic complementation analysis we determined that DL is a hypomorphic allele of Ptch1, leading to increased Hedgehog signaling. Two aberrant transcripts are generated by the mutated Ptch1(DL) gene, which would be predicted to reduce significantly the levels of functional Patched1 protein. This new Ptch1 allele broadens the mouse genetic reagents available to study the Hedgehog pathway and provides a valuable means to study the underlying skeletal abnormalities in BCNS. In addition, these results strengthen the connection between elevated Hedgehog signaling and craniosynostosis. PMID:23897749

  7. Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.

    PubMed

    De Filippis, Bianca; Valenti, Daniela; de Bari, Lidia; De Rasmo, Domenico; Musto, Mattia; Fabbri, Alessia; Ricceri, Laura; Fiorentini, Carla; Laviola, Giovanni; Vacca, Rosa Anna

    2015-06-01

    Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and

  8. An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

    PubMed Central

    Lima-Cabello, Elena; Garcia-Guirado, Francisco; Calvo-Medina, Rocio; el Bekay, Rajaa; Perez-Costillas, Lucia; Quintero-Navarro, Carolina; Sanchez-Salido, Lourdes

    2016-01-01

    Background. Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome. PMID:26788253

  9. Altered Cortical GABAA Receptor Composition, Physiology, and Endocytosis in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome*

    PubMed Central

    Zhou, Chengwen; Huang, Zhiling; Ding, Li; Deel, M. Elizabeth; Arain, Fazal M.; Murray, Clark R.; Patel, Ronak S.; Flanagan, Christopher D.; Gallagher, Martin J.

    2013-01-01

    Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetα1KO) of the human epilepsy gene, the GABAAR α1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetα1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetα1KO caused modest reductions in the total and surface expression of the β2 subunit but did not alter β1 or β3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetα1KO by increasing the fraction of residual α1 subunit on the cell surface and by increasing total and surface expression of α3, but not α2, subunits. Co-immunoprecipitation experiments revealed that Hetα1KO increased the fraction of α1 subunits, and decreased the fraction of α3 subunits, that associated in hybrid α1α3βγ receptors. Patch clamp electrophysiology studies showed that Hetα1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetα1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetα1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant α1βγ GABAARs. PMID:23744069

  10. Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models

    SciTech Connect

    Ding, Feng; Prints, Yelena; Dhar, Madhu; Johnson, Dabney K; Garnacho-Montero, Carmen; Nicholls, Robert; Francke, Uta

    2005-01-01

    Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11-13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438 snoRNA genes. The existing mouse models of PWS that lack the expression of multiple genes, including Snrpn, Ube3a, and many intronic snoRNA genes, are characterized by 80%-100% neonatal lethality. To define the candidate region for PWS-like phenotypes in mice,we analyzed the expression of several genetic elements in mice carrying the large radiation-induced p30PUb deletion that includes the p locus. Mice having inherited this deletion from either parent develop normally into adulthood. By Northern blot and RTPCR assays of brain tissue, we found that Pwcr1/MBII-85 snoRNAs are expressed normally, while MBII-52 snoRNAs are not expressed when the deletion is paternally inherited. Mapping of the distal deletion breakpoint indicated that the p30PUb deletion includes the entire MBII-52 snoRNA gene cluster and three previously unmapped EST sequences. The lack of expression of these elements in mice with a paternal p30PUb deletion indicates that they are not critical for the neonatal lethality observed in PWS mouse models. In addition, we identified MBII-436, the mouse homolog of the HBII-436 snoRNA, confirmed its imprinting status, and mapped it outside of the p30PUb deletion. Taking together all available data, we conclude that the lack of Pwcr1/MBII-85 snoRNA expression is the most likely cause for the neonatal lethality in PWS model mice.

  11. The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors

    PubMed Central

    Golubeva, Anna V.; Zhdanov, Alexander V.; Mallel, Giuseppe; Dinan, Timothy G.; Cryan, John F.

    2014-01-01

    Abstract Painful bladder syndrome/Interstitial cystitis (PBS/IC) is a chronic disorder characterized clinically by recurring episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Despite this, there is an unmet medical need in terms of effective diagnostics and treatment. Animal models are crucial in this endeavor. Systemic chronic administration of cyclophosphamide (CYP) in mice has been proposed as a relevant preclinical model of chronic bladder pain. However, molecular mechanisms underlying the pathogenesis of this model are lacking. Here, we show that mice, subjected to repetitive systemic injections of CYP, developed mild inflammatory response in bladder tissue characterized by submucosal edema, moderate increase in proinflammatory cytokine gene expression, and mastocytosis. No signs of massive inflammatory infiltrate, tissue hemorrhages, mucosal ulcerations and urothelium loss were observed. Instead, CYP treatment induced urothelium hyperplasia, accompanied by activation of proliferative signaling cascades, and a decrease in the expression of urothelium‐specific markers. Metabotropic glutamate (mGlu) receptors have been implicated in chronic pain disorders. CYP administration induced differential changes in mGlu receptors mRNA levels in bladder tissue, without affecting gene expression at spinal cord level, pointing to the potential link between peripheral mGlu receptors and inflammation‐induced bladder malfunction and hyperalgesia. Taken together, these data indicate that chronic CYP treatment in mice is a model of PBS mostly relevant to the major, nonulcerative subtype of the syndrome, characterized by a relatively unaltered mucosa and a sparse inflammatory response. This model can help to elucidate the pathogenetic mechanisms of the disease. PMID:24760514

  12. Cauli: A Mouse Strain with an Ift140 Mutation That Results in a Skeletal Ciliopathy Modelling Jeune Syndrome

    PubMed Central

    Miller, Kerry A.; Ah-Cann, Casey J.; Welfare, Megan F.; Tan, Tiong Y.; Pope, Kate; Caruana, Georgina; Freckmann, Mary-Louise; Savarirayan, Ravi; Bertram, John F.; Dobbie, Michael S.; Bateman, John F.; Farlie, Peter G.

    2013-01-01

    Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies. PMID:24009529

  13. Improvement of the Rett Syndrome Phenotype in a Mecp2 Mouse Model Upon Treatment with Levodopa and a Dopa-Decarboxylase Inhibitor

    PubMed Central

    Szczesna, Karolina; de la Caridad, Olga; Petazzi, Paolo; Soler, Marta; Roa, Laura; Saez, Mauricio A; Fourcade, Stéphane; Pujol, Aurora; Artuch-Iriberri, Rafael; Molero-Luis, Marta; Vidal, August; Huertas, Dori; Esteller, Manel

    2014-01-01

    Rett Syndrome is a neurodevelopmental autism spectrum disorder caused by mutations in the gene coding for methyl CpG-binding protein (MeCP2). The disease is characterized by abnormal motor, respiratory, cognitive impairment, and autistic-like behaviors. No effective treatment of the disorder is available. Mecp2 knockout mice have a range of physiological and neurological abnormalities that resemble the human syndrome and can be used as a model to interrogate new therapies. Herein, we show that the combined administration of Levodopa and a Dopa-decarboxylase inhibitor in RTT mouse models is well tolerated, diminishes RTT-associated symptoms, and increases life span. The amelioration of RTT symptomatology is particularly significant in those features controlled by the dopaminergic pathway in the nigrostratium, such as mobility, tremor, and breathing. Most important, the improvement of the RTT phenotype upon use of the combined treatment is reflected at the cellular level by the development of neuronal dendritic growth. However, much work is required to extend the duration of the benefit of the described preclinical treatment. PMID:24917201

  14. The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

    PubMed Central

    Mese, Gulistan; Sellitto, Caterina; Li, Leping; Wang, Hong-Zhan; Valiunas, Virginijus; Richard, Gabriele; Brink, Peter R.; White, Thomas W.

    2011-01-01

    Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders. PMID:22031297

  15. Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome.

    PubMed

    Nishio, Ayako; Ito, Taku; Cheng, Hui; Fitzgerald, Tracy S; Wangemann, Philine; Griffith, Andrew J

    2016-08-01

    SLC26A4 mutations cause fluctuating and progressive hearing loss associated with enlargement of the vestibular aqueduct (EVA). SLC26A4 encodes a transmembrane anion exchanger called pendrin expressed in nonsensory epithelial cells of the lateral wall of cochlea, vestibular organs and endolymphatic sac. We previously described a transgenic mouse model of EVA with doxycycline (dox)-inducible expression of Slc26a4 in which administration of dox from conception to embryonic day 17.5 (DE17.5) resulted in hearing fluctuation between 1 and 3months of age. In the present study, we hypothesized that Slc26a4 is required to stabilize hearing in DE17.5 ears between 1 and 3months of age. We tested our hypothesis by evaluating the effect of postnatal re-induction of Slc26a4 expression on hearing. Readministration of dox to DE17.5 mice at postnatal day 6 (P6), but not at 1month of age, resulted in reduced click-evoked auditory brainstem response (ABR) thresholds, less fluctuation of hearing and a higher surface density of pendrin expression in spindle-shaped cells of the stria vascularis. Pendrin expression in spindle-shaped cells was inversely correlated with ABR thresholds. These findings suggest that stabilization of hearing by readministration of dox at P6 is mediated by pendrin expression in spindle-shaped cells. We conclude that early re-induction of Slc26a4 expression can prevent fluctuation of hearing in our Slc26a4-insufficient mouse model. Restoration of SLC26A4 expression and function could reduce or prevent fluctuation of hearing in EVA patients. PMID:27155149

  16. Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome.

    PubMed

    García-Cerro, Susana; Martínez, Paula; Vidal, Verónica; Corrales, Andrea; Flórez, Jesús; Vidal, Rebeca; Rueda, Noemí; Arbonés, María L; Martínez-Cué, Carmen

    2014-01-01

    Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may

  17. Overexpression of Dyrk1A Is Implicated in Several Cognitive, Electrophysiological and Neuromorphological Alterations Found in a Mouse Model of Down Syndrome

    PubMed Central

    García-Cerro, Susana; Martínez, Paula; Vidal, Verónica; Corrales, Andrea; Flórez, Jesús; Vidal, Rebeca; Rueda, Noemí; Arbonés, María L.; Martínez-Cué, Carmen

    2014-01-01

    Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/−) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene

  18. An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair▿

    PubMed Central

    Andressoo, Jaan-Olle; Weeda, Geert; de Wit, Jan; Mitchell, James R.; Beems, Rudolf B.; van Steeg, Harry; van der Horst, Gijsbertus T. J.; Hoeijmakers, Jan H.

    2009-01-01

    Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPBXPCS are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the XpbXPCS Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the XpbXPCS mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS. PMID:19114557

  19. Copper utilization in cultured skin fibroblasts of the mottled mouse, an animal model for Menkes' kinky hair syndrome.

    PubMed

    Packman, S; Chin, P; O'Toole, C

    1984-01-01

    An animal model for Menkes' kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. Two mechanisms have been invoked to explain disease manifestations in mottled and in kinky hair syndrome: relative tissue copper deficiencies and corresponding reductions in cuproenzyme activities; or defective intracellular copper utilization, with impaired intracellular translocation to cuproenzymes or to copper-dependent processes. We addressed the second possibility through measurements of soluble superoxide dismutase (SOD-1) in cytosol extracts of confluent mottled (blotchy) cultured skin fibroblasts. At comparable intracellular copper concentrations over a broad range, SOD-1 specific activities in the mutant cells were not distinguishable from those in controls, or, in some instances, were actually higher. These data suggest that the excess copper anomalously sequestered in a cell expressing the mutation remains available for binding to a cytosolic cuproenzyme. When taken together with data in other systems, the results are consistent with the thesis that the basic lesion in blotchy may primarily affect copper transport or delivery to specific copper transport systems.

  20. Truncation of Ube3a-ATS Unsilences Paternal Ube3a and Ameliorates Behavioral Defects in the Angelman Syndrome Mouse Model

    PubMed Central

    Meng, Linyan; Person, Richard Erwin; Huang, Wei; Zhu, Ping Jun; Costa-Mattioli, Mauro; Beaudet, Arthur L.

    2013-01-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A. Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a, implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome. PMID:24385930

  1. Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome

    PubMed Central

    Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi

    2015-01-01

    Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1−/− mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0–P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner’s membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1−/− mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss. PMID:26084842

  2. Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome.

    PubMed

    Chang, Qing; Wang, Jianjun; Li, Qi; Kim, Yeunjung; Zhou, Binfei; Wang, Yunfeng; Li, Huawei; Lin, Xi

    2015-06-17

    Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.

  3. Mouse Models of Acute Respiratory Distress Syndrome: A Review of Analytical Approaches, Pathologic Features, and Common Measurements.

    PubMed

    Aeffner, Famke; Bolon, Brad; Davis, Ian C

    2015-12-01

    Acute respiratory distress syndrome (ARDS) is a severe pulmonary reaction requiring hospitalization, which is incited by many causes, including bacterial and viral pneumonia as well as near drowning, aspiration of gastric contents, pancreatitis, intravenous drug use, and abdominal trauma. In humans, ARDS is very well defined by a list of clinical parameters. However, until recently no consensus was available regarding the criteria of ARDS that should be evident in an experimental animal model. This lack was rectified by a 2011 workshop report by the American Thoracic Society, which defined the main features proposed to delineate the presence of ARDS in laboratory animals. These should include histological changes in parenchymal tissue, altered integrity of the alveolar capillary barrier, inflammation, and abnormal pulmonary function. Murine ARDS models typically are defined by such features as pulmonary edema and leukocyte infiltration in cytological preparations of bronchoalveolar lavage fluid and/or lung sections. Common pathophysiological indicators of ARDS in mice include impaired pulmonary gas exchange and histological evidence of inflammatory infiltrates into the lung. Thus, morphological endpoints remain a vital component of data sets assembled from animal ARDS models.

  4. Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling.

    PubMed

    Tamada, Kota; Tomonaga, Shozo; Hatanaka, Fumiyuki; Nakai, Nobuhiro; Takao, Keizo; Miyakawa, Tsuyoshi; Nakatani, Jin; Takumi, Toru

    2010-12-15

    Autism spectrum disorders (ASDs) have garnered significant attention as an important grouping of developmental brain disorders. Recent genomic studies have revealed that inherited or de novo copy number variations (CNVs) are significantly involved in the pathophysiology of ASDs. In a previous report from our laboratory, we generated mice with CNVs as a model of ASDs, with a duplicated mouse chromosome 7C that is orthologous to human chromosome 15q11-13. Behavioral analyses revealed paternally duplicated (patDp/+) mice displayed abnormal behaviors resembling the symptoms of ASDs. In the present study, we extended these findings by performing various behavioral tests with C57BL/6J patDp/+ mice, and comprehensively measuring brain monoamine levels with ex vivo high performance liquid chromatography. Compared with wild-type controls, patDp/+ mice exhibited decreased locomotor and exploratory activities in the open field test, Y-maze test, and fear-conditioning test. Furthermore, their decreased activity levels overcame increased appetite induced by 24 hours of food deprivation in the novelty suppressed feeding test. Serotonin levels in several brain regions of adult patDp/+ mice were lower than those of wild-type control, with no concurrent changes in brain levels of dopamine or norepinephrine. Moreover, analysis of monoamines in postnatal developmental stages demonstrated reduced brain levels of serotonin in young patDp/+ mice. These findings suggest that a disrupted brain serotonergic system, especially during postnatal development, may generate the phenotypes of patDp/+ mice.

  5. Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model.

    PubMed

    Hajihosseini, Mohammad K; Duarte, Raquel; Pegrum, Jean; Donjacour, Anne; Lana-Elola, Eva; Rice, David P; Sharpe, James; Dickson, Clive

    2009-02-01

    Apert syndrome (AS) is a severe congenital disease caused by mutations in fibroblast growth factor receptor-2 (FGFR2), and characterised by craniofacial, limb, visceral, and neural abnormalities. AS-type FGFR2 molecules exert a gain-of-function effect in a ligand-dependent manner, but the causative FGFs and their relative contribution to each of the abnormalities observed in AS remains unknown. We have generated mice that harbour an AS mutation but are deficient in or heterozygous for Fgf10. The genetic knockdown of Fgf10 can rescue the skeletal as well as some of the visceral defects observed in this AS model, and restore a near normal level of FgfR2 signaling involving an apparent switch between ERK(p44/p42) and p38 phosphorylation. Surprisingly, it can also yield de novo cleft palate and blind colon in a subset of the compound mutants. These findings strongly suggest that Fgf10 contributes to AS-like pathologies and highlight a complexity of Fgf10 function in different tissues.

  6. Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome.

    PubMed

    Godavarthi, Swetha K; Dey, Parthanarayan; Sharma, Ankit; Jana, Nihar Ranjan

    2015-09-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice.

  7. Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling.

    PubMed

    Chiao, Eric; Fisher, Peter; Crisponi, Laura; Deiana, Manila; Dragatsis, Ioannis; Schlessinger, David; Pilia, Giuseppe; Efstratiadis, Argiris

    2002-03-01

    The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBS1, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBS1 features (omphalocele and skeletal defects) were manifested. However, results from a detailed comparative analysis of growth patterns in double mutants lacking GPC3 and also IGF2, IGF1, or the type 1 IGF receptor (IGF1R) provided conclusive genetic evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by sequestering or downregulating an IGF ligand. Nevertheless, our data are compatible with a model positing that there is downstream convergence of the independent signaling pathways in which either IGFs or (indirectly) GPC3 participate.

  8. Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

    PubMed

    Kelley, Christy M; Powers, Brian E; Velazquez, Ramon; Ash, Jessica A; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

    2014-01-01

    In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5-8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype-matched males. Further, relative to genotype-matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post-processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice.

  9. Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

    PubMed

    Kelley, Christy M; Powers, Brian E; Velazquez, Ramon; Ash, Jessica A; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

    2014-01-01

    In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5-8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype-matched males. Further, relative to genotype-matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post-processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice. PMID:23802663

  10. Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome.

    PubMed

    Godavarthi, Swetha K; Dey, Parthanarayan; Sharma, Ankit; Jana, Nihar Ranjan

    2015-09-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice. PMID:26231800

  11. Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation.

    PubMed

    Schiller, Stina A; Seebode, Christina; Wieser, Georg L; Goebbels, Sandra; Möbius, Wiebke; Horowitz, Mia; Sarig, Ofer; Sprecher, Eli; Emmert, Steffen

    2016-03-01

    Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte-specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation. PMID:26747696

  12. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome.

    PubMed

    Costa, Alberto C S; Grybko, Michael J

    2005-07-15

    Down syndrome (DS) is the most common genetically defined cause of intellectual disabilities. Both hippocampal function and volume seem to be disproportionally reduced in individuals with DS and in at least one aneuploid murine model of DS, the Ts65Dn mouse. Two previous studies by one research group have reported deficits in long-term potentiation (LTP) induced by in vitro high-frequency stimulation (HFS) of hippocampal CA1 synapses of adult Ts65Dn mice. Here, we report on the results of our own investigation on LTP in Ts65Dn mice. This study was designed to confirm the previous findings and possibly shed some light onto potential mechanisms underlying the reported deficit in this important form of long-term synaptic plasticity in a mouse model of DS. LTP was induced in area CA1 with either theta burst stimulation (TBS) or HFS. Contrary to the previous reports, our results showed no significant difference in HFS-induced LTP between Ts65Dn and euploid littermate mice. We have found, however, a significant reduction of the amount of TBS-induced LTP in Ts65Dn mice compared to euploid controls. Because this specific LTP deficit can be rescued by bath application of picrotoxin (10 microM), we hypothesize that an increase in GABA(A)-mediated inhibition or in plasticity of the inhibitory circuitry in Ts65Dn mice may underlie the observed deficits. However, future experiments to examine the state of hippocampus CA1 GABAergic inhibition in Ts65Dn mice will be necessary to further explore these hypotheses.

  13. A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.

    PubMed

    Carpanini, Sarah M; McKie, Lisa; Thomson, Derek; Wright, Ann K; Gordon, Sarah L; Roche, Sarah L; Handley, Mark T; Morrison, Harris; Brownstein, David; Wishart, Thomas M; Cousin, Michael A; Gillingwater, Thomas H; Aligianis, Irene A; Jackson, Ian J

    2014-06-01

    Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18-mutant mouse model of WARBM. Rab18-mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating the characteristic ocular features that are associated with WARBM. Additionally, Rab18-mutant cells exhibit an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of cells taken from WARBM individuals, as well as cells taken from individuals with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18-mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are, most likely, not caused by gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals, and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerves in Rab18-mutant mice reveals significant alterations in several core molecular pathways that regulate cytoskeletal dynamics in neurons. The apparent similarities between the WARBM phenotype and the phenotype that we describe here indicate that the Rab18-mutant mouse provides an important platform for investigation of the disease pathogenesis and therapeutic interventions.

  14. CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome

    PubMed Central

    Galloway, Jocelyn N.; Shaw, Chad; Yu, Peng; Parghi, Deena; Poidevin, Mickael; Jin, Peng; Nelson, David L.

    2014-01-01

    Determining the molecular mechanism(s) leading to Purkinje neuron loss in the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS) is limited by the complex morphology of this cell type. Purkinje neurons are notoriously difficult to isolate and maintain in culture presenting considerable difficultly to identify molecular changes in response to expanded CGG repeat (rCGG)-containing mRNA that induces neurotoxicity in FXTAS. Several studies have uncovered a number of RNA-binding proteins involved in translation that aberrantly interact with the CGG-containing RNA; however, whether these interactions alter the translational profile of cells has not been investigated. Here we employ bacTRAP translational profiling to demonstrate that Purkinje neurons ectopically expressing 90 CGG repeats exhibit a dramatic change in their translational profile even prior to the onset of rCGG-induced phenotypes. This approach identified ∼500 transcripts that are differentially associated with ribosomes in r(CGG)90-expressing mice. Functional annotation cluster analysis revealed broad ontologies enriched in the r(CGG)90 list, including RNA binding and response to stress. Intriguingly, a transcript for the Tardbp gene, implicated in a number of other neurodegenerative disorders, exhibits altered association with ribosomes in the presence of r(CGG)90 repeats. We therefore tested and showed that reduced association of Tardbp mRNA with the ribosomes results in a loss of TDP-43 protein expression in r(CGG)90-expressing Purkinje neurons. Furthermore, we showed that TDP-43 could modulate the rCGG repeat-mediated toxicity in a Drosophila model that we developed previously. These findings together suggest that translational dysregulation may be an underlying mechanism of rCGG-induced neurotoxicity in FXTAS. PMID:24986919

  15. Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome.

    PubMed

    Mardirossian, Sandrine; Rampon, Claire; Salvert, Denise; Fort, Patrice; Sarda, Nicole

    2009-12-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, seizures and sleep disturbances. It results from lack of the functional maternal allele of UBE3A gene. Ube3a maternal-deficient mice (Ube3a m-/p+), animal models for AS, are impaired in hippocampal-dependent learning tasks as compared with control (Ube3a m+/p+) mice. We first examined the basal expression of immediate early genes which expression is required for synaptic plasticity and memory formation. We found that basal expression of c-fos and Arc genes is reduced in the DG of Ube3a maternal deficient mice compared to their non-transgenic littermates. We then examined whether adult hippocampal neurogenesis, which likely serves as a mechanism toward brain plasticity, is altered in these transgenic mice. Neurogenesis occurs throughout life in mammalian dentate gyrus (DG) and recent findings suggest that newborn granule cells are involved in some forms of learning and memory. Whether maternal Ube3a deletion is detrimental on hippocampal neurogenesis is unclear. Herein, we show, using the mitotic marker Ki67, the birthdating marker 5-bromo-2'-dexoyuridine (BrdU) and the marker doublecortin (DCX) to respectively label cell proliferation, cell survival or young neuron production, that the Ube3a maternal deletion does not affect the proliferation nor the survival of newborn cells in the hippocampus. In contrast, using the postmitotic neuronal marker (NeuN), we show that Ube3a maternal deletion is associated with a lower fraction of BrdU+/NeuN+ newborn neurons among the population of surviving new cells in the hippocampus. Collectively, these findings suggest that some aspects of adult neurogenesis and plasticity are affected by Ube3a deletion and may contribute to the hippocampal dysfunction observed in AS mice.

  16. Weaker control of the electrical properties of cerebellar granule cells by tonically active GABAA receptors in the Ts65Dn mouse model of Down’s syndrome

    PubMed Central

    2013-01-01

    Background Down’s syndrome (DS) is caused by triplication of all or part of human chromosome 21 and is characterized by a decrease in the overall size of the brain. One of the brain regions most affected is the cerebellum, in which the number of granule cells (GCs) is markedly decreased. GCs process sensory information entering the cerebellum via mossy fibres and pass it on to Purkinje cells and inhibitory interneurons. How GCs transform incoming signals depends on their input–output relationship, which is adjusted by tonically active GABAA receptor channels. Results We report that in the Ts65Dn mouse model of DS, in which cerebellar volume and GC number are decreased as in DS, the tonic GABAA receptor current in GCs is smaller than in wild-type mice and is less effective in moderating input resistance and raising the minimum current required for action potential firing. We also find that tonically active GABAA receptors curb the height and broaden the width of action potentials in wild-type GCs but not in Ts65Dn GCs. Single-cell real-time quantitative PCR reveals that these electrical differences are accompanied by decreased expression of the gene encoding the GABAA receptor β3 subunit but not genes coding for some of the other GABAA receptor subunits expressed in GCs (α1, α6, β2 and δ). Conclusions Weaker moderation of excitability and action potential waveform in GCs of the Ts65Dn mouse by tonically active GABAA receptors is likely to contribute to atypical transfer of information through the cerebellum. Similar changes may occur in DS. PMID:23870245

  17. Altered epidermal lipid processing and calcium distribution in the KID syndrome mouse model Cx26S17F

    PubMed Central

    Bosen, Felicitas; Celli, Anna; Crumrine, Debra; vom Dorp, Katharina; Ebel, Philipp; Jastrow, Holger; Dörmann, Peter; Winterhager, Elke; Mauro, Theodora; Willecke, Klaus

    2016-01-01

    The keratitis–ichthyosis–deafness (KID) syndrome is caused by mutations in the gap junctional channel protein connexin 26 (Cx26), among them the mutation Cx26S17F. Heterozygous Cx26S17F mice resemble the human KID syndrome, i.e. exhibiting epidermal hyperplasia and hearing impairments. Newborn Cx26S17F mice show a defective epidermal water barrier as well as altered epidermal lipid secretion and location. Linoleoyl ω-esterified ceramides are strongly decreased on the skin surface of Cx26S17F mice. Moreover, the epidermal calcium gradient is altered in the mutant mice. These alterations may be caused by an abnormal Cx26S17F channel function that leads to a defective epidermal water barrier, which in turn may trigger the hyperproliferation seen in the KID syndrome. PMID:26070424

  18. Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome.

    PubMed

    Kurt, M Ayberk; Kafa, M Ilker; Dierssen, Mara; Davies, D Ceri

    2004-10-01

    Ts65Dn mice are partially trisomic for the distal region of MMU16, which is homologous with the obligate segment of HSA21 triplicated in Down syndrome (DS). Ts65Dn mice are impaired in learning tasks that require an intact hippocampus. In order to investigate the neural basis of these deficits in this mouse model of Down syndrome, quantitative light and electron microscopy were used to compare the volume densities of neurons and synapses in the hippocampus of adult Ts65Dn (n=4) and diploid mice (n=4). Neuron density was significantly lower in the CA1 of Ts65Dn compared to diploid mice (p<0.01). Total synapse density was significantly lower in the dentate gyrus (DG; p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. The synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. When the data were broken down by synapse type, asymmetric synapse density was found to be significantly lower in the DG (p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, while such a difference in symmetric synapse density was only present in the DG (p<0.01). The asymmetric synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, but there were no such significant differences in symmetric synapse-to-neuron ratios. These results suggest that impaired synaptic connectivity in the hippocampus of Ts65Dn mice underlies, at least in part, their cognitive impairment.

  19. Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome.

    PubMed

    Llewellyn, Katrina J; Nalbandian, Angèle; Gomez, Arianna; Wei, Don; Walker, Naomi; Kimonis, Virginia E

    2015-04-01

    Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000-20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/p+) mice. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ10 analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ10 therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000mg/day in patients with disorders of CoQ10 biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ10 analogue, to the Ube3a(m-/p+) mouse model corrects motor coordination and anxiety levels, and also improves the expression of complexes III and IV in hippocampus CA1 and CA2 neurons and cerebellum in these Ube3a(m-/p+) mice. However, treatment with idebenone illustrated no beneficial effects in the reduction of oxidative stress. To our knowledge, this is the first study to suggest an improvement in mitochondrial respiratory chain dysfunction via bioenergetics modulation with a CoQ10 analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome. PMID:25684537

  20. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

    PubMed Central

    Meechan, Daniel W.; Tucker, Eric S.; Maynard, Thomas M.; LaMantia, Anthony-Samuel

    2009-01-01

    The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for “diseases of cortical connectivity” thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. PMID:19805316

  1. WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4

    PubMed Central

    Kawai, Toshinao; Choi, Uimook; Cardwell, Lanise; DeRavin, Suk See; Naumann, Nora; Whiting-Theobald, Narda L.; Linton, Gilda F.; Moon, Jaehyun; Murphy, Philip M.; Malech, Harry L.

    2007-01-01

    WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34+ peripheral blood–mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell–derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4. PMID:16946301

  2. Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome.

    PubMed

    Usowicz, Maria M; Garden, Claire L P

    2012-07-17

    Down syndrome (DS) is characterized by intellectual disability and impaired motor control. Lack of coordinated movement, poor balance, and unclear speech imply dysfunction of the cerebellum, which is known to be reduced in volume in DS. The principal cause of the smaller cerebellum is a diminished number of granule cells (GCs). These neurons form the 'input layer' of the cerebellar cortex, where sensorimotor information carried by incoming mossy fibers is transformed before it is conveyed to Purkinje cells and inhibitory interneurons. However, it is not known how processing of this information is affected in the hypogranular cerebellum that characterizes DS. Here we explore the possibility that the electrical properties of the surviving GCs are changed. We find that in the Ts65Dn mouse model of DS, GCs have a higher input resistance at voltages approaching the threshold for firing, which causes them to be more excitable. In addition, they fire narrower and larger amplitude action potentials. These subtly modified electrical properties may result in atypical transfer of information at the input layer of the cerebellum.

  3. Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model.

    PubMed

    Lu, Hui; Ash, Ryan T; He, Lingjie; Kee, Sara E; Wang, Wei; Yu, Dinghui; Hao, Shuang; Meng, Xiangling; Ure, Kerstin; Ito-Ishida, Aya; Tang, Bin; Sun, Yaling; Ji, Daoyun; Tang, Jianrong; Arenkiel, Benjamin R; Smirnakis, Stelios M; Zoghbi, Huda Y

    2016-08-17

    Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice. PMID:27499081

  4. Mouse models for cancer research

    PubMed Central

    Zhang, Wei; Moore, Lynette; Ji, Ping

    2011-01-01

    Mouse models of cancer enable researchers to learn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Journal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue. PMID:21352691

  5. Mouse Models of Gastric Carcinogenesis

    PubMed Central

    Yu, Sungsook; Yang, Mijeong

    2014-01-01

    Gastric cancer is one of the most common cancers in the world. Animal models have been used to elucidate the details of the molecular mechanisms of various cancers. However, most inbred strains of mice have resistance to gastric carcinogenesis. Helicobacter infection and carcinogen treatment have been used to establish mouse models that exhibit phenotypes similar to those of human gastric cancer. A large number of transgenic and knockout mouse models of gastric cancer have been developed using genetic engineering. A combination of carcinogens and gene manipulation has been applied to facilitate development of advanced gastric cancer; however, it is rare for mouse models of gastric cancer to show aggressive, metastatic phenotypes required for preclinical studies. Here, we review current mouse models of gastric carcinogenesis and provide our perspectives on future developments in this field. PMID:25061535

  6. Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Fish, Eric W.; Krouse, Michael C.; Stringfield, Sierra J.; DiBerto, Jeffrey F.; Robinson, J. Elliott; Malanga, C. J.

    2013-01-01

    Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1-/Y) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS. PMID:24205018

  7. A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury.

    PubMed

    Hirsch, Sara; El-Achkar, Tarek; Robbins, Lynn; Basta, Jeannine; Heitmeier, Monique; Nishinakamura, Ryuichi; Rauchman, Michael

    2015-11-15

    It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS (Sall1TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury. PMID:26311113

  8. Differential Gene Expression Reveals Mitochondrial Dysfunction in an Imprinting Center Deletion Mouse Model of Prader-Willi Syndrome

    PubMed Central

    Fan, Weiwei; Coskun, Pinar E.; Nalbandian, Angèle; Knoblach, Susan; Resnick, James L.; Hoffman, Eric; Wallace, Douglas C.; Kimonis, Virginia E.

    2013-01-01

    Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity and diabetes. Previous clinical studies suggest that a defect in energy metabolism may be involved in the pathogenesis of PWS. We focused our attention on the genes associated with energy metabolism and found that there were 95 and 66 mitochondrial genes differentially expressed in PWS muscle and brain, respectively. Assessment of enzyme activities of mitochondrial oxidative phosphorylation (OXPHOS) complexes in the brain, heart, liver and muscle were assessed. We found the enzyme activities of the cardiac mitochondrial complexes II+III were upregulated in the imprinting center deletion (PWS-IC) mice compared to the wild type littermates. These studies suggest that differential gene expression, especially of the mitochondrial genes may contribute to the pathophysiology of PWS. PMID:24127921

  9. Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins.

    PubMed

    Wagner, Carsten A; Loffing-Cueni, Dominique; Yan, Qingshang; Schulz, Nicole; Fakitsas, Panagiotis; Carrel, Monique; Wang, Tong; Verrey, Francois; Geibel, John P; Giebisch, Gerhard; Hebert, Steven C; Loffing, Johannes

    2008-06-01

    Bartter's syndrome represents a group of hereditary salt- and water-losing renal tubulopathies caused by loss-of-function mutations in proteins mediating or regulating salt transport in the thick ascending limb (TAL) of Henle's loop. Mutations in the ROMK channel cause type II antenatal Bartter's syndrome that presents with maternal polyhydramnios and postnatal life-threatening volume depletion. We have developed a colony of Romk null mice showing a Bartter-like phenotype and with increased survival to adulthood, suggesting the activation of compensatory mechanisms. To test the hypothesis that upregulation of Na(+)-transporting proteins in segments distal to the TAL contributes to compensation, we studied expression of salt-transporting proteins in ROMK-deficient (Romk(-/-)) mice. Plasma aldosterone was 40% higher and urinary PGE(2) excretion was 1.5-fold higher in Romk(-/-) compared with wild-type littermates. Semiquantitative immunoblotting of kidney homogenates revealed decreased abundances of proximal tubule Na(+)/H(+) exchanger (NHE3) and Na(+)-P(i) cotransporter (NaPi-IIa) and TAL-specific Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2/BSC1) in Romk(-/-) mice, while the distal convoluted tubule (DCT)-specific Na(+)-Cl(-) cotransporter (NCC/TSC) was markedly increased. The abundance of the alpha-,beta-, and gamma-subunits of the epithelial Na(+) channel (ENaC) was slightly increased, although only differences for gamma-ENaC reached statistical significance. Morphometry revealed a fourfold increase in the fractional volume of DCT but not of connecting tubule (CNT) and collecting duct (CCD). Consistently, CNT and CD of Romk(-/-) mice revealed no apparent increase in the luminal abundance of the ENaC compared with those of wild-type mice. These data suggest that the loss of ROMK-dependent Na(+) absorption in the TAL is compensated predominately by upregulation of Na(+) transport in downstream DCT cells. These adaptive changes in Romk(-/-) mice may help to limit renal Na

  10. MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome.

    PubMed

    Tai, Derek J C; Liu, Yen C; Hsu, Wei L; Ma, Yun L; Cheng, Sin J; Liu, Shau Y; Lee, Eminy H Y

    2016-02-04

    The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT.

  11. MeCP2-mediated alterations of striatal features accompany psychomotor deficits in a mouse model of Rett syndrome.

    PubMed

    Kao, Fang-Chi; Su, San-Hua; Carlson, Gregory C; Liao, Wenlin

    2015-01-01

    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Affected individuals develop motor deficits including stereotypic hand movements, impaired motor learning and difficulties with movement. To understand the neural mechanisms of motor deficits in RTT, we characterized the molecular and cellular phenotypes in the striatum, the major input nucleus of the basal ganglia that controls psychomotor function, in mice carrying a null allele of Mecp2. These mice showed significant hypoactivity associated with impaired motor coordination and motor skill learning. We found that dopamine content was significantly reduced in the striatum of Mecp2 null mice. Reduced dopamine was accompanied by down-regulation of tyrosine hydroxylase and up-regulation of dopamine D2 receptors, particularly in the rostral striatum. We also observed that loss of MeCP2 induced compartment-specific alterations in the striatum, including reduced expression of μ-opioid receptors in the striosomes and increased number of calbindin-positive neurons in the striatal matrix. The total number of parvalbumin-positive interneurons and their dendritic arborization were also significantly increased in the striatum of Mecp2 null mice. Together, our findings support that MeCP2 regulates a unique set of genes critical for modulating motor output of the striatum, and that aberrant structure and function of the striatum due to MeCP2 deficiency may underlie the motor deficits in RTT.

  12. Self-Organizing Feature Maps Identify Proteins Critical to Learning in a Mouse Model of Down Syndrome.

    PubMed

    Higuera, Clara; Gardiner, Katheleen J; Cios, Krzysztof J

    2015-01-01

    Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins obtained from normal genotype control mice and from their trisomic littermates (Ts65Dn) both with and without treatment with the drug memantine. Control mice learn successfully while the trisomic mice fail, unless they are first treated with the drug, which rescues their learning ability. The SOM approach identified reduced subsets of proteins predicted to make the most critical contributions to normal learning, to failed learning and rescued learning, and provides a visual representation of the data that allows the user to extract patterns that may underlie novel biological responses to the different kinds of learning and the response to memantine. Results suggest that the application of SOM to new experimental data sets of complex protein profiles can be used to identify common critical protein responses, which in turn may aid in identifying potentially more effective drug targets.

  13. Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

    PubMed

    Herrera, José A; Ward, Christopher S; Pitcher, Meagan R; Percy, Alan K; Skinner, Steven; Kaufmann, Walter E; Glaze, Daniel G; Wehrens, Xander H T; Neul, Jeffrey L

    2015-04-01

    One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.

  14. Self-Organizing Feature Maps Identify Proteins Critical to Learning in a Mouse Model of Down Syndrome.

    PubMed

    Higuera, Clara; Gardiner, Katheleen J; Cios, Krzysztof J

    2015-01-01

    Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins obtained from normal genotype control mice and from their trisomic littermates (Ts65Dn) both with and without treatment with the drug memantine. Control mice learn successfully while the trisomic mice fail, unless they are first treated with the drug, which rescues their learning ability. The SOM approach identified reduced subsets of proteins predicted to make the most critical contributions to normal learning, to failed learning and rescued learning, and provides a visual representation of the data that allows the user to extract patterns that may underlie novel biological responses to the different kinds of learning and the response to memantine. Results suggest that the application of SOM to new experimental data sets of complex protein profiles can be used to identify common critical protein responses, which in turn may aid in identifying potentially more effective drug targets. PMID:26111164

  15. Self-Organizing Feature Maps Identify Proteins Critical to Learning in a Mouse Model of Down Syndrome

    PubMed Central

    Higuera, Clara; Gardiner, Katheleen J.; Cios, Krzysztof J.

    2015-01-01

    Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins obtained from normal genotype control mice and from their trisomic littermates (Ts65Dn) both with and without treatment with the drug memantine. Control mice learn successfully while the trisomic mice fail, unless they are first treated with the drug, which rescues their learning ability. The SOM approach identified reduced subsets of proteins predicted to make the most critical contributions to normal learning, to failed learning and rescued learning, and provides a visual representation of the data that allows the user to extract patterns that may underlie novel biological responses to the different kinds of learning and the response to memantine. Results suggest that the application of SOM to new experimental data sets of complex protein profiles can be used to identify common critical protein responses, which in turn may aid in identifying potentially more effective drug targets. PMID:26111164

  16. Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

    PubMed Central

    Santos, Rosaysela; Lopez-Burks, Martha E.; Young, Clint M.; Hoang, Michelle P.; Chua, Abigail; Lao, Taotao; Lechner, Mark S.; Daniel, Jeremy A.; Nussenzweig, Andre; Kitzes, Leonard; Yokomori, Kyoko; Hallgrimsson, Benedikt; Lander, Arthur D.

    2009-01-01

    Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS. PMID:19763162

  17. MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome

    PubMed Central

    Tai, Derek J. C.; Liu, Yen C.; Hsu, Wei L.; Ma, Yun L.; Cheng, Sin J.; Liu, Shau Y.; Lee, Eminy H. Y.

    2016-01-01

    The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT. PMID:26842955

  18. Elevated CaMKIIα and hyperphosphorylation of Homer mediate circuit dysfunction in a Fragile X Syndrome mouse model

    PubMed Central

    Guo, Weirui; Ceolin, Laura; Collins, Katie; Perroy, Julie; Huber, Kimberly M.

    2015-01-01

    Summary Abnormal metabotropic glutamate receptor 5 (mGluR5) function, as a result of disrupted scaffolding with its binding partner Homer, contributes to the pathophysiology of Fragile X Syndrome, a common inherited from of intellectual disability and autism caused by mutations in Fmr1. How loss of Fmr1 disrupts mGluR5-Homer scaffolds is unknown, and little is known about the dynamic regulation of mGluR5-Homer scaffolds in wildtype neurons. Here we demonstrate that brief (minutes) elevations in neural activity cause CaMKIIα-mediated phosphorylation of long Homer proteins and dissociation from mGluR5 at synapses. In Fmr1 knockout cortex, Homers are hyperphosphorylated as a result of elevated CaMKIIα protein. Genetic or pharmacological inhibition of CaMKIIα or replacement of Homers with dephosphomimetics restores mGluR5-Homer scaffolds and multiple Fmr1 KO phenotypes, including circuit hyperexcitability and/or seizures. This work links translational control of an FMRP target mRNA, CaMKIIα, to the molecular, cellular and circuit level brain dysfunction in a complex neurodevelopmental disorder. PMID:26670047

  19. Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Giacomini, Andrea; Stagni, Fiorenza; Trazzi, Stefania; Guidi, Sandra; Emili, Marco; Brigham, Elizabeth; Ciani, Elisabetta; Bartesaghi, Renata

    2015-10-01

    Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS. PMID:26254735

  20. Up-regulation of miR-21 and 146a expression and increased DNA damage frequency in a mouse model of polycystic ovary syndrome (PCOS)

    PubMed Central

    Salimi-Asl, Mohammad; Mozdarani, Hossein; Kadivar, Mehdi

    2016-01-01

    Introduction: Polycystic ovary syndrome (PCOS), a multigenic endocrine disorder, is highly associated with low-grade chronic inflammation, however its etiology remains unclear. In this study, we employed dehydroepiandrosterone (DHEA)-treated mice to reveal the molecular mechanism of inflammation and its correlation with oxidative stress in PCOS patients. Methods: miR-21 and miR-146a expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). DNA strand breakage frequency was measured using the single cell gel electrophoresis (SCGE) assay (comet assay) and micronucleus test (MN). CRP levels were measured by ELISA method and ESR values were measured by means of Micro-Dispette (Fisher No: 02-675-256) tubes according to the manufacturer’s instructions. Data were analyzed using one-way ANOVA in SPSS 21.0 software. Results: Our results showed that miR-21 and miR-146a as inflammation markers were upregulated in the sample group in comparison with control group. Erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) levels were also increased in mouse models of PCOS (p < 0.000). Micronucleated polychromatic erythrocyte (MNPCE) rates per 1000 polychromatic erythrocyte (PCE) significantly increased in DHEA treated mice (6.22 ± 3.28) in comparison with the controls (2.33 ± 2.23, p < 0.000). Moreover, mean arbitrary unit in DHEA treated animals (277 ± 92) was significantly higher than that in controls (184 ± 76, p = 0.005). Conclusion: To conclude, increased DNA strand breakage frequency and increased expression levels of miR-21 and miR-146a in DHEA administrated animals suggest that low grade chronic inflammation and oxidative stress can act as the main etiologies of PCOS. PMID:27525225

  1. Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Giacomini, Andrea; Stagni, Fiorenza; Trazzi, Stefania; Guidi, Sandra; Emili, Marco; Brigham, Elizabeth; Ciani, Elisabetta; Bartesaghi, Renata

    2015-10-01

    Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.

  2. Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Stagni, Fiorenza; Giacomini, Andrea; Emili, Marco; Trazzi, Stefania; Guidi, Sandra; Sassi, Martina; Ciani, Elisabetta; Rimondini, Roberto; Bartesaghi, Renata

    2016-10-01

    Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology

  3. Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

    PubMed Central

    Bortolussi, Giulia; Zentillin, Lorena; Vaníkova, Jana; Bockor, Luka; Bellarosa, Cristina; Mancarella, Antonio; Vianello, Eleonora; Tiribelli, Claudio; Giacca, Mauro; Vitek, Libor

    2014-01-01

    Abstract Null mutations in the UGT1A1 gene result in Crigler–Najjar syndrome type I (CNSI), characterized by severe hyperbilirubinemia and constant risk of developing neurological damage. Phototherapy treatment lowers plasma bilirubin levels, but its efficacy is limited and liver transplantation is required. To find alternative therapies, we applied AAV liver-specific gene therapy to a lethal mouse model of CNSI. We demonstrated that a single neonatal hUGT1A1 gene transfer was successful and the therapeutic effect lasted up to 17 months postinjection. The therapeutic effect was mediated by the presence of transcriptionally active double-stranded episomes. We also compared the efficacy of two different gene therapy approaches: liver versus skeletal muscle transgene expression. We observed that 5–8% of normal liver expression and activity levels were sufficient to significantly reduce bilirubin levels and maintain lifelong low plasma bilirubin concentration (3.1±1.5 mg/dl). In contrast, skeletal muscle was not able to efficiently lower bilirubin (6.4±2.0 mg/dl), despite 20–30% of hUgt1a1 expression levels, compared with normal liver. We propose that this remarkable difference in gene therapy efficacy could be related to the absence of the Mrp2 and Mrp3 transporters of conjugated bilirubin in muscle. Taken together, our data support the concept that liver is the best organ for efficient and long-term CNSI gene therapy, and suggest that the use of extra-hepatic tissues should be coupled to the presence of bilirubin transporters. PMID:25072305

  4. Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Stagni, Fiorenza; Giacomini, Andrea; Emili, Marco; Trazzi, Stefania; Guidi, Sandra; Sassi, Martina; Ciani, Elisabetta; Rimondini, Roberto; Bartesaghi, Renata

    2016-10-01

    Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology.

  5. Pharmacotherapy with Fluoxetine Restores Functional Connectivity from the Dentate Gyrus to Field CA3 in the Ts65Dn Mouse Model of Down Syndrome

    PubMed Central

    Guidi, Sandra; Ciani, Elisabetta; Mangano, Chiara; Calzà, Laura; Bartesaghi, Renata

    2013-01-01

    Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45–60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. PMID:23620781

  6. Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome

    PubMed Central

    Giacomini, Andrea; Stagni, Fiorenza; Trazzi, Stefania; Guidi, Sandra; Emili, Marco; Brigham, Elizabeth; Ciani, Elisabetta; Bartesaghi, Renata

    2015-01-01

    Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3–P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS. PMID:26254735

  7. Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome.

    PubMed

    Kelley, Christy M; Ash, Jessica A; Powers, Brian E; Velazquez, Ramon; Alldred, Melissa J; Ikonomovic, Milos D; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

    2016-01-01

    Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer's disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and 14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS. PMID:26391045

  8. Mouse models of ciliopathies: the state of the art

    PubMed Central

    Norris, Dominic P.; Grimes, Daniel T.

    2012-01-01

    The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects. PMID:22566558

  9. Mouse Models of Rheumatoid Arthritis.

    PubMed

    Caplazi, P; Baca, M; Barck, K; Carano, R A D; DeVoss, J; Lee, W P; Bolon, B; Diehl, L

    2015-09-01

    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.

  10. Mouse Genetic Models of Human Brain Disorders.

    PubMed

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  11. Mouse Genetic Models of Human Brain Disorders

    PubMed Central

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  12. Mouse Models of Frailty: an Emerging Field.

    PubMed

    Seldeen, K L; Pang, M; Troen, B R

    2015-10-01

    Frailty is highly prevalent in the elderly, increasing the risk of poor outcomes that include falls, incident disability, hospitalization, and mortality. Thus, a great need exists to characterize the underlying mechanisms and ultimately identify strategies that prevent, delay, and even reverse frailty. Mouse models can provide insight into molecular mechanisms of frailty by reducing variability in lifestyle and genetic factors that can complicate interpretation of human clinical data. Frailty, generally recognized as a syndrome involving reduced homeostatic reserve in response to physiologic challenges and increasing susceptibility to poor health outcomes, is predominantly assessed using two independent strategies, integrated phenotype and deficit accumulation. The integrated phenotype defines frailty by the presentation of factors affecting functional capacity such as weight loss, exhaustion, low activity levels, slow gait, and grip strength. The deficit accumulation paradigm draws parameters from a greater range of physiological systems, such as the ability to perform daily activities, coordination and gait, mental components, physiological problems, and history and presence of medical morbidities. This strategic division also applies within the emerging field of mouse frailty models, with both methodologies showing usefulness in providing insight into physiologic mechanisms and testing interventions. Our review will explore the strategies used, caveats in methodology, and future directions in the application of animal models for the study of the frailty syndrome.

  13. Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

    PubMed

    Jiang, Yong-Hui; Pan, Yanzhen; Zhu, Li; Landa, Luis; Yoo, Jong; Spencer, Corinne; Lorenzo, Isabel; Brilliant, Murray; Noebels, Jeffrey; Beaudet, Arthur L

    2010-08-20

    communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

  14. Mouse Models of Diabetic Neuropathy

    PubMed Central

    O'Brien, Phillipe D.; Sakowski, Stacey A.; Feldman, Eva L.

    2014-01-01

    Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and is associated with significant morbidity and mortality. DPN is characterized by progressive, distal-to-proximal degeneration of peripheral nerves that leads to pain, weakness, and eventual loss of sensation. The mechanisms underlying DPN pathogenesis are uncertain, and other than tight glycemic control in type 1 patients, there is no effective treatment. Mouse models of type 1 (T1DM) and type 2 diabetes (T2DM) are critical to improving our understanding of DPN pathophysiology and developing novel treatment strategies. In this review, we discuss the most widely used T1DM and T2DM mouse models for DPN research, with emphasis on the main neurologic phenotype of each model. We also discuss important considerations for selecting appropriate models for T1DM and T2DM DPN studies and describe the promise of novel emerging diabetic mouse models for DPN research. The development, characterization, and comprehensive neurologic phenotyping of clinically relevant mouse models for T1DM and T2DM will provide valuable resources for future studies examining DPN pathogenesis and novel therapeutic strategies. PMID:24615439

  15. Modeling metastasis in the mouse

    PubMed Central

    Bos, Paula D.; Nguyen, Don X.; Massagué, Joan

    2010-01-01

    Metastasis is a complex clinical and biological problem presently under intense study, and several model systems are in use to experimentally recapitulate and dissect the various steps of the metastatic process. Genetically engineered mouse models provide faithful renditions of events in tumor progression, angiogenesis, and local invasion that set the stage for metastasis, whereas engrafting of human or mouse tumor tissues into mouse hosts has been successfully exploited to investigate metastatic dissemination and colonization of distant organs. Real-time, high-resolution microscopy in live animals, and comprehensive genetic and molecular profiling are effective tools to interrogate diverse metastatic cancer cell phenotypes as well as the metastatic tumor microenvironment in different organs. By integrating the information obtained with these complementary approaches the field is currently obtaining an unprecedented level of understanding of the biology, molecular basis, and therapeutic vulnerabilities of metastasis. PMID:20598638

  16. Mouse models of myasthenia gravis.

    PubMed

    Ban, Joanne; Phillips, William D

    2015-01-01

    Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

  17. Berberine Improves Intestinal Motility and Visceral Pain in the Mouse Models Mimicking Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) Symptoms in an Opioid-Receptor Dependent Manner

    PubMed Central

    Pan, Qiuhui; Fichna, Jakub; Zheng, Lijun; Wang, Kesheng; Yu, Zhen; Li, Yongyu; Li, Kun; Song, Aihong; Liu, Zhongchen; Song, Zhenshun; Kreis, Martin

    2015-01-01

    Background and Aims Berberine and its derivatives display potent analgesic, anti-inflammatory and anticancer activity. Here we aimed at characterizing the mechanism of action of berberine in the gastrointestinal (GI) tract and cortical neurons using animal models and in vitro tests. Methods The effect of berberine was characterized in murine models mimicking diarrhea-predominant irritable bowel syndrome (IBS-D) symptoms. Then the opioidantagonists were used to identify the receptors involved. Furthermore, the effect of berberineon opioid receptors expression was established in the mouse intestine and rat fetal cortical neurons. Results In mouse models, berberine prolonged GI transit and time to diarrhea in a dose-dependent manner, and significantly reduced visceral pain. In physiological conditions the effects of berberine were mediated by mu- (MOR) and delta- (DOR) opioidreceptors; hypermotility, excessive secretion and nociception were reversed by berberine through MOR and DOR-dependent action. We also found that berberine increased the expression of MOR and DOR in the mouse bowel and rat fetal cortical neurons. Conclusion Berberine significantly improved IBS-D symptoms in animal models, possibly through mu- and delta- opioid receptors. Berberine may become a new drug candidate for the successful treatment of IBS-D in clinical conditions. PMID:26700862

  18. Role of Standardized Grape Polyphenol Preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model

    PubMed Central

    Wang, Jun; Tang, Cheuk; Ferruzzi, Mario G.; Gong, Bing; Song, Brian J.; Janle, Elsa M.; Chen, Tzu-Ying; Cooper, Bruce; Varghese, Merina; Cheng, Alice; Freire, Daniel; Bilski, Amanda; Roman, Jessica; Nguyen, Tuyen; Ho, Lap; Talcott, Stephen T.; Simon, James E.; Wu, Qingli; Pasinetti, Giulio M.

    2013-01-01

    Scope Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies are critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract and resveratrol, referred to as Standardized Grape Polyphenol Preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome. Methods We found dietary fat content had minimal effects on absorption and metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity. Conclusion Our study demonstrated that SGP comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome-related pathological features provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory. PMID:23963661

  19. Mouse models of the laminopathies

    SciTech Connect

    Stewart, Colin L. . E-mail: stewartc@ncifcrf.gov; Kozlov, Serguei; Fong, Loren G.; Young, Stephen G. . E-mail: sgyoung@mednet.ucla.edu

    2007-06-10

    The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

  20. Mouse Models of Gastric Cancer

    PubMed Central

    Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

    2013-01-01

    Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

  1. Mouse Models of Human Phenylketonuria

    PubMed Central

    Shedlovsky, A.; McDonald, J. D.; Symula, D.; Dove, W. F.

    1993-01-01

    Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy. PMID:8375656

  2. Divergent cellular phenotypes of human and mouse cells lacking the Werner syndrome RecQ helicase

    PubMed Central

    Dhillon, Kiranjit K.; Sidorova, Julia M.; Albertson, Tina M.; Anderson, Judith B.; Ladiges, Warren C.; Rabinovitch, Peter S.; Preston, Bradley D.; Monnat, Raymond J.

    2009-01-01

    Werner syndrome (WS) is a human autosomal recessive genetic instability and cancer predisposition syndrome with features of premature aging. Several genetically determined mouse models of WS have been generated, however none develops features of premature aging or an elevated risk of neoplasia unless additional genetic perturbations are introduced. In order to determine whether differences in cellular phenotype could explain the discrepant phenotypes of Wrn−/− mice and WRN-deficient humans, we compared the cellular phenotype of newly derived Wrn−/− mouse primary fibroblasts with previous analyses of primary and transformed fibroblasts from WS patients and with newly derived, WRN-depleted human primary fibroblasts. These analyses confirmed previously reported cellular phenotypes of WRN-mutant and WRN-deficient human fibroblasts, and demonstrated that the human WRN-deficient cellular phenotype can be detected in cells grown in 5% or in 20% oxygen. In contrast, we did not identify prominent cellular phenotypes present in WRN-deficient human cells in Wrn−/− mouse fibroblasts. Our results indicate that human and mouse fibroblasts have different functional requirements for WRN protein, and that the absence of a strong cellular phenotype may in part explain the failure of Wrn−/− mice to develop an organismal phenotype resembling Werner syndrome. PMID:19896421

  3. Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome

    PubMed Central

    Gage, Philip J.; Hurd, Elizabeth A.; Martin, Donna M.

    2015-01-01

    Purpose CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary tract abnormalities, and Ear abnormalities and deafness) is the second-leading cause of deaf-blindness after Usher syndrome. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients. We tested the hypothesis that tissue-specific mutant mice provide models for molecularly dissecting CHD7 functions during eye development. Methods The conditional Chd7flox allele was mated together with tissue-specific Cre transgenes. Immunohistochemistry was used to determine the normal CHD7 pattern in the early eye primordia and to assess Chd7 mutants for expression of region-specific protein markers. Results CHD7 is present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm results in severely dysmorphic eyes generally lacking recognizable optic cup structures and small lenses. Deletion from the neural ectoderm results in similar defects. Deletion from the surface ectoderm results in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm are present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depends on the Chd7 gene dose within the neural ectoderm. Conclusions Eye development requires CHD7 in multiple embryonic tissues. Lens development requires CHD7 in the surface ectoderm, whereas optic cup and stalk morphogenesis require CHD7 in the neural ectoderm. CHD7 is not absolutely required for specification of the major subdivisions within the neural ectoderm. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. These data indicate the Chd7 mutant mice are models for determining the molecular etiology of ocular defects in CHARGE syndrome. PMID:26670829

  4. Aging Research Using Mouse Models

    PubMed Central

    Ackert-Bicknell, Cheryl L.; Anderson, Laura; Sheehan, Susan; Hill, Warren G.; Chang, Bo; Churchill, Gary A.; Chesler, Elissa J.; Korstanje, Ron; Peters, Luanne L.

    2015-01-01

    Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in “health-span”, or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, immune function and physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process. PMID:26069080

  5. Modelling Down Syndrome

    ERIC Educational Resources Information Center

    Buckley, Frank

    2008-01-01

    Animal models are extensively used in genetics, neuroscience and biomedical research. Recent studies illustrate the usefulness and the challenges of research utilising genetically engineered mice to explore the developmental biology of Down syndrome. These studies highlight many of the issues at the centre of what we understand about Down…

  6. Mouse Models of Tumor Immunotherapy.

    PubMed

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.

  7. Identification of a Van der Woude syndrome mutation in the cleft palate 1 mutant mouse.

    PubMed

    Stottmann, R W; Bjork, B C; Doyle, J B; Beier, D R

    2010-05-01

    Mutations in Interferon Regulatory Factor 6 (IRF6) have been identified in two human allelic syndromes with cleft lip and/or palate: Van der Woude (VWS) and Popliteal Pterygium syndromes (PPS). Furthermore, common IRF6 haplotypes and single nucleotide polymorphisms (SNP) alleles are strongly associated with nonsyndromic clefting defects in multiple ethnic populations. Mutations in the mouse often provide good models for the study of human diseases and developmental processes. We identified the cleft palate 1 (clft1) mouse mutant in a forward genetic screen for phenotypes modeling human congenital disease. In the clft1 mutant, we have identified a novel missense point mutation in the mouse Irf6 gene, which confers an amino acid alteration that has been found in a VWS family. Phenotypic comparison of clft1 mutants to previously reported Irf6 mutant alleles demonstrates the Irf6(clft1) allele is a hypomorphic allele. The cleft palate seen in these mutants appears to be due to abnormal adhesion between the palate and tongue. The Irf6(clft1) allele provides the first mouse model for the study of an etiologic IRF6 missense mutation observed in a human VWS family. PMID:20196077

  8. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    PubMed Central

    Janc, Oliwia A.; Müller, Michael

    2014-01-01

    Rett syndrome (RS) causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2 (methyl-CpG-binding protein 2)-deficient mouse (Mecp2-/y) hippocampus confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3–5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved synaptic short-term plasticity, and fully restored synaptic long-term potentiation (LTP). Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves the hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation. PMID:24605086

  9. Reversible lacrimal gland-protective regulatory T-cell dysfunction underlies male-specific autoimmune dacryoadenitis in the non-obese diabetic mouse model of Sjögren syndrome.

    PubMed

    Lieberman, Scott M; Kreiger, Portia A; Koretzky, Gary A

    2015-06-01

    CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are required to maintain immunological tolerance; however, defects in specific organ-protective Treg cell functions have not been demonstrated in organ-specific autoimmunity. Non-obese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity and are a well-characterized model of Sjögren syndrome. Lacrimal gland disease in NOD mice is male-specific, but the role of Treg cells in this sex-specificity is not known. This study aimed to determine if male-specific autoimmune dacryoadenitis in the NOD mouse model of Sjögren syndrome is the result of lacrimal gland-protective Treg cell dysfunction. An adoptive transfer model of Sjögren syndrome was developed by transferring cells from the lacrimal gland-draining cervical lymph nodes of NOD mice to lymphocyte-deficient NOD-SCID mice. Transfer of bulk cervical lymph node cells modelled the male-specific dacryoadenitis that spontaneously develops in NOD mice. Female to female transfers resulted in dacryoadenitis if the CD4(+) CD25(+) Treg-enriched population was depleted before transfer; however, male to male transfers resulted in comparable dacryoadenitis regardless of the presence or absence of Treg cells within the donor cell population. Hormone manipulation studies suggested that this Treg cell dysfunction was mediated at least in part by androgens. Surprisingly, male Treg cells were capable of preventing the transfer of dacryoadenitis to female recipients. These data suggest that male-specific factors promote reversible dysfunction of lacrimal gland-protective Treg cells and, to our knowledge, form the first evidence for reversible organ-protective Treg cell dysfunction in organ-specific autoimmunity.

  10. Mouse models for liver cancer.

    PubMed

    Bakiri, Latifa; Wagner, Erwin F

    2013-04-01

    Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities.

  11. Occupational Overuse Syndrome (Technological Diseases): Carpal Tunnel Syndrome, a Mouse Shoulder, Cervical Pain Syndrome

    PubMed Central

    Tiric-Campara, Merita; Krupic, Ferid; Biscevic, Mirza; Spahic, Emina; Maglajlija, Kerima; Masic, Zlatan; Zunic, Lejla; Masic, Izet

    2014-01-01

    ABSTRACT Technological diseases are diseases of the modern era. Some are caused by occupational exposures, and are marked with direct professional relation, or the action of harmful effects in the workplace. Due to the increasing incidence of these diseases on specific workplaces which may be caused by one or more causal factors present in the workplace today, these diseases are considered as professional diseases. Severity of technological disease usually responds to the level and duration of exposure, and usually occurs after many years of exposure to harmful factor. Technological diseases occur due to excessive work at the computer, or excessive use of keyboards and computer mice, especially the non-ergonomic ones. This paper deals with the diseases of the neck, shoulder, elbow and wrist (cervical radiculopathy, mouse shoulder and carpal tunnel syndrome), as is currently the most common diseases of technology in our country and abroad. These three diseases can be caused by long-term load and physical effort, and are tied to specific occupations, such as occupations associated with prolonged sitting, working at the computer and work related to the fixed telephone communication, as well as certain types of sports (tennis, golf and others). PMID:25568584

  12. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely "functional," i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  13. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed Central

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  14. Mouse model of intracerebellar haemorrhage.

    PubMed

    Tijjani Salihu, Abubakar; Muthuraju, Sangu; Aziz Mohamed Yusoff, Abdul; Ahmad, Farizan; Zulkifli Mustafa, Mohd; Jaafar, Hasnan; Idris, Zamzuri; Rahman Izaini Ghani, Abdul; Malin Abdullah, Jafri

    2016-10-01

    The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment. PMID:27327104

  15. The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model.

    PubMed

    Valenti, Daniela; de Bari, Lidia; de Rasmo, Domenico; Signorile, Anna; Henrion-Caude, Alexandra; Contestabile, Andrea; Vacca, Rosa Anna

    2016-06-01

    Mitochondrial dysfunctions critically impair nervous system development and are potentially involved in the pathogenesis of various neurodevelopmental disorders, including Down syndrome (DS), the most common genetic cause of intellectual disability. Previous studies from our group demonstrated impaired mitochondrial activity in peripheral cells from DS subjects and the efficacy of epigallocatechin-3-gallate (EGCG) - a natural polyphenol major component of green tea - to counteract the mitochondrial energy deficit. In this study, to gain insight into the possible role of mitochondria in DS intellectual disability, mitochondrial functions were analyzed in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice, a widely used model of DS which recapitulates many major brain structural and functional phenotypes of the syndrome, including impaired hippocampal neurogenesis. We found that, during NPC proliferation, mitochondrial bioenergetics and mitochondrial biogenic program were strongly compromised in Ts65Dn cells, but not associated with free radical accumulation. These data point to a central role of mitochondrial dysfunction as an inherent feature of DS and not as a consequence of cell oxidative stress. Further, we disclose that, besides EGCG, also the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis, and improves proliferation of NPCs. These effects were associated with the activation of PGC-1α/Sirt1/AMPK axis by both polyphenols. This research paves the way for using nutraceuticals as a potential therapeutic tool in preventing or managing some energy deficit-associated DS clinical manifestations. PMID:26964795

  16. Hypoxia inducible factor-1α inhibition produced anti-allodynia effect and suppressed inflammatory cytokine production in early stage of mouse complex regional pain syndrome model.

    PubMed

    Hsiao, Hung-Tsung; Lin, Ya-Chi; Wang, Jeffrey Chi-Fei; Tsai, Yu-Chuan; Liu, Yen-Chin

    2016-03-01

    Complex regional pain syndrome (CRPS) is related to microcirculation impairment associated with tissue hypoxia and peripheral cytokine overproduction in the affected limb. Previous studies suggest that the pathogenesis involves hypoxia inducible factor-1α (HIF-1α) and exaggerated regional inflammatory response. 1-methylpropyl 2-imidazolyl disulfide (PX-12) acts as the thioredoxin-1 (Trx-1) inhibitor and decreases the level of HIF-1α, and can rapidly be metabolized for Trx-1 redox inactivation. This study hypothesized that PX-12 can decrease the cytokine production for nociceptive sensitization in the hypoxia-induced pain model. CD1 mice weighing around 30 g were used. The animal CRPS model was developed via the chronic post-ischaemic pain (CPIP) model. The model was induced by using O-rings on the ankles of the mice hind limbs to produce 3-h ischaemia-reperfusion injury on the paw. PX-12 (25 mg/kg, 5 mg/kg) was given through tail vein injection immediately after ischaemia. Animal behaviour was tested using the von Frey method for 7 days. Local paw skin tissue was harvest from three groups (control, 5 mg/kg, 25 mg/kg) 2 h after injection of PX-12. The protein expression of interleukin-1β (IL-1β) and HIF-1α was analysed with the Western blotting method. Mice significantly present an anti-allodynia effect in a dose-related manner after the PX-12 administration. Furthermore, PX-12 not only decreased the expression of HIF-1α but also decreased the expression of IL-1β over the injured palm. This study, therefore, shows the first evidence of the anti-allodynia effect of PX-12 in a CPIP animal model for pain behaviour. The study concluded that inhibition of HIF-1α may produce an analgesic effect and the associated suppression of inflammatory cytokine IL-1β in a CPIP model. PMID:26711019

  17. Mouse Models of Diabetic Neuropathy

    PubMed Central

    Sullivan, Kelli A.; Hayes, John M.; Wiggin, Timothy D.; Backus, Carey; Oh, Sang Su; Lentz, Stephen I.; Brosius, Frank; Feldman, Eva L.

    2007-01-01

    Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. We examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2Akita] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db]. DN was defined using the criteria of the Animal Models of Diabetic Complications Consortium (http://www.amdcc.org). Despite persistent hyperglycemia, the STZ-treated B6 and B6Ins2Akita mice were resistant to the development of DN. In contrast, DN developed in both type 2 diabetes models: the B6-db/db and BKS-db/db mice. The persistence of hyperglycemia and development of DN in the B6-db/db mice required an increased fat diet while the BKS-db/db mice developed severe DN and remained hyperglycemic on standard mouse chow. Our data support the hypothesis that genetic background and diet influence the development of DN and should be considered when developing new models of DN. PMID:17804249

  18. Mouse Models of Rare Craniofacial Disorders.

    PubMed

    Achilleos, Annita; Trainor, Paul A

    2015-01-01

    A rare disease is defined as a condition that affects less than 1 in 2000 individuals. Currently more than 7000 rare diseases have been documented, and most are thought to be of genetic origin. Rare diseases primarily affect children, and congenital craniofacial syndromes and disorders constitute a significant proportion of rare diseases, with over 700 having been described to date. Modeling craniofacial disorders in animal models has been instrumental in uncovering the etiology and pathogenesis of numerous conditions and in some cases has even led to potential therapeutic avenues for their prevention. In this chapter, we focus primarily on two general classes of rare disorders, ribosomopathies and ciliopathies, and the surprising finding that the disruption of fundamental, global processes can result in tissue-specific craniofacial defects. In addition, we discuss recent advances in understanding the pathogenesis of an extremely rare and specific craniofacial condition known as syngnathia, based on the first mouse models for this condition. Approximately 1% of all babies are born with a minor or major developmental anomaly, and individuals suffering from rare diseases deserve the same quality of treatment and care and attention to their disease as other patients. PMID:26589934

  19. Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.

    PubMed

    Ilkun, Olesya; Wilde, Nicole; Tuinei, Joseph; Pires, Karla M P; Zhu, Yi; Bugger, Heiko; Soto, Jamie; Wayment, Benjamin; Olsen, Curtis; Litwin, Sheldon E; Abel, E Dale

    2015-08-01

    Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism. PMID:26004364

  20. Mouse models of membranous nephropathy: the road less travelled by

    PubMed Central

    Borza, Dorin-Bogdan; Zhang, Jun-Jun; Beck, Laurence H; Meyer-Schwesinger, Catherine; Luo, Wentian

    2013-01-01

    Membranous nephropathy (MN) is a major cause of idiopathic nephrotic syndrome in adults, often progressing to end-stage kidney disease. The disease is mediated by IgG antibodies that form subepithelial immune complexes upon binding to antigens expressed by podocytes or planted in the subepithelial space. Subsequent activation of the complement cascade, podocyte injury by the membrane attack complex and the expansion of the glomerular basement membrane cause proteinuria and nephrotic syndrome. The blueprint for our current understanding of the pathogenic mechanisms of MN has largely been provided by studies in rat Heymann nephritis, an excellent animal model that closely replicates human disease. However, further progress in this area has been hindered by the lack of robust mouse models of MN that can leverage the power of genetic approaches for mechanistic studies. This critical barrier has recently been overcome by the development of new mouse models that faithfully recapitulate the clinical and morphologic hallmarks of human MN. In these mouse models, subepithelial ICs mediating proteinuria and nephrotic syndrome are induced by injection of cationized bovine serum albumin, by passive transfer of heterologous anti-podocyte antibodies, or by active immunization with the NC1 domain of α3(IV) collagen. These mouse models of MN will be instrumental for addressing unsolved questions about the basic pathomechanisms of MN and also for preclinical studies of novel therapeutics. We anticipate that the new knowledge to be gained from these studies will eventually translate into much needed novel mechanism-based therapies for MN, more effective, more specific, and less toxic. PMID:23885331

  1. Autosomal dominant frontonasal dysplasia (atypical Greig syndrome): Lessons from the Xt mutant mouse

    SciTech Connect

    Cunningham, M.L.; Nunes, M.E.

    1994-09-01

    Greig syndrome is the autosomal dominant association of mild hypertelorism, variable polysyndactyly, and normal intelligence. Several families have been found to have translocations or deletions of 7p13 interrupting the normal expression of GLI3 (a zinc finger, DNA binding, transcription repressor). Recently, a mutation in the mouse homologue of GLI3 was found in the extra-toes mutant mouse (Xt). The phenotypic features of this mouse model include mild hypertelorism, postaxial polydactyly of the forelimbs, preaxial polydactyly of the hindlimbs, and variable tibial hemimelia. The homozygous mutant Xt/Xt have severe frontonasal dysplasia (FND), polysyndactyly of fore-and hindlimbs and invariable tibial hemimelia. We have recently evaluated a child with severe (type D) frontonasal dysplasia, fifth finger camptodactyly, preaxial polydactyly of one foot, and ispilateral tibial hemimelia. His father was born with a bifid nose, broad columnella, broad feet, and a two centimeter leg length discrepancy. The paternal grandmother of the proband is phenotypically normal; however, her fraternal twin died at birth with severe facial anomalies. The paternal great-grandmother of the proband is phenotypically normal however her niece was born with moderate ocular hypertelorism. This pedigree is suggestive of an autosomal dominant form of frontonasal dysplasia with variable expressivity. The phenotypic features of our case more closely resemble the Xt mouse than the previously defined features of Greig syndrome in humans. This suggests that a mutation in GLI3 may be responsible for FND in this family. We are currently using polymorphic dinucleotide repeat markers flanking GLI3 in a attempt to demonstrate linkage in this pedigree. Demonstration of a GLI3 mutation in this family would broaden our view of the spectrum of phenotypes possible in Greig syndrome and could provide insight into genotype/phenotype correlation in FND.

  2. Mouse models for human hereditary deafness.

    PubMed

    Leibovici, Michel; Safieddine, Saaid; Petit, Christine

    2008-01-01

    Hearing impairment is a frequent condition in humans. Identification of the causative genes for the early onset forms of isolated deafness began 15 years ago and has been very fruitful. To date, approximately 50 causative genes have been identified. Yet, limited information regarding the underlying pathogenic mechanisms can be derived from hearing tests in deaf patients. This chapter describes the success of mouse models in the elucidation of some pathophysiological processes in the auditory sensory organ, the cochlea. These models have revealed a variety of defective structures and functions at the origin of deafness genetic forms. This is illustrated by three different examples: (1) the DFNB9 deafness form, a synaptopathy of the cochlear sensory cells where otoferlin is defective; (2) the Usher syndrome, in which deafness is related to abnormal development of the hair bundle, the mechanoreceptive structure of the sensory cells to sound; (3) the DFNB1 deafness form, which is the most common form of inherited deafness in Caucasian populations, mainly caused by connexin-26 defects that alter gap junction communication between nonsensory cochlear cells. PMID:19186249

  3. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome

    PubMed Central

    Catuara-Solarz, Silvina; Espinosa-Carrasco, Jose; Erb, Ionas; Langohr, Klaus; Notredame, Cedric; Gonzalez, Juan R.; Dierssen, Mara

    2015-01-01

    Down syndrome (DS) individuals present increased risk for Alzheimer's disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals. PMID:26696850

  4. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome.

    PubMed

    Catuara-Solarz, Silvina; Espinosa-Carrasco, Jose; Erb, Ionas; Langohr, Klaus; Notredame, Cedric; Gonzalez, Juan R; Dierssen, Mara

    2015-01-01

    Down syndrome (DS) individuals present increased risk for Alzheimer's disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals. PMID:26696850

  5. Delivery of the 7-dehydrocholesterol reductase gene to the central nervous system using adeno-associated virus vector in a mouse model of Smith-Lemli-Opitz Syndrome

    PubMed Central

    Pasta, Saloni; Akhile, Omoye; Tabron, Dorothy; Ting, Flora; Shackleton, Cedric; Watson, Gordon

    2015-01-01

    Smith Lemli Opitz syndrome (SLOS) is an inherited malformation and mental retardation metabolic disorder with no cure. Mutations in the last enzyme of the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (DHCR7), lead to cholesterol insufficiency and accumulation of its dehyrdocholesterol precursors, and contribute to its pathogenesis. The central nervous system (CNS) constitutes a major pathophysiological component of this disorder and remains unamenable to dietary cholesterol therapy due to the impenetrability of the blood brain barrier (BBB). The goal of this study was to restore sterol homeostasis in the CNS. To bypass the BBB, gene therapy using an adeno-associated virus (AAV-8) vector carrying a functional copy of the DHCR7 gene was administered by intrathecal (IT) injection directly into the cerebrospinal fluid of newborn mice. Two months post-treatment, vector DNA and DHCR7 expression was observed in the brain and a corresponding improvement of sterol levels seen in the brain and spinal cord. Interestingly, sterol levels in the peripheral nervous system also showed a similar improvement. This study shows that IT gene therapy can have a positive biochemical effect on sterol homeostasis in the central and peripheral nervous systems in a SLOS animal model. A single dose delivered three days after birth had a sustained effect into adulthood, eight weeks post-treatment. These observations pave the way for further studies to understand the effect of biochemical improvement of sterol levels on neuronal function, to provide a greater understanding of neuronal cholesterol homeostasis, and to develop potential therapies. PMID:26347274

  6. Changes in the Submandibular Salivary Gland Epithelial Cell Subpopulations During Progression of Sjögren's Syndrome-Like Disease in the NOD/ShiLtJ Mouse Model.

    PubMed

    Gervais, Elise M; Desantis, Kara A; Pagendarm, Nicholas; Nelson, Deirdre A; Enger, Tone; Skarstein, Kathrine; Liaaen Jensen, Janicke; Larsen, Melinda

    2015-09-01

    Sjögren's syndrome (SS), an autoimmune exocrinopathy, is associated with dysfunction of the secretory salivary gland epithelium, leading to xerostomia. The etiology of SS disease progression is poorly understood as it is typically not diagnosed until late stage. Since mouse models allow the study of disease progression, we investigated the NOD/ShiLtJ mouse to explore temporal changes to the salivary epithelium. In the NOD/ShiLtJ model, SS presents secondary to autoimmune diabetes, and SS disease is reportedly fully established by 20 weeks. We compared epithelial morphology in the submandibular salivary glands (SMG) of NOD/ShiLtJ mice with SMGs from the parental strain at 12, 18, and 22 weeks of age and used immunofluorescence to detect epithelial proteins, including the acinar marker, aquaporin 5, ductal cell marker, cytokeratin 7, myoepithelial cell marker, smooth muscle α-actin, and the basal cell marker, cytokeratin 5, while confirming immune infiltrates with CD45R. We also compared these proteins in the labial salivary glands of human SS patients with control tissues. In the NOD/ShiLtJ SMG, regions of lymphocytic infiltrates were not associated with widespread epithelial tissue degradation; however, there was a decrease in the area of the gland occupied by secretory epithelial cells in favor of ductal epithelial cells. We observed an expansion of cells expressing cytokeratin 5 within the ducts and within the smooth muscle α-actin(+) basal myoepithelial population. The altered acinar/ductal ratio within the NOD/ShiLtJ SMG likely contributes to salivary hypofunction, while the expansion of cytokeratin 5 positive-basal cells may reflect loss of function or indicate a regenerative response.

  7. The Mouse Genome Database (MGD): mouse biology and model systems.

    PubMed

    Bult, Carol J; Eppig, Janan T; Kadin, James A; Richardson, Joel E; Blake, Judith A

    2008-01-01

    The Mouse Genome Database, (MGD, http://www.informatics.jax.org/), integrates genetic, genomic and phenotypic information about the laboratory mouse, a primary animal model for studying human biology and disease. MGD data content includes comprehensive characterization of genes and their functions, standardized descriptions of mouse phenotypes, extensive integration of DNA and protein sequence data, normalized representation of genome and genome variant information including comparative data on mammalian genes. Data within MGD are obtained from diverse sources including manual curation of the biomedical literature, direct contributions from individual investigator's laboratories and major informatics resource centers such as Ensembl, UniProt and NCBI. MGD collaborates with the bioinformatics community on the development of data and semantic standards such as the Gene Ontology (GO) and the Mammalian Phenotype (MP) Ontology. MGD provides a data-mining platform that enables the development of translational research hypotheses based on comparative genotype, phenotype and functional analyses. Both web-based querying and computational access to data are provided. Recent improvements in MGD described here include the association of gene trap data with mouse genes and a new batch query capability for customized data access and retrieval.

  8. Modeling cytomegalovirus infection in mouse tumor models.

    PubMed

    Price, Richard Lee; Chiocca, Ennio Antonio

    2015-01-01

    The hypothesis that cytomegalovirus (CMV) modulates cancer is evolving. Originally discovered in glioblastoma in 2002, the number of cancers, where intratumoral CMV antigen is detected, has increased in recent years suggesting that CMV actively affects the pathobiology of certain tumors. These findings are controversial as several groups have also reported inability to replicate these results. Regardless, several clinical trials for glioblastoma are underway or have been completed that target intratumoral CMV with anti-viral drugs or immunotherapy. Therefore, a better understanding of the possible pathobiology of CMV in cancer needs to be ascertained. We have developed genetic, syngeneic, and orthotopic malignant glioma mouse models to study the role of CMV in cancer development and progression. These models recapitulate for the most part intratumoral CMV expression as seen in human tumors. Additionally, we discovered that CMV infection in Trp53(-/+) mice promotes pleomorphic rhabdomyosarcomas. These mouse models are not only a vehicle for studying pathobiology of the viral-tumor interaction but also a platform for developing and testing cancer therapeutics. PMID:25853089

  9. Melatonin receptors: latest insights from mouse models

    PubMed Central

    Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

    2014-01-01

    Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

  10. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.

    PubMed

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-Jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-01-01

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome. PMID:27328321

  11. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.

    PubMed

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-Jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-06-21

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

  12. Mouse models for human otitis media

    PubMed Central

    Trune, Dennis R.; Zheng, Qing Yin

    2010-01-01

    Otitis media (OM) remains the most common childhood disease and its annual costs exceed $5 billion. Its potential for permanent hearing impairment also emphasizes the need to better understand and manage this disease. The pathogenesis of OM is multifactorial and includes infectious pathogens, anatomy, immunologic status, genetic predisposition, and environment. Recent progress in mouse model development is helping to elucidate the respective roles of these factors and to significantly contribute toward efforts of OM prevention and control. Genetic predisposition is recognized as an important factor in OM and increasing numbers of mouse models are helping to uncover the potential genetic bases for human OM. Furthermore, the completion of the mouse genome sequence has offered a powerful set of tools for investigating gene function and is generating a rich resource of mouse mutants for studying the genetic factors underlying OM. PMID:19272362

  13. A mouse model of renal tubular injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice.

    PubMed

    Sun, M S; Hattori, S; Kubo, S; Awata, H; Matsuda, I; Endo, F

    2000-02-01

    Hereditary tyrosinemia type 1 (HT1) (McKusick 276700), a severe autosomal recessive disorder of tyrosine metabolism, is caused by mutations in the fumarylacetoacetate hydrolase gene Fah (EC 3.7.1.2), which encodes the last enzyme in the tyrosine catabolic pathway. HT1 is characterized by severe progressive liver disease and renal tubular dysfunction. Homozygous disruption of the gene encoding Fah in mice causes neonatal lethality (e.g., lethal Albino deletion c14CoS mice), an event that limits use of this animal as a model for HT1. A new mouse model was developed with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd). The Fah-/- Hpd-/- mice grew normally without evidence of liver and renal disease, and the phenotype is similar to that in Fah+/+ Hpd-/- mice. The renal tubular cells of Fah-/- Hpd-/- mice, particularly proximal tubular cells, underwent rapid apoptosis when homogentisate, the intermediate metabolite between HPD and FAH, was administered to the Fah-/- Hpd-/- mice. Simultaneously, renal tubular function was impaired and Fanconi syndrome occurred. Apoptotic death of renal tubular cells, but not renal dysfunction, was prevented by pretreatment of the animals with YVAD, a specific inhibitor of caspases. In the homogentisate-treated Fah-/- Hpd-/- mice, massive amounts of succinylacetone were excreted into the urine, regardless of treatment with inhibitors. It is suggested that apoptotic death of renal tubular cells, as induced by administration of homogentisate to Fah-/- Hpd-/- mice, was caused by an intrinsic process, and that renal apoptosis and tubular dysfunctions in tubular cells occurred through different pathways. These observations shed light on the pathogenesis of renal tubular injury in subjects with FAH deficiency. These Fah-/- Hpd-/- mice can serve as a model in experiments related to renal tubular damage.

  14. Pathology of Mouse Models of Accelerated Aging.

    PubMed

    Harkema, L; Youssef, S A; de Bruin, A

    2016-03-01

    Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of "geroscience," which aims at elucidating the molecular mechanisms involved in aging. Progeroid mouse models are frequently used in geroscience as they provide insight into the molecular mechanisms that are involved in the highly complex process of natural aging. This review provides an overview of the most commonly reported nonneoplastic macroscopic and microscopic pathologic findings in progeroid mouse models (eg, osteoporosis, osteoarthritis, degenerative joint disease, intervertebral disc degeneration, kyphosis, sarcopenia, cutaneous atrophy, wound healing, hair loss, alopecia, lymphoid atrophy, cataract, corneal endothelial dystrophy, retinal degenerative diseases, and vascular remodeling). Furthermore, several shortcomings in pathologic analysis and descriptions of these models are discussed. Progeroid mouse models are valuable models for aging, but thorough knowledge of both the mouse strain background and the progeria-related phenotype is required to guide interpretation and translation of the pathology data. PMID:26864891

  15. Reduction of α1GABAA receptor mediated by tyrosine kinase C (PKC) phosphorylation in a mouse model of fragile X syndrome

    PubMed Central

    Zhao, Weidong; Wang, Jiaqin; Song, Shunyi; Li, Fang; Yuan, Fangfang

    2015-01-01

    Fragile X syndrome (FXS) caused by lack of fragile X mental retardation protein (Fmr1) is the most common cause of inherited intellectual disability and characterized by many cognitive disturbances like attention deficit, autistic behavior, and audiogenic seizure and have region-specific altered expression of some gamma-aminobutyric acid (GABAA) receptor subunits. Quantitative real-time polymerase chain reaction and western blot experiments were performed in the cultured cortical neurons and forebrain obtained from wild-type (WT) and Fmr1 KO mice demonstrate the reduction in the expression of α1 gamma-aminobutyric acid (α1GABAA) receptor, phospho-α1GABAA receptor, PKC and phosphor-PKC in Fmr1 KO mice comparing with WT mice, both in vivo and in vitro. Furthermore, we found that the phosphorylation of the α1GABAA receptor was mediated by PKC. Our results elucidate that the lower phosphorylation of the α1GABAA receptor mediated by PKC neutralizes the seizure-promoting effects in Fmr1 KO mice and point to the potential therapeutic targets of α1GABAA agonists for the treatment of fragile X syndrome. PMID:26550246

  16. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome.

    PubMed

    Fitzky, B U; Moebius, F F; Asaoka, H; Waage-Baudet, H; Xu, L; Xu, G; Maeda, N; Kluckman, K; Hiller, S; Yu, H; Batta, A K; Shefer, S; Chen, T; Salen, G; Sulik, K; Simoni, R D; Ness, G C; Glossmann, H; Patel, S B; Tint, G S

    2001-09-01

    Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates. Despite reduced sterol concentrations in Dhcr7(-/-) mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, protein levels and activities of HMG-CoA reductase were markedly reduced. Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins. These results demonstrate that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally. This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency. PMID:11560960

  17. 7-Dehydrocholesterol–dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome

    PubMed Central

    Fitzky, Barbara U.; Moebius, Fabian F.; Asaoka, Hitoshi; Waage-Baudet, Heather; Xu, Liwen; Xu, Guorong; Maeda, Nobuyo; Kluckman, Kimberly; Hiller, Sylvia; Yu, Hongwei; Batta, Ashok K.; Shefer, Sarah; Chen, Thomas; Salen, Gerald; Sulik, Kathleen; Simoni, Robert D.; Ness, Gene C.; Glossmann, Hartmut; Patel, Shailendra B.; Tint, G.S.

    2001-01-01

    Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates. Despite reduced sterol concentrations in Dhcr7–/– mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, protein levels and activities of HMG-CoA reductase were markedly reduced. Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins. These results demonstrate that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally. This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency. PMID:11560960

  18. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

    PubMed Central

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-01-01

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome. DOI: http://dx.doi.org/10.7554/eLife.14198.001 PMID:27328321

  19. GlyT2-Dependent Preservation of MECP2-Expression in Inhibitory Neurons Improves Early Respiratory Symptoms but Does Not Rescue Survival in a Mouse Model of Rett Syndrome

    PubMed Central

    Hülsmann, Swen; Mesuret, Guillaume; Dannenberg, Julia; Arnoldt, Mauricio; Niebert, Marcus

    2016-01-01

    Mutations in methyl-CpG-binding protein 2 (MECP2) gene have been shown to manifest in a neurodevelopmental disorder that is called Rett syndrome. A typical problem that occurs during development is a disturbance of breathing. To address the role of inhibitory neurons, we generated a mouse line that restores MECP2 in inhibitory neurons in the brainstem by crossbreeding a mouse line that expresses the Cre-recombinase (Cre) in inhibitory neurons under the control of the glycine transporter 2 (GlyT2, slc6a5) promotor (GlyT2-Cre) with a mouse line that has a floxed-stop mutation of the Mecp2 gene (Mecp2stop/y). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2stop/y mice. In contrast, GlyT2-Cre positive Mecp2stop/y mice (Cre+; Mecp2stop/y) showed greatly improved respiration and were indistinguishable from wild type littermates. These data support the concept that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome.

  20. GlyT2-Dependent Preservation of MECP2-Expression in Inhibitory Neurons Improves Early Respiratory Symptoms but Does Not Rescue Survival in a Mouse Model of Rett Syndrome

    PubMed Central

    Hülsmann, Swen; Mesuret, Guillaume; Dannenberg, Julia; Arnoldt, Mauricio; Niebert, Marcus

    2016-01-01

    Mutations in methyl-CpG-binding protein 2 (MECP2) gene have been shown to manifest in a neurodevelopmental disorder that is called Rett syndrome. A typical problem that occurs during development is a disturbance of breathing. To address the role of inhibitory neurons, we generated a mouse line that restores MECP2 in inhibitory neurons in the brainstem by crossbreeding a mouse line that expresses the Cre-recombinase (Cre) in inhibitory neurons under the control of the glycine transporter 2 (GlyT2, slc6a5) promotor (GlyT2-Cre) with a mouse line that has a floxed-stop mutation of the Mecp2 gene (Mecp2stop/y). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2stop/y mice. In contrast, GlyT2-Cre positive Mecp2stop/y mice (Cre+; Mecp2stop/y) showed greatly improved respiration and were indistinguishable from wild type littermates. These data support the concept that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome. PMID:27672368

  1. GlyT2-Dependent Preservation of MECP2-Expression in Inhibitory Neurons Improves Early Respiratory Symptoms but Does Not Rescue Survival in a Mouse Model of Rett Syndrome.

    PubMed

    Hülsmann, Swen; Mesuret, Guillaume; Dannenberg, Julia; Arnoldt, Mauricio; Niebert, Marcus

    2016-01-01

    Mutations in methyl-CpG-binding protein 2 (MECP2) gene have been shown to manifest in a neurodevelopmental disorder that is called Rett syndrome. A typical problem that occurs during development is a disturbance of breathing. To address the role of inhibitory neurons, we generated a mouse line that restores MECP2 in inhibitory neurons in the brainstem by crossbreeding a mouse line that expresses the Cre-recombinase (Cre) in inhibitory neurons under the control of the glycine transporter 2 (GlyT2, slc6a5) promotor (GlyT2-Cre) with a mouse line that has a floxed-stop mutation of the Mecp2 gene (Mecp2 (stop/y)). Unrestrained whole-body-plethysmography at postnatal day P60 revealed a low respiratory rate and prolonged respiratory pauses in Mecp2 (stop/y) mice. In contrast, GlyT2-Cre positive Mecp2 (stop/y) mice (Cre(+) ; Mecp2 (stop/y)) showed greatly improved respiration and were indistinguishable from wild type littermates. These data support the concept that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome. PMID:27672368

  2. Peripheral Neuropathy in Mouse Models of Diabetes.

    PubMed

    Jolivalt, Corinne G; Frizzi, Katie E; Guernsey, Lucie; Marquez, Alex; Ochoa, Joseline; Rodriguez, Maria; Calcutt, Nigel A

    2016-01-01

    Peripheral neuropathy is a frequent complication of chronic diabetes that most commonly presents as a distal degenerative polyneuropathy with sensory loss. Around 20% to 30% of such patients may also experience neuropathic pain. The underlying pathogenic mechanisms are uncertain, and therapeutic options are limited. Rodent models of diabetes have been used for more than 40 years to study neuropathy and evaluate potential therapies. For much of this period, streptozotocin-diabetic rats were the model of choice. The emergence of new technologies that allow relatively cheap and routine manipulations of the mouse genome has prompted increased use of mouse models of diabetes to study neuropathy. In this article, we describe the commonly used mouse models of type 1 and type 2 diabetes, and provide protocols to phenotype the structural, functional, and behavioral indices of peripheral neuropathy, with a particular emphasis on assays pertinent to the human condition. © 2016 by John Wiley & Sons, Inc. PMID:27584552

  3. Cancer mouse models: past, present and future.

    PubMed

    Khaled, Walid T; Liu, Pentao

    2014-03-01

    The development and advances in gene targeting technology over the past three decades has facilitated the generation of cancer mouse models that recapitulate features of human malignancies. These models have been and still remain instrumental in revealing the complexities of human cancer biology. However, they will need to evolve in the post-genomic era of cancer research. In this review we will highlight some of the key developments over the past decades and will discuss the new possibilities of cancer mouse models in the light of emerging powerful gene manipulating tools.

  4. Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.

    PubMed

    Grier, Mark D; Carson, Robert P; Lagrange, Andre Hollis

    2015-01-01

    Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development. PMID:25894543

  5. Citrobacter rodentium mouse model of bacterial infection.

    PubMed

    Crepin, Valerie F; Collins, James W; Habibzay, Maryam; Frankel, Gad

    2016-10-01

    Infection of mice with Citrobacter rodentium is a robust model to study bacterial pathogenesis, mucosal immunology, the health benefits of probiotics and the role of the microbiota during infection. C. rodentium was first isolated by Barthold from an outbreak of mouse diarrhea in Yale University in 1972 and was 'rediscovered' by Falkow and Schauer in 1993. Since then the use of the model has proliferated, and it is now the gold standard for studying virulence of the closely related human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Here we provide a detailed protocol for various applications of the model, including bacterial growth, site-directed mutagenesis, mouse inoculation (from cultured cells and after cohabitation), monitoring of bacterial colonization, tissue extraction and analysis, immune responses, probiotic treatment and microbiota analysis. The main protocol, from mouse infection to clearance and analysis of tissues and host responses, takes ∼5 weeks to complete. PMID:27606775

  6. The Neuraminidase Inhibitor Oseltamivir Is Effective Against A/Anhui/1/2013 (H7N9) Influenza Virus in a Mouse Model of Acute Respiratory Distress Syndrome

    PubMed Central

    Baranovich, Tatiana; Burnham, Andrew J.; Marathe, Bindumadhav M.; Armstrong, Jianling; Guan, Yi; Shu, Yuelong; Peiris, Joseph Malik Sriyal; Webby, Richard J.; Webster, Robert G.; Govorkova, Elena A.

    2014-01-01

    Background. High mortality and uncertainty about the effectiveness of neuraminidase inhibitors (NAIs) in humans infected with influenza A(H7N9) viruses are public health concerns. Methods. Susceptibility of N9 viruses to NAIs was determined in a fluorescence-based assay. The NAI oseltamivir (5, 20, or 80 mg/kg/day) was administered to BALB/c mice twice daily starting 24, 48, or 72 hours after A/Anhui/1/2013 (H7N9) virus challenge. Results. All 12 avian N9 and 3 human H7N9 influenza viruses tested were susceptible to NAIs. Without prior adaptation, A/Anhui/1/2013 (H7N9) caused lethal infection in mice that was restricted to the respiratory tract and resulted in pulmonary edema and acute lung injury with hyaline membrane formation, leading to decreased oxygenation, all characteristics of human acute respiratory distress syndrome. Oseltamivir at 20 and 80 mg/kg protected 80% and 88% of mice when initiated after 24 hours, and the efficacy decreased to 70% and 60%, respectively, when treatment was delayed by 48 hours. Emergence of oseltamivir-resistant variants was not detected. Conclusions. H7N9 viruses are comparable to currently circulating influenza A viruses in susceptibility to NAIs. Based on these animal studies, early treatment is associated with improved outcomes. PMID:24133191

  7. Biochemical and Physiological Improvement in a Mouse Model of Smith-Lemli-Opitz Syndrome (SLOS) Following Gene Transfer with AAV Vectors.

    PubMed

    Ying, Lee; Matabosch, Xavier; Serra, Montserrat; Watson, Berna; Shackleton, Cedric; Watson, Gordon

    2014-01-01

    Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis resulting from a defect in 7-dehydrocholesterol reductase (DHCR7), the enzyme that produces cholesterol from its immediate precursor 7-dehydrocholesterol. Current therapy employing dietary cholesterol is inadequate. As SLOS is caused by a defect in a single gene, restoring enzyme functionality through gene therapy may be a direct approach for treating this debilitating disorder. In the present study, we first packaged a human DHCR7 construct into adeno-associated virus (AAV) vectors having either type-2 (AAV2) or type-8 (AAV2/8) capsid, and administered treatment to juvenile mice. While a positive response (assessed by increases in serum and liver cholesterol) was seen in both groups, the improvement was greater in the AAV2/8-DHCR7 treated mice. Newborn mice were then treated with AAV2/8-DHCR7 and these mice, compared to mice treated as juveniles, showed higher DHCR7 mRNA expression in liver and a greater improvement in serum and liver cholesterol levels. Systemic treatment did not affect brain cholesterol in any of the experimental groups. Both juvenile and newborn treatments with AAV2/8-DHCR7 resulted in increased rates of weight gain indicating that gene transfer had a positive physiological effect.

  8. Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome

    PubMed Central

    Wood, Lydia; Shepherd, Gordon M. G.

    2010-01-01

    Motor and cognitive functions are severely impaired in Rett syndrome (RTT). Here, we examined local synaptic circuits of layer 2/3 (L2/3) pyramidal neurons in motor-frontal cortex of male hemizygous MeCP2-null mice at 3–4 weeks of age. We mapped local excitatory input to L2/3 neurons using glutamate uncaging and laser scanning photostimulation, and compared synaptic input maps recorded from MeCP2-null and wild type (WT) mice. Local excitatory input was significantly reduced in the mutants. The strongest phenotype was observed for lateral (horizontal, intralaminar) inputs, that is, L2/3→2/3 inputs, which showed a large reduction in MeCP2−/y animals. Neither the amount of local inhibitory input to these L2/3 pyramidal neurons nor their intrinsic electrophysiological properties differed by genotype. Our findings provide further evidence that excitatory networks are selectively reduced in RTT. We discuss our findings in the context of recently published parallel studies using selective MeCP2 knockdown in individual L2/3 neurons. PMID:20138994

  9. Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B.

    PubMed

    Willing, Alison E; Garbuzova-Davis, Svitlana N; Zayko, Olga; Derasari, Hiranya M; Rawls, Ashley E; James, Chris R; Mervis, Ron F; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Sanberg, Paul R

    2014-01-01

    Sanfilippo syndrome type III B (MPS III B) is an inherited disorder characterized by a deficiency of α-N-acetylglucosaminidase (Naglu) enzyme leading to accumulation of heparan sulfate in lysosomes and severe neurological deficits. We have previously shown that a single administration of human umbilical cord mononuclear cells (hUCB MNCs) into Naglu knockout mice decreased behavioral abnormalities and tissue pathology. In this study, we tested whether repeated doses of hUCB MNCs would be more beneficial than a single dose of cells. Naglu mice at 3 months of age were randomly assigned to either a Media-only group or one of three hUCB MNC treatment groups--single low dose (3 × 10(6) cells), single high dose (1.8 × 10(7) cells), or multiple doses (3 × 10(6) cells monthly for 6 months) delivered intravenously; cyclosporine was injected intraperitoneally to immune suppress the mice for the duration of the study. An additional control group of wild-type mice was also used. We measured anxiety in an open field test and cognition in an active avoidance test prior to treatment and then at monthly intervals for 6 months. hUCB MNCs restored normal anxiety-like behavior in these mice (p < 0.001). The repeated cell administrations also restored hippocampal cytoarchitecture, protected the dendritic tree, decreased GM3 ganglioside accumulation, and decreased microglial activation, particularly in the hippocampus and cortex. These data suggest that the neuroprotective effect of hUCB MNCs can be enhanced by repeated cell administrations. PMID:25565636

  10. Retinoic acid-induced caudal regression syndrome in the mouse fetus.

    PubMed

    Padmanabhan, R

    1998-01-01

    Caudal regression syndrome (CRS) comprises developmental anomalies of the caudal vertebrae, neural tube, urogenital and digestive organs, and hind limbs, the precursors of all of which are derived from the caudal eminence. Although the syndrome is well recognized, the etiology and pathogenetic mechanisms are poorly understood. Genetic and experimental models may provide some important clues to the early events that precede the dysmorphogenesis in CRS. The objectives of this study were to determine the susceptible stages for induction of CRS and to ascertain the early events that precede the development of this syndrome in a mouse model. Single oral doses of 100, 150, or 200 mg/kg retinoic acid (RA) were administered to TO mice on one of Gestation Days (GD) 8 to 12, and fetuses were observed on GD 18. All doses administered on GD 8 or 9 resulted in CRS in a large number of survivors. Agenesis of the tail, caudal vertebral defects, spina bifida occulta/aperta, imperforate anus, rectovesicle or rectourethral fistula, renal malformations, cryptorchidism, gastroschisis, and limb malformations, including the classical mermaid syndrome (sirenomelia), were characteristic features of this animal model. Several craniofacial malformations accompanied CRS in the GD 8 treatment group. Chronologic examination of treated embryos at early stages revealed pronounced cell death in the caudal median axis, hindgut, and neural tube and consequently, failure of development of the tail bud in the high-dose groups. In the 100 mg/kg RA group, patches of hemorrhage occurred initially that subsequently coalesced into large hematomas and the tail progressively regressed. Histologic examination revealed the onset and progression of hemorrhage, edema, and cell death in these embryos. Transillumination and histologic preparations also revealed dilation of the caudal neural tube in the prospective CRS embryos. Thus, a combination of cell death, vascular disruption, and tissue deficiency appears

  11. Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel

    PubMed Central

    Lana-Elola, Eva; Watson-Scales, Sheona; Slender, Amy; Gibbins, Dorota; Martineau, Alexandrine; Douglas, Charlotte; Mohun, Timothy; Fisher, Elizabeth MC; Tybulewicz, Victor LJ

    2016-01-01

    Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, two of these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion. DOI: http://dx.doi.org/10.7554/eLife.11614.001 PMID:26765563

  12. Transgenic mouse model of cutaneous adnexal tumors

    PubMed Central

    Kito, Yusuke; Saigo, Chiemi; Atsushi, Kurabayashi; Mutsuo, Furihata; Tamotsu, Takeuchi

    2014-01-01

    TMEM207 was first characterized as being an important molecule for the invasion activity of gastric signet-ring cell carcinoma cells. In order to unravel the pathological properties of TMEM207, we generated several transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), in which murine TMEM207 was ectopically expressed under a truncated (by ~200 bp) proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). Unexpectedly, a C57BL/6-Tg (ITF-TMEM207) mouse line exhibited a high incidence of spontaneous intradermal tumors with histopathological features that resembled those of various human cutaneous adnexal tumors. These tumors were found in ~14% female and 13% of male 6- to 12-month-old mice. TMEM207 immunoreactivity was found in hair follicle bulge cells in non-tumorous skin, as well as in cutaneous adnexal tumors of the transgenic mouse. The ITF-TMEM207 construct in this line appeared to be inserted to a major satellite repeat sequence at chromosome 2, in which no definite coding molecule was found. In addition, we also observed cutaneous adnexal tumors in three other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. We believe that the C57BL/6-Tg (ITF-TMEM207) mouse might be a useful model to understand human cutaneous adnexal tumors. PMID:25305140

  13. Engineering a new mouse model for vitiligo.

    PubMed

    Manga, Prashiela; Orlow, Seth J

    2012-07-01

    Although the precise mechanisms that trigger vitiligo remain elusive, autoimmune responses mediate its progression. The development of therapies has been impeded by a paucity of animal models, since mice lack interfollicular melanocytes, the primary targets in vitiligo. In this issue, Harris et al. describe a mouse model in which interfollicular melanocytes are retained by Kit ligand overexpression and an immune response is initiated by transplanting melanocyte-targeting CD8+ T cells.

  14. Mouse Models of Neurofibromatosis 1 and 21

    PubMed Central

    Gutmann, David H; Giovannini, Marco

    2002-01-01

    Abstract The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors. PMID:12082543

  15. ALIGNING MOUSE MODELS OF ASTHMA TO HUMAN ENDOTYPES OF DISEASE

    PubMed Central

    Martin, Rebecca A; Hodgkins, Samantha R; Dixon, Anne E; Poynter, Matthew E

    2014-01-01

    Substantial gains in understanding the pathophysiologic mechanisms underlying asthma have been made using preclinical mouse models. However, because asthma is a complex, heterogeneous syndrome that is rarely due to a single allergen and that often presents in the absence of atopy, few of the promising therapeutics that demonstrated effectiveness in mouse models have translated into new treatments for patients. This has resulted in an urgent need to characterize Th2-low, noneosinophilic subsets of asthma, to study models that are resistant to conventional treatments such as corticosteroids, and to develop therapies targeting patients with severe disease. Classifying asthma based on underlying pathophysiologic mechanisms, known as endotyping, offers a stratified approach for the development of new therapies for asthma. In preclinical research, new models of asthma are being utilized that more closely resemble the clinical features of different asthma endotypes, including the presence of IL-17 and a Th17 response, a biomarker of severe disease. These models utilize more physiologically relevant sensitizing agents, exacerbating factors, and allergens, as well as incorporate time points that better reflect the natural history and chronicity of clinical asthma. Importantly, some models better represent nonclassical asthma endotypes that facilitate the study of non-Th2 driven pathology and resemble the complex nature of clinical asthma, including corticosteroid resistance. Placing mouse asthma models into the context of human asthma endotypes will afford a more relevant approach to the understanding of pathophysiological mechanisms of disease that will afford the development of new therapies for those asthmatics that remain difficult to treat. PMID:24811131

  16. A novel mouse model of creatine transporter deficiency

    PubMed Central

    Baroncelli, Laura; Alessandrì, Maria Grazia; Tola, Jonida; Putignano, Elena; Migliore, Martina; Amendola, Elena; Gross, Cornelius; Leuzzi, Vincenzo; Cioni, Giovanni; Pizzorusso, Tommaso

    2014-01-01

    Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT −/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease. PMID:25485098

  17. Mouse kidney transplantation: models of allograft rejection.

    PubMed

    Tse, George H; Hesketh, Emily E; Clay, Michael; Borthwick, Gary; Hughes, Jeremy; Marson, Lorna P

    2014-01-01

    Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

  18. Mouse Kidney Transplantation: Models of Allograft Rejection

    PubMed Central

    Clay, Michael; Borthwick, Gary; Hughes, Jeremy; Marson, Lorna P.

    2014-01-01

    Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique. PMID:25350513

  19. Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjögren's Syndrome: the influence of sex hormones and genetic background.

    PubMed

    Czerwinski, Stefanie; Mostafa, Safinaz; Rowan, Vanessa Seamon; Azzarolo, Ana Maria

    2014-11-01

    Sjögren's Syndrome (SS) is a chronic, inflammatory autoimmune disease characterized by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Although the symptoms of this syndrome are well characterized, patients are not diagnosed until 5-10 years into disease progression; furthermore, the early series of events leading to the initiation of SS are not well understood. In order to better understand the early events of the disease, we have been using ovariectomized (OVX) NOD.B10.H2(b) mice as a genetically predisposed model of SS. Previously, we have shown that removal of ovarian hormones through ovariectomy accelerated the symptoms of this disease, and in early events of SS in the lacrimal glands, lymphocytic infiltration preceded acinar cell apoptosis. To further elucidate the earlier events of this disease in the SS animal model, we investigated the expression and concentration of pro-inflammatory cytokines in the lacrimal glands as well as the presence of autoantibodies in both lacrimal glands and serum. Six weeks old NOD.B10.H2(b) and C57BL/10 control mice were either sham-operated, OVX, OVX and treated with 17β-estradiol (E2), or OVX and treated with dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21, and 30 days after surgery and analyzed for cytokines IL-1β, TNF-α, IFN-γ, IL-10, and IL-4 gene expression by using quantitative RT-PCR and for cytokine levels using ELISA. Furthermore, anti-Ro/SSA and anti-La/SSB autoantibodies were measured in the serum and lacrimal glands supernatants using ELISA. The results of this study showed that OVX caused a significant increase in the expression and levels of the cytokines IL-1β, TNF-α, and IL-4 in the lacrimal glands of the NOD.B10.H2(b) mice starting at 3 days after OVX, while a significant increase of IL-10 gene expression and levels was observed only at later experimental time points. A small but significant increase in the

  20. Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjögren’s Syndrome: the influence of sex hormones and genetic background

    PubMed Central

    Czerwinski, Stefanie; Mostafa, Safinaz; Rowan, Vanessa Seamon; Azzarolo, Ana Maria

    2014-01-01

    Sjögren’s Syndrome (SS) is a chronic, inflammatory autoimmune disease characterized by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Although the symptoms of this syndrome are well characterized, patients are not diagnosed until 5–10 years into disease progression; furthermore, the early series of events leading to the initiation of SS are not well understood. In order to better understand the early events of the disease, we have been using ovariectomized (OVX) NOD.B10.H2b mice as a genetically predisposed model of SS. Previously, we have shown that removal of ovarian hormones through ovariectomy accelerated the symptoms of this disease, and in early events of SS in the lacrimal glands, lymphocytic infiltration preceded acinar cell apoptosis. To further elucidate the earlier events of this disease in the SS animal model, we investigated the expression and concentration of pro-inflammatory cytokines in the lacrimal glands as well as the presence of autoantibodies in both lacrimal glands and serum. Six weeks old NOD.B10.H2b and C57BL/10 control mice were either sham-operated, OVX, OVX and treated with 17β-estradiol (E2), or OVX and treated with dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21, and 30 days after surgery and analyzed for cytokines IL-1β, TNF-α, IFN-γ, IL-10, and IL-4 gene expression by using quantitative RT-PCR and for cytokine levels using ELISA. Furthermore, anti-Ro/SSA and anti-La/SSB autoantibodies were measured in the serum and lacrimal glands supernatants using ELISA. The results of this study showed that OVX caused a significant increase in the expression and levels of the cytokines IL-1β, TNF-α, and IL-4 in the lacrimal glands of the NOD.B10.H2b mice starting at 3 days after OVX, while a significant increase of IL-10 gene expression and levels was observed only at later experimental time points. A small but significant increase in the

  1. Chromosomal protein HMG-14 gene maps to the Down syndrome region of human chromosome 21 and is overexpressed in mouse trisomy 16

    SciTech Connect

    Pash, J.; Popescu, N.; Matocha, M.; Rapoport, S.; Bustin, M. )

    1990-05-01

    The gene for human high-mobility-group (HMG) chromosomal protein HMG-14 is located in region 21q22.3, a region associated with the pathogenesis of Down syndrome, one of the most prevalent human birth defects. The expression of this gene is analyzed in mouse embryos that are trisomic in chromosome 16 and are considered to be an animal model for Down syndrome. RNA blot-hybridization analysis and detailed analysis of HMG-14 protein levels indicate that mouse trisomy 16 embryos have approximately 1.5 times more HMG-14 mRNA and protein than their normal littermates, suggesting a direct gene dosage effect. The HMG-14 gene may be an additional marker for the Down syndrome. Chromosomal protein HMG-14 is a nucleosomal binding protein that may confer distinct properties to the chromatin structure of transcriptionally active genes and therefore may be a contributing factor in the etiology of the syndrome.

  2. On Models and Mickey Mouse

    ERIC Educational Resources Information Center

    Petherbridge, Deanna

    2005-01-01

    The re-issue of a nineteenth-century French "Drawing Course" is the occasion for an examination of issues of "models of good practice" in current art teaching. These are listed as an expanded set of student-centred pedagogical paradigms, which embrace the forceful popular imagery of electronic games and comic strips. The formalist adaptations of…

  3. Action of Lambert-Eaton myasthenic syndrome IgG at mouse motor nerve terminals.

    PubMed

    Prior, C; Lang, B; Wray, D; Newsom-Davis, J

    1985-06-01

    We have studied the electrophysiological effects of IgG obtained from four patients with Lambert-Eaton myasthenic syndrome (LEMS) (two with small cell carcinoma), using the mouse passive transfer model. Mice received LEMS or control IgG or plasma, 10 to 60 mg daily. Microelectrode intracellular recordings were made from diaphragm muscle. LEMS IgG and plasma decreased end-plate potential quantal content similarly, confirming IgG as the active factor. LEMS IgG was equally effective in C5-deficient mice, indicating that late complement components are not required. The time course of decline and recovery of quantal content closely followed that of the human IgG in the mouse serum, with time to half-maximal effect of about 1.5 days in each case. Binding/dissociation of IgG or down/up regulation of the antigenic determinants, possibly Ca2+ channels, has a half-life of between 2 and 36 hours. The results confirm our concept that IgG antibody to nerve terminal determinants underlies the disorder of transmitter release in LEMS.

  4. Mouse models of human disease

    PubMed Central

    Perlman, Robert L.

    2016-01-01

    The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans. PMID:27121451

  5. Digenic Inheritance in Cystinuria Mouse Model

    PubMed Central

    Espino, Meritxell; Font-Llitjós, Mariona; Vilches, Clara; Salido, Eduardo; Prat, Esther; López de Heredia, Miguel; Palacín, Manuel; Nunes, Virginia

    2015-01-01

    Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/-) present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients. PMID:26359869

  6. Genetically Engineered Mouse Models of Pituitary Tumors

    PubMed Central

    Cano, David A.; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso

    2014-01-01

    Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary-tumor formation remain poorly understood, particularly in sporadic adenomas, thus, making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, we review various GEMMs of pituitary tumors, highlighting their contributions and limitations, and discuss opportunities for research in the field. PMID:25136513

  7. Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

    PubMed

    Begley, Dale A; Sundberg, John P; Krupke, Debra M; Neuhauser, Steven B; Bult, Carol J; Eppig, Janan T; Morse, Herbert C; Ward, Jerrold M

    2015-12-01

    Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. PMID:26302176

  8. Experimental photoallergic contact dermatitis: a mouse model

    SciTech Connect

    Maguire, H.C. Jr.; Kaidbey, K.

    1982-09-01

    We have induced photoallergic contact dermatitis in mice to 3,3',4',5 tetrachlorosalicylanilide (TCSA), chlorpromazine and 6-methylcoumarin. These compounds are known to produce photoallergic contact dermatitis in humans. The photoallergic contact dermatitis reaction in the mouse is immunologically specific viz. mice photosensitized to TCSA react, by photochallenge, to that compound and not to chlorpromazine, and conversely. The reaction requires UVA at both sensitization and challenge. It appears to be T-cell mediated in that it can be passively transferred to syngeneic mice by lymph node cells from actively sensitized mice, the histology of the reactions resembles that of classic allergic contact dermatitis in mice, challenge reactions are seen at 24 but not at 4 hr, and photoallergic contact dermatitis can be induced in B-cell deficient mice. The availability of a mouse model for the study of photo-ACD will facilitate the identification of pertinent control mechanisms and may aid in the management of the disease. It is likely that a bioassay for photoallergens of humans can be based on this mouse model.

  9. Unstressing intemperate models: how cold stress undermines mouse modeling.

    PubMed

    Karp, Christopher L

    2012-06-01

    Mus musculus enjoys pride of place at the center of contemporary biomedical research. Despite being the current model system of choice for in vivo mechanistic analysis, mice have clear limitations. The literature is littered with examples of therapeutic approaches that showed promise in mouse models but failed in clinical trials. More generally, mice often provide poor mimics of the human diseases being modeled. Available data suggest that the cold stress to which laboratory mice are ubiquitously subjected profoundly affects mouse physiology in ways that impair the modeling of human homeostasis and disease. Experimental attention to this key, albeit largely ignored, environmental variable is likely to have a broad transformative effect on biomedical research.

  10. A vertical mouse and ergonomic mouse pads alter wrist position but do not reduce carpal tunnel pressure in patients with carpal tunnel syndrome.

    PubMed

    Schmid, Annina B; Kubler, Paul A; Johnston, Venerina; Coppieters, Michel W

    2015-03-01

    Non-neutral wrist positions and external pressure leading to increased carpal tunnel pressure during computer use have been associated with a heightened risk of carpal tunnel syndrome (CTS). This study investigated whether commonly used ergonomic devices reduce carpal tunnel pressure in patients with CTS. Carpal tunnel pressure was measured in twenty-one patients with CTS before, during and after a computer mouse task using a standard mouse, a vertical mouse, a gel mouse pad and a gliding palm support. Carpal tunnel pressure increased while operating a computer mouse. Although the vertical mouse significantly reduced ulnar deviation and the gel mouse pad and gliding palm support decreased wrist extension, none of the ergonomic devices reduced carpal tunnel pressure. The findings of this study do therefore not endorse a strong recommendation for or against any of the ergonomic devices commonly recommended for patients with CTS. Selection of ergonomic devices remains dependent on personal preference. PMID:25479984

  11. A vertical mouse and ergonomic mouse pads alter wrist position but do not reduce carpal tunnel pressure in patients with carpal tunnel syndrome.

    PubMed

    Schmid, Annina B; Kubler, Paul A; Johnston, Venerina; Coppieters, Michel W

    2015-03-01

    Non-neutral wrist positions and external pressure leading to increased carpal tunnel pressure during computer use have been associated with a heightened risk of carpal tunnel syndrome (CTS). This study investigated whether commonly used ergonomic devices reduce carpal tunnel pressure in patients with CTS. Carpal tunnel pressure was measured in twenty-one patients with CTS before, during and after a computer mouse task using a standard mouse, a vertical mouse, a gel mouse pad and a gliding palm support. Carpal tunnel pressure increased while operating a computer mouse. Although the vertical mouse significantly reduced ulnar deviation and the gel mouse pad and gliding palm support decreased wrist extension, none of the ergonomic devices reduced carpal tunnel pressure. The findings of this study do therefore not endorse a strong recommendation for or against any of the ergonomic devices commonly recommended for patients with CTS. Selection of ergonomic devices remains dependent on personal preference.

  12. Mouse models of intestinal inflammation and cancer.

    PubMed

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  13. Mouse Model of Coxiella burnetii Aerosolization.

    PubMed

    Melenotte, Cléa; Lepidi, Hubert; Nappez, Claude; Bechah, Yassina; Audoly, Gilles; Terras, Jérôme; Raoult, Didier; Brégeon, Fabienne

    2016-07-01

    Coxiella burnetii is mainly transmitted by aerosols and is responsible for multiple-organ lesions. Animal models have shown C. burnetii pathogenicity, but long-term outcomes still need to be clarified. We used a whole-body aerosol inhalation exposure system to mimic the natural route of infection in immunocompetent (BALB/c) and severe combined immunodeficient (SCID) mice. After an initial lung inoculum of 10(4) C. burnetii cells/lung, the outcome, serological response, hematological disorders, and deep organ lesions were described up to 3 months postinfection. C. burnetii-specific PCR, anti-C. burnetii immunohistochemistry, and fluorescent in situ hybridization (FISH) targeting C. burnetii-specific 16S rRNA completed the detection of the bacterium in the tissues. In BALB/c mice, a thrombocytopenia and lymphopenia were first observed, prior to evidence of C. burnetii replication. In all SCID mouse organs, DNA copies increased to higher levels over time than in BALB/c ones. Clinical signs of discomfort appeared in SCID mice, so follow-up had to be shortened to 2 months in this group. At this stage, all animals presented bone, cervical, and heart lesions. The presence of C. burnetii could be attested in situ for all organs sampled using immunohistochemistry and FISH. This mouse model described C. burnetii Nine Mile strain spread using aerosolization in a way that corroborates the pathogenicity of Q fever described in humans and completes previously published data in mouse models. C. burnetii infection occurring after aerosolization in mice thus seems to be a useful tool to compare the pathogenicity of different strains of C. burnetii. PMID:27160294

  14. Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome[S

    PubMed Central

    Kiebish, Michael A.; Yang, Kui; Liu, Xinping; Mancuso, David J.; Guan, Shaoping; Zhao, Zhongdan; Sims, Harold F.; Cerqua, Rebekah; Cade, W. Todd; Han, Xianlin; Gross, Richard W.

    2013-01-01

    Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. Recently, an inducible tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs and prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as decreases in Complex III and V activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in tafazzin-deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic, and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease. PMID:23410936

  15. Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq

    PubMed Central

    Hawkins, Nicole A.; Zachwieja, Nicole J.; Miller, Alison R.; Anderson, Lyndsey L.; Kearney, Jennifer A.

    2016-01-01

    A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. SCN1A mutations result in a spectrum of severity ranging from mild febrile seizures to Dravet syndrome, an infant-onset epileptic encephalopathy. Dravet syndrome patients experience multiple seizures types that are often refractory to treatment, developmental delays, and elevated risk for SUDEP. The same sodium channel mutation can produce epilepsy phenotypes of varying clinical severity. This suggests that other factors, including genetic, modify the primary mutation and change disease severity. Mouse models provide a useful tool in studying the genetic basis of epilepsy. The mouse strain background can alter phenotype severity, supporting a contribution of genetic modifiers in epilepsy. The Scn1a+/- mouse model has a strain-dependent epilepsy phenotype. Scn1a+/- mice on the 129S6/SvEvTac (129) strain have a normal phenotype and lifespan, while [129xC57BL/6J]F1-Scn1a+/- mice experience spontaneous seizures, hyperthermia-induced seizures and high rates of premature death. We hypothesize the phenotypic differences are due to strain-specific genetic modifiers that influence expressivity of the Scn1a+/- phenotype. Low resolution mapping of Scn1a+/- identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival. One locus of interest, Dsm1 located on chromosome 5, was fine mapped to a 9 Mb region using interval specific congenics. RNA-Seq was then utilized to identify candidate modifier genes within this narrowed region. Three genes with significant total gene expression differences between 129S6/SvEvTac and [129xC57BL/6J]F1 were identified, including the GABAA receptor subunit, Gabra2. Further analysis of Gabra2 demonstrated allele-specific expression. Pharmological manipulation by clobazam, a common anticonvulsant with preferential affinity for the GABRA2 receptor, revealed

  16. Mouse Genome Database: From sequence to phenotypes and disease models.

    PubMed

    Eppig, Janan T; Richardson, Joel E; Kadin, James A; Smith, Cynthia L; Blake, Judith A; Bult, Carol J

    2015-08-01

    The Mouse Genome Database (MGD, www.informatics.jax.org) is the international scientific database for genetic, genomic, and biological data on the laboratory mouse to support the research requirements of the biomedical community. To accomplish this goal, MGD provides broad data coverage, serves as the authoritative standard for mouse nomenclature for genes, mutants, and strains, and curates and integrates many types of data from literature and electronic sources. Among the key data sets MGD supports are: the complete catalog of mouse genes and genome features, comparative homology data for mouse and vertebrate genes, the authoritative set of Gene Ontology (GO) annotations for mouse gene functions, a comprehensive catalog of mouse mutations and their phenotypes, and a curated compendium of mouse models of human diseases. Here, we describe the data acquisition process, specifics about MGD's key data areas, methods to access and query MGD data, and outreach and user help facilities. PMID:26150326

  17. The first knockin mouse model of episodic ataxia type 2.

    PubMed

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes. PMID:25109669

  18. The first knockin mouse model of episodic ataxia type 2.

    PubMed

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes.

  19. Insights from mouse models into human retinoblastoma

    PubMed Central

    MacPherson, David

    2008-01-01

    Novel murine models of retinoblastoma based on Rb gene deletion in concert with inactivation of Rb family members have recently been developed. These new Rb knockout models of retinoblastoma provide excellent tools for pre-clinical studies and for the exploration of the genetics of tumorigenesis driven by RB inactivation. This review focuses on the developmental consequences of Rb deletion in the retina and the genetic interactions between Rb and the two other members of the pocket protein family, p107 (Rbl1) and p130 (Rbl2). There is increasing appreciation that homozygous RB mutations are insufficient for human retinoblastoma. Identifying and understanding secondary gene alterations that cooperate with RB inactivation in tumorigenesis may be facilitated by mouse models. Recent investigation of the p53 pathway in retinoblastoma, and evidence of spatial topology to early murine retinoblastoma are also discussed in this review. PMID:18489754

  20. Pathophysiology of gene-targeted mouse models for cystic fibrosis.

    PubMed

    Grubb, B R; Boucher, R C

    1999-01-01

    Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193-S214, 1999. - Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models. PMID:9922382

  1. Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

    PubMed Central

    Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

  2. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    PubMed

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models-mainly mouse models-have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  3. Quantitative bioluminescence imaging of mouse tumor models.

    PubMed

    Tseng, Jen-Chieh; Kung, Andrew L

    2015-01-05

    Bioluminescence imaging (BLI) has become an essential technique for preclinical evaluation of anticancer therapeutics and provides sensitive and quantitative measurements of tumor burden in experimental cancer models. For light generation, a vector encoding firefly luciferase is introduced into human cancer cells that are grown as tumor xenografts in immunocompromised hosts, and the enzyme substrate luciferin is injected into the host. Alternatively, the reporter gene can be expressed in genetically engineered mouse models to determine the onset and progression of disease. In addition to expression of an ectopic luciferase enzyme, bioluminescence requires oxygen and ATP, thus only viable luciferase-expressing cells or tissues are capable of producing bioluminescence signals. Here, we summarize a BLI protocol that takes advantage of advances in hardware, especially the cooled charge-coupled device camera, to enable detection of bioluminescence in living animals with high sensitivity and a large dynamic range.

  4. Mouse intragastric infusion (iG) model

    PubMed Central

    Ueno, Akiko; Lazaro, Raul; Wang, Ping-Yen; Higashiyama, Reiichi; Machida, Keigo; Tsukamoto, Hidekazu

    2014-01-01

    Direct intragastric delivery of a diet, nutrient or test substance can be achieved in rodents (mice and rats) on a long-term (2–3 months) basis using a chronically implanted gastrostomy catheter and a flow-through swivel system. This rodent intragastric infusion (iG) model has broad applications in research on food intake, gastrointestinal (GI) physiology, GI neuroendocrinology, drug metabolism and toxicity, obesity and liver disease. It achieves maximal control over the rate and pattern of delivery and it can be combined with normal ad libitum feeding of solid diet if so desired. It may be adopted to achieve infusion at other sites of the GI system to test the role of a bypassed GI segment in neuroendocrine physiology, and its use in genetic mouse models facilitates the genetic analysis of a central question under investigation. PMID:22461066

  5. Molecular characterization of hepatocarcinogenesis using mouse models

    PubMed Central

    Teoh, Wei Wei; Xie, Min; Vijayaraghavan, Aadhitthya; Yaligar, Jadegoud; Tong, Wei Min; Goh, Liang Kee; Sabapathy, Kanaga

    2015-01-01

    ABSTRACT Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed until the late stages, when treatment options become limited. Thus, there is a crucial need to identify biomarkers for early detection of developing HCC, as well as molecular pathways that would be amenable to therapeutic intervention. Although analysis of human HCC tissues and serum components may serve these purposes, inability of early detection also precludes possibilities of identification of biomarkers or pathways that are sequentially perturbed at earlier phases of disease progression. We have therefore explored the option of utilizing mouse models to understand in a systematic and longitudinal manner the molecular pathways that are progressively deregulated by various etiological factors in contributing to HCC formation, and we report the initial findings in characterizing their validity. Hepatitis B surface antigen transgenic mice, which had been exposed to aflatoxin B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a gender bias towards males for HCC predisposition. Time-based aflatoxin B1 treatment also demonstrated the requirement of non-quiescent liver for effective transformation. Tumors from these models with various etiologies resemble human HCCs histologically and at the molecular level. Extensive molecular characterization revealed the presence of an 11-gene HCC-expression signature that was able to discern transformed human hepatocytes from primary cells, regardless of etiology, and from other cancer types. Moreover, distinct molecular pathways appear to be deregulated by various etiological agents en route to formation of HCCs, in which common pathways converge, highlighting the existence of etiology-specific as well as common HCC-specific molecular perturbations. This study therefore highlights the utility of these mouse models, which provide a rich resource for the

  6. Wnt signaling and gastrointestinal tumorigenesis in mouse models.

    PubMed

    Taketo, M M

    2006-12-01

    The canonical Wnt signaling plays important roles in embryonic development and tumorigenesis. For the latter, induced mutations in mice have greatly contributed to our understanding of the molecular mechanisms of cancer initiation and progression. Here, I will review recent reports on gastrointestinal cancer model mice, with an emphasis on the roles of the Wnt signal pathway. They include: mouse models for familial adenomatous polyposis; modifying factors that affect mouse intestinal polyposis, including the genes that help cancer progression; Wnt target genes that affect mouse intestinal polyposis; and a mouse model of gastric cancer that mimics Helicobacter pyroli infection. PMID:17143296

  7. Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse

    PubMed Central

    Solcà, Curzio; Pandit, Bhaswati; Yu, Hongwei; Tint, G. Stephen; Patel, Shailendra B.

    2007-01-01

    The Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic defect in cholesterol biosynthesis; mutations in the enzyme 3ß-hydroxysterol Δ7 reductase (Dhcr7) lead to a failure of cholesterol (and desmosterol) synthesis, with an accumulation of precursor sterols, such as 7-dehydrocholesterol. Extensive genotype–phenotype analyses have indicated that there is considerable variation in the severity of the disease, much of which is not explained by defects in the Dhcr7 gene alone. Factors ranging from variations in maternal–fetal cholesterol transfer during pregnancy, to other genetic factors have been proposed to account for this variability. Variations at the APOE locus affect plasma cholesterol levels in humans and this polymorphic gene has been found to be associated with cardiovascular as well as neurological disorders. This locus has recently been implicated in accounting for some of the variations in SLOS. To address whether maternal hypercholesterolemia can affect fetal outcome, we tested the ability of maternal hypercholesterolemia to rescue the neonatal lethality in a mouse model of SLOS. Maternal hypercholesterolemia, induced by ApoE or Ldl-r deficiency not only failed to ameliorate the postnatal lethality, it increased the prenatal mortality of Dhcr7 deficient pups. Thus the murine data suggest that maternal loss of ApoE or Ldl-r function further exacerbates the neonatal lethality, suggesting they may play a role in maternal transfer of cholesterol to the embryo. PMID:17197219

  8. Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome

    PubMed Central

    McIntyre, Rebecca E.; Lakshminarasimhan Chavali, Pavithra; Forment, Josep V.; Fu, Beiyuan; Del Castillo Velasco-Herrera, Martin; Edwards, Andrew; van der Weyden, Louise; Yang, Fengtang; Ramirez-Solis, Ramiro; Estabel, Jeanne; Gallagher, Ferdia A.; Logan, Darren W.; Arends, Mark J.; Tsang, Stephen H.; Mahajan, Vinit B.; Scudamore, Cheryl L.; White, Jacqueline K.; Jackson, Stephen P.; Gergely, Fanni; Adams, David J.

    2012-01-01

    Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpjtm/tm) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpjtm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpjtm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome. PMID:23166506

  9. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    PubMed Central

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

  10. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

    PubMed

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn; Holmberg, Dan

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  11. Three mouse models of human thalassemia.

    PubMed Central

    Martinell, J; Whitney, J B; Popp, R A; Russell, L B; Anderson, W F

    1981-01-01

    Three types of mice with globin gene mutations, called 352HB, 27HB, and Hbath-J, appear to be true animal models of human thalassemia. Expression of the alpha-globin genes in three stocks of mice, each one heterozygous for one of the alpha-globin mutations, was examined at the polypeptide, RNA, and DNA levels. alpha-Globin polypeptide chains, relative to beta-globin chains in heterozygous thalassemic mice, are present at approximately 80% of normal. The ratios of alpha-globin to beta-globin RNA sequences are also 75-80% of normal, exactly reflecting the alpha-globin to beta-globin chain ratios. In the case of mutant 352HB, at least one alpha-globin gene is deleted. Thalassemic mouse erythroid cells appear to compensate partially for the loss of half of their alpha-globin genes. Images PMID:6946454

  12. Memory B cells in mouse models.

    PubMed

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, I-L

    2013-08-01

    One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. PMID:23679222

  13. A mouse model for testing remyelinating therapies.

    PubMed

    Bai, C Brian; Sun, Sunny; Roholt, Andrew; Benson, Emily; Edberg, Dale; Medicetty, Satish; Dutta, Ranjan; Kidd, Grahame; Macklin, Wendy B; Trapp, Bruce

    2016-09-01

    Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothyronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination. PMID:27384502

  14. Preclinical fluorescent mouse models of pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  15. A Mouse Model of Zika Virus Pathogenesis.

    PubMed

    Lazear, Helen M; Govero, Jennifer; Smith, Amber M; Platt, Derek J; Fernandez, Estefania; Miner, Jonathan J; Diamond, Michael S

    2016-05-11

    The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis.

  16. Mouse models for BRAF-induced cancers.

    PubMed

    Pritchard, C; Carragher, L; Aldridge, V; Giblett, S; Jin, H; Foster, C; Andreadi, C; Kamata, T

    2007-11-01

    Oncogenic mutations in the BRAF gene are detected in approximately 7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine-->glutamate mutation at residue 600 ((V600E)BRAF). In cells cultured in vitro, (V600E)BRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that (V600E)BRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

  17. Mouse models of p53 functions.

    PubMed

    Lozano, Guillermina

    2010-04-01

    Studies in mice have yielded invaluable insight into our understanding of the p53 pathway. Mouse models with activated p53, no p53, and mutant p53 have queried the role of p53 in development and tumorigenesis. In these models, p53 is activated and stabilized via redundant posttranslational modifications. On activation, p53 initiates two major responses: inhibition of proliferation (via cell-cycle arrest, quiescence, senescence, and differentiation) and induction of apoptosis. Importantly, these responses are cell-type and tumor-type-specific. The analysis of mutant p53 alleles has established a gain-of-function role for p53 mutants in metastasis. The development of additional models that can precisely time the oncogenic events in single cells will provide further insight into the evolution of tumors, the importance of the stroma, and the cooperating events that lead to disruption of the p53 pathway. Ultimately, these models should serve to study the effects of novel drugs on tumor response as well as normal homeostasis.

  18. Generation of transgenic mouse model using PTTG as an oncogene.

    PubMed

    Kakar, Sham S; Kakar, Cohin

    2015-01-01

    The close physiological similarity between the mouse and human has provided tools to understanding the biological function of particular genes in vivo by introduction or deletion of a gene of interest. Using a mouse as a model has provided a wealth of resources, knowledge, and technology, helping scientists to understand the biological functions, translocation, trafficking, and interaction of a candidate gene with other intracellular molecules, transcriptional regulation, posttranslational modification, and discovery of novel signaling pathways for a particular gene. Most importantly, the generation of the mouse model for a specific human disease has provided a powerful tool to understand the etiology of a disease and discovery of novel therapeutics. This chapter describes in detail the step-by-step generation of the transgenic mouse model, which can be helpful in guiding new investigators in developing successful models. For practical purposes, we will describe the generation of a mouse model using pituitary tumor transforming gene (PTTG) as the candidate gene of interest. PMID:25636481

  19. Mouse model for sublethal Leptospira interrogans infection.

    PubMed

    Richer, Luciana; Potula, Hari-Hara; Melo, Rita; Vieira, Ana; Gomes-Solecki, Maria

    2015-12-01

    Although Leptospira can infect a wide range of mammalian species, most studies have been conducted in golden Syrian hamsters, a species particularly sensitive to acute disease. Chronic disease has been well characterized in the rat, one of the natural reservoir hosts. Studies in another asymptomatic reservoir host, the mouse, have occasionally been done and have limited infection to mice younger than 6 weeks of age. We analyzed the outcome of sublethal infection of C3H/HeJ mice older than age 10 weeks with Leptospira interrogans serovar Copenhageni. Infection led to bloodstream dissemination of Leptospira, which was followed by urinary shedding, body weight loss, hypothermia, and colonization of the kidney by live spirochetes 2 weeks after infection. In addition, Leptospira dissemination triggered inflammation in the kidney but not in the liver or lung, as determined by increased levels of mRNA transcripts for the keratinocyte-derived chemokine, RANTES, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, interleukin-6, and gamma interferon in kidney tissue. The acquired humoral response to Leptospira infection led to the production of IgG mainly of the IgG1 subtype. Flow cytometric analysis of splenocytes from infected mice revealed that cellular expansion was primarily due to an increase in the levels of CD4(+) and double-negative T cells (not CD8(+) cells) and that CD4(+) T cells acquired a CD44(high) CD62L(low) effector phenotype not accompanied by increases in memory T cells. A mouse model for sublethal Leptospira infection allows understanding of the bacterial and host factors that lead to immune evasion, which can result in acute or chronic disease or resistance to infection (protection).

  20. Mouse model for sublethal Leptospira interrogans infection.

    PubMed

    Richer, Luciana; Potula, Hari-Hara; Melo, Rita; Vieira, Ana; Gomes-Solecki, Maria

    2015-12-01

    Although Leptospira can infect a wide range of mammalian species, most studies have been conducted in golden Syrian hamsters, a species particularly sensitive to acute disease. Chronic disease has been well characterized in the rat, one of the natural reservoir hosts. Studies in another asymptomatic reservoir host, the mouse, have occasionally been done and have limited infection to mice younger than 6 weeks of age. We analyzed the outcome of sublethal infection of C3H/HeJ mice older than age 10 weeks with Leptospira interrogans serovar Copenhageni. Infection led to bloodstream dissemination of Leptospira, which was followed by urinary shedding, body weight loss, hypothermia, and colonization of the kidney by live spirochetes 2 weeks after infection. In addition, Leptospira dissemination triggered inflammation in the kidney but not in the liver or lung, as determined by increased levels of mRNA transcripts for the keratinocyte-derived chemokine, RANTES, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, interleukin-6, and gamma interferon in kidney tissue. The acquired humoral response to Leptospira infection led to the production of IgG mainly of the IgG1 subtype. Flow cytometric analysis of splenocytes from infected mice revealed that cellular expansion was primarily due to an increase in the levels of CD4(+) and double-negative T cells (not CD8(+) cells) and that CD4(+) T cells acquired a CD44(high) CD62L(low) effector phenotype not accompanied by increases in memory T cells. A mouse model for sublethal Leptospira infection allows understanding of the bacterial and host factors that lead to immune evasion, which can result in acute or chronic disease or resistance to infection (protection). PMID:26416909

  1. Transgenic Mouse Model of Chronic Beryllium Disease

    SciTech Connect

    Gordon, Terry

    2009-05-26

    Animal models provide powerful tools for dissecting dose-response relationships and pathogenic mechanisms and for testing new treatment paradigms. Mechanistic research on beryllium exposure-disease relationships is severely limited by a general inability to develop a sufficient chronic beryllium disease animal model. Discovery of the Human Leukocyte Antigen (HLA) - DPB1Glu69 genetic susceptibility component of chronic beryllium disease permitted the addition of this human beryllium antigen presentation molecule to an animal genome which may permit development of a better animal model for chronic beryllium disease. Using FVB/N inbred mice, Drs. Rubin and Zhu, successfully produced three strains of HLA-DPB1 Glu 69 transgenic mice. Each mouse strain contains a haplotype of the HLA-DPB1 Glu 69 gene that confers a different magnitude of odds ratio (OR) of risk for chronic beryllium disease: HLA-DPB1*0401 (OR = 0.2), HLA-DPB1*0201 (OR = 15), HLA-DPB1*1701 (OR = 240). In addition, Drs. Rubin and Zhu developed transgenic mice with the human CD4 gene to permit better transmission of signals between T cells and antigen presenting cells. This project has maintained the colonies of these transgenic mice and tested the functionality of the human transgenes.

  2. Mouse infection models for space flight immunology

    NASA Technical Reports Server (NTRS)

    Chapes, Stephen Keith; Ganta, Roman Reddy; Chapers, S. K. (Principal Investigator)

    2005-01-01

    Several immunological processes can be affected by space flight. However, there is little evidence to suggest that flight-induced immunological deficits lead to illness. Therefore, one of our goals has been to define models to examine host resistance during space flight. Our working hypothesis is that space flight crews will come from a heterogeneous population; the immune response gene make-up will be quite varied. It is unknown how much the immune response gene variation contributes to the potential threat from infectious organisms, allergic responses or other long term health problems (e.g. cancer). This article details recent efforts of the Kansas State University gravitational immunology group to assess how population heterogeneity impacts host health, either in laboratory experimental situations and/or using the skeletal unloading model of space-flight stress. This paper details our use of several mouse strains with several different genotypes. In particular, mice with varying MHCII allotypes and mice on the C57BL background with different genetic defects have been particularly useful tools with which to study infections by Staphylococcus aureus, Salmonella typhimurium, Pasteurella pneumotropica and Ehrlichia chaffeensis. We propose that some of these experimental challenge models will be useful to assess the effects of space flight on host resistance to infection.

  3. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    PubMed Central

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  4. Mouse models for gastric cancer: Matching models to biological questions.

    PubMed

    Poh, Ashleigh R; O'Donoghue, Robert J J; Ernst, Matthias; Putoczki, Tracy L

    2016-07-01

    Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics. PMID:26809278

  5. Mouse models for gastric cancer: Matching models to biological questions.

    PubMed

    Poh, Ashleigh R; O'Donoghue, Robert J J; Ernst, Matthias; Putoczki, Tracy L

    2016-07-01

    Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.

  6. Genetically modified mouse models addressing gonadotropin function.

    PubMed

    Ratner, Laura D; Rulli, Susana B; Huhtaniemi, Ilpo T

    2014-03-01

    The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions.

  7. Mouse models for radiation-induced cancers.

    PubMed

    Rivina, Leena; Davoren, Michael J; Schiestl, Robert H

    2016-09-01

    Potential ionising radiation exposure scenarios are varied, but all bring risks beyond the simple issues of short-term survival. Whether accidentally exposed to a single, whole-body dose in an act of terrorism or purposefully exposed to fractionated doses as part of a therapeutic regimen, radiation exposure carries the consequence of elevated cancer risk. The long-term impact of both intentional and unintentional exposure could potentially be mitigated by treatments specifically developed to limit the mutations and precancerous replication that ensue in the wake of irradiation The development of such agents would undoubtedly require a substantial degree of in vitro testing, but in order to accurately recapitulate the complex process of radiation-induced carcinogenesis, well-understood animal models are necessary. Inbred strains of the laboratory mouse, Mus musculus, present the most logical choice due to the high number of molecular and physiological similarities they share with humans. Their small size, high rate of breeding and fully sequenced genome further increase its value for use in cancer research. This chapter will review relevant m. musculus inbred and F1 hybrid animals of radiation-induced myeloid leukemia, thymic lymphoma, breast and lung cancers. Method of cancer induction and associated molecular pathologies will also be described for each model. PMID:27209205

  8. Characterization of a mouse model of headache.

    PubMed

    Huang, Dongyue; Ren, Lynn; Qiu, Chang-Shen; Liu, Ping; Peterson, Jonathan; Yanagawa, Yuchio; Cao, Yu-Qing

    2016-08-01

    Migraine and other primary headache disorders affect a large population and cause debilitating pain. Establishing animal models that display behavioral correlates of long-lasting and ongoing headache, the most common and disabling symptom of migraine, is vital for the elucidation of disease mechanisms and identification of drug targets. We have developed a mouse model of headache, using dural application of capsaicin along with a mixture of inflammatory mediators (IScap) to simulate the induction of a headache episode. This elicited intermittent head-directed wiping and scratching as well as the phosphorylation of c-Jun N-terminal kinase in trigeminal ganglion neurons. Interestingly, dural application of IScap preferentially induced FOS protein expression in the excitatory but not inhibitory cervical/medullary dorsal horn neurons. The duration of IScap-induced behavior and the number of FOS-positive neurons correlated positively in individual mice; both were reduced to the control level by the pretreatment of antimigraine drug sumatriptan. Dural application of CGRP(8-37), the calcitonin gene-related peptide (CGRP) receptor antagonist, also effectively blocked IScap-induced behavior, which suggests that the release of endogenous CGRP in the dura is necessary for IScap-induced nociception. These data suggest that dural IScap-induced nocifensive behavior in mice may be mechanistically related to the ongoing headache in humans. In addition, dural application of IScap increased resting time in female mice. Taken together, we present the first detailed study using dural application of IScap in mice. This headache model can be applied to genetically modified mice to facilitate research on the mechanisms and therapeutic targets for migraine headache. PMID:27058678

  9. Development of a novel mouse constipation model

    PubMed Central

    Liang, Chao; Wang, Kai-Yue; Yu, Zhi; Xu, Bin

    2016-01-01

    AIM: To establish a novel mouse constipation model. METHODS: Animals were randomly divided into three groups, and intragastrically administered 0-4 °C saline (ice-cold group) or 15-20 °C saline (saline control group) daily for 14 d, or were left untreated (blank control group). Stools were collected 3-24 h after treatment to record the wet and dry weights and the stool form. Intestinal propulsion experiments were carried out and defecation time was measured for six days continuously after suspending treatments. The expressions of PGP9.5 were detected by immunohistochemistry. RESULTS: Based on the percentage of stool weight changes compared with baseline (before irritation) in 9-14 d, stool weight changes were classified into three levels. Each level shows a different body state, which is state I (no change: plus or minus 5%), state II (slightly decreased: 5%-15%) and state III (decreased: 15%-25%). In state III, between day 9-14, the stool weights decreased by 15%-25% compared with the baseline, and changed at a rate > 10% compared with blank control values, and the stools became small and dry. Additionally, intestinal functions degenerated in these animals, and PGP9.5-positive expression markedly decreased in jejunum, ileum and proximal colon myenteric plexus. CONCLUSION: Irritation with ice-cold saline is a stable, repeatable method in building constipation model in mice for exploring the pathogenesis and treatment options of constipation, and the change of stool weight and size may serve as a useful tool to judge a constipation model success or not. PMID:26973418

  10. A Mouse Model of Zika Virus Pathogenesis.

    PubMed

    Lazear, Helen M; Govero, Jennifer; Smith, Amber M; Platt, Derek J; Fernandez, Estefania; Miner, Jonathan J; Diamond, Michael S

    2016-05-11

    The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis. PMID:27066744

  11. Increased Opioid Dependence in a Mouse Model of Panic Disorder

    PubMed Central

    Gallego, Xavier; Murtra, Patricia; Zamalloa, Teresa; Canals, Josep Maria; Pineda, Joseba; Amador-Arjona, Alejandro; Maldonado, Rafael; Dierssen, Mara

    2009-01-01

    Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients. PMID:20204153

  12. Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.

    PubMed

    Kuracha, Murali R; Thomas, Peter; Loggie, Brian W; Govindarajan, Venkatesh

    2016-04-01

    Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor-stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient-derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low- and high-grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL-6 and IL-8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse-derived, tumor-associated stromal cells rather than by human-derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor-stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

  13. Understanding the Basis of Auriculocondylar Syndrome: Insights From Human and Mouse Genetic Studies

    PubMed Central

    Clouthier, David E.; Passos Bueno, Maria Rita; Tavares, Andre L.P.; Lyonnet, Stanislas; Amiel, Jeanne; Gordon, Christopher T.

    2014-01-01

    Among human birth defect syndromes, malformations affecting the face are perhaps the most striking due to cultural and psychological expectations of facial shape. One such syndrome is auriculocondylar syndrome (ACS), in which patients present with defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of cells in the embryo that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face. Recent studies have found that most cases of ACS arise from defects in signaling molecules associated with the endothelin signaling pathway. Disruption of this signaling pathway in both mouse and zebrafish results in loss of identity of neural crest cells of the mandibular portion of the first pharyngeal arch and the subsequent repatterning of these cells, leading to homeosis of lower jaw structures into more maxillary-like structures. These findings illustrate the importance of endothelin signaling in normal human craniofacial development and illustrate how clinical and basic science approaches can coalesce to improve our understanding of the genetic basis of human birth syndromes. Further, understanding the genetic basis for ACS that lies outside of known endothelin signaling components may help elucidate unknown aspects critical to the establishment of neural crest cell patterning during facial morphogenesis. PMID:24123988

  14. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.

    PubMed

    Muscatelli, F; Abrous, D N; Massacrier, A; Boccaccio, I; Le Moal, M; Cau, P; Cremer, H

    2000-12-12

    Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

  15. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models

    PubMed Central

    Su, Nan; Jin, Min; Chen, Lin

    2014-01-01

    Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis. PMID:26273516

  16. Humanized Mouse Models of HIV Infection

    PubMed Central

    Denton, Paul W.; Garcia, J. Victor

    2013-01-01

    Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses such as SIV that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in non-human hosts. For these reasons much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34+ hematopoietic progenitor cell transplanted immunodeficient mice and in particular mice also implanted with human thymic/liver tissue (BLT mice) that develop a functional human immune system, have been the focus of a great deal of attention as possible models to study virtually all aspects of HIV biology and pathogenesis. Humanized mice are systemically reconstituted with human lymphoid cells offering rapid, reliable and reproducible experimental systems for HIV research. Peripheral blood of humanized mice can be readily sampled longitudinally to assess reconstitution with human cells and to monitor HIV replication permitting the evaluation of multiple parameters of HIV infection such as viral load levels, CD4+ T cell depletion, immune activation, as well as the effects of therapeutic interventions. Of high relevance to HIV transmission is the extensive characterization and validation of the reconstitution with human lymphoid cells of the female reproductive tract and of the gastrointestinal tract of humanized BLT mice that renders them susceptible to both vaginal and rectal HIV infection. Other important attributes of all types of humanized mice include: 1) their small size and cost that make them broadly accessible; 2) multiple cohorts of humanized mice can be made from multiple human donors and each cohort has identical human cells, permitting control of

  17. A humanized mouse model of hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia.

    PubMed

    Lee, Seong Min; Goellner, Joseph J; O'Brien, Charles A; Pike, J Wesley

    2014-11-01

    The syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a genetic disease of altered mineral homeostasis due to mutations in the vitamin D receptor (VDR) gene. It is frequently, but not always, accompanied by the presence of alopecia. Mouse models that recapitulate this syndrome have been prepared through genetic deletion of the Vdr gene and are characterized by the presence of rickets and alopecia. Subsequent studies have revealed that VDR expression in hair follicle keratinocytes protects against alopecia and that this activity is independent of the protein's ability to bind 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In the present study, we introduced into VDR-null mice a human VDR (hVDR) bacterial artificial chromosome minigene containing a mutation that converts leucine to serine at amino acid 233 in the hVDR protein, which prevents 1,25(OH)2D3 binding. We then assessed whether this transgene recreated features of the HVDRR syndrome without alopecia. RT-PCR and Western blot analysis in one strain showed an appropriate level of mutant hVDR expression in all tissues examined including skin. The hVDR-L233S mutant failed to rescue the aberrant systemic and skeletal phenotype characteristic of the VDR null mouse due to the inability of the mutant receptor to activate transcription after treatment with 1,25(OH)2D3. Importantly, however, neither alopecia nor the dermal cysts characteristic of VDR-null mice were observed in the skin of these hVDR-L233S mutant mice. This study confirms that we have created a humanized mouse model of HVDRR without alopecia that will be useful in defining additional features of this syndrome and in identifying potential novel functions of the unoccupied VDR.

  18. The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men.

    SciTech Connect

    Lehman, J M; Michaud III, Edward J; Schoeb, T; Aydin Son, Yesim; Miller, M; Yoder, Bradley

    2008-08-01

    The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive polycystic kidney disease. The ORPK mouse arose through integration of a transgene into an intron of the Ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Furthermore, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner's syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle.

  19. The Oak Ridge Polycystic Kidney Mouse: Modeling Ciliopathies of Mice and Men

    PubMed Central

    Lehman, Jonathan M.; Michaud, Edward J.; Schoeb, Trenton R.; Aydin-Son, Yesim; Miller, Michael; Yoder, Bradley K.

    2009-01-01

    The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive Polycystic Kidney Disease. The ORPK mouse arose through integration of a transgene into an intron of the ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Further, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner’s syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle. PMID:18366137

  20. A human neurodevelopmental model for Williams syndrome.

    PubMed

    Chailangkarn, Thanathom; Trujillo, Cleber A; Freitas, Beatriz C; Hrvoj-Mihic, Branka; Herai, Roberto H; Yu, Diana X; Brown, Timothy T; Marchetto, Maria C; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M Colin; Hanson, Kari L; Romero, Sarah; Jacobs, Bob; Dale, Anders M; Dai, Li; Korenberg, Julie R; Gage, Fred H; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R

    2016-08-18

    Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. PMID:27509850

  1. A human neurodevelopmental model for Williams syndrome.

    PubMed

    Chailangkarn, Thanathom; Trujillo, Cleber A; Freitas, Beatriz C; Hrvoj-Mihic, Branka; Herai, Roberto H; Yu, Diana X; Brown, Timothy T; Marchetto, Maria C; Bardy, Cedric; McHenry, Lauren; Stefanacci, Lisa; Järvinen, Anna; Searcy, Yvonne M; DeWitt, Michelle; Wong, Wenny; Lai, Philip; Ard, M Colin; Hanson, Kari L; Romero, Sarah; Jacobs, Bob; Dale, Anders M; Dai, Li; Korenberg, Julie R; Gage, Fred H; Bellugi, Ursula; Halgren, Eric; Semendeferi, Katerina; Muotri, Alysson R

    2016-08-18

    Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

  2. Novel mouse models for understanding HIV-1 pathogenesis.

    PubMed

    Joseph, Aviva; Sango, Kaori; Goldstein, Harris

    2009-01-01

    Small animal models in which in vivo HIV-1 infection, pathogenesis, and immune responses can be studied would permit both basic research on the biology of the disease, as well as a system to rapidly screen developmental therapeutics and/or vaccines. To date, the most widely-used models have been the severe combined immunodeficient (SCID)-hu (also known as the thy/liv SCID-hu) and the huPBL-SCID mouse models. Recently three new models have emerged, i.e., the intrasplenic huPBL/SPL-SCID model, the NOD/SCID/IL2Rgamma(null) mouse model, and the Rag2(-/-)gamma(c) (-/-) mouse model. Details on the construction, maintenance and HIV-1 infection of these models are discussed.

  3. Genetically modified mouse models in studies of luteinising hormone action.

    PubMed

    Huhtaniemi, Ilpo; Ahtiainen, Petteri; Pakarainen, Tomi; Rulli, Susana B; Zhang, Fu-Ping; Poutanen, Matti

    2006-06-27

    Numerous genetically modified mouse models have recently been developed for the study of the pituitary-gonadal interactions. They include spontaneous or engineered knockouts (KO) of the gonadotrophin-releasing hormone (GnRH) and its receptor, the gonadotrophin common-alpha(Calpha), luteinising hormone (LH) beta and follicle-stimulating hormone (FSH) beta subunits, and the two gonadotrophin receptors (R), LHR and FSHR. In addition, there are also transgenic (TG) mice overexpressing gonadotrophin subunits and producing supraphysiological levels of these hormones. These models have offered relevant phenocopies for similar mutations in humans and to a great extent expanded our knowledge on normal and pathological functions of the hypothalamic-pituitary-gonadal (HPG) axis. The purpose of this article is to review some of our recent findings on two such mouse models, the LHR KO mouse (LuRKO), and the hCG overexpressing TG mouse (hCG+).

  4. System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

  5. Spontaneous acute tumor lysis syndrome in a DBA/1J mouse: a case report and review.

    PubMed

    Lovelace, Karen; vanGessel, Yvonne; Asher, Ludmila V; Vogel, Peter

    2003-01-01

    Spontaneous acute tumor lysis syndrome (ATLS) was diagnosed in a 10-month-old female DBA/1J sentinel mouse with leukemic lymphoma. The mouse was unable to maintain balance and died shortly after being observed rolling around in its cage. Disseminated neoplastic disease, including a large cranial mediastinal mass, enlarged lymph nodes and splenomegaly, was present at necropsy. Histopathologic examination revealed widespread massive necrosis of lymphoblastic tumor cells, and widely disseminated microemboli composed of nuclear and cytoplasmic cell debris. Although ATLS is widely recognized as an oncologic emergency in humans, acute lesions of ATLS have not been described. The mechanical obstruction of capillary beds by microemboli originating from disintegrating necrotic tumor cells was the likely cause of clinical signs and death in this mouse. We propose that similar microemboli may contribute to the pathogenesis of the acute renal failure and other clinical signs associated with ATLS in humans. Recognition of spontaneous ATLS in laboratory animals is especially important in studies that assess the efficacy and/or toxicity of anticancer treatments, where early deaths due to ATLS might mistakenly be attributed to a direct test article effect.

  6. Characterizing social behavior in genetically targeted mouse models of brain disorders.

    PubMed

    Burrows, Emma L; Hannan, Anthony J

    2013-01-01

    Fragile X syndrome, the leading inherited cause of mental retardation and autism spectrum disorders worldwide, is caused by a tandem repeat expansion in the FMR1 (fragile X mental retardation 1) gene. It presents with a distinct behavioral phenotype which overlaps significantly with that of autism. Emerging evidence suggests that tandem repeat polymorphisms (TRPs) might also play a key role in modulating disease susceptibility for a range of common polygenic disorders, including the broader autism spectrum of disorders (ASD) and other forms of psychiatric illness such as schizophrenia, depression, and bipolar disorder [1]. In order to understand how TRPs and associated gene mutations mediate pathogenesis, various mouse models have been generated. A crucial step in such functional genomics is high-quality behavioral and cognitive phenotyping. This chapter presents a basic behavioral battery for standardized tests for assaying social phenotypes in mouse models of brain disorders, with a focus on aggression.

  7. Behavioral phenotypes of genetic mouse models of autism.

    PubMed

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

  8. Behavioral phenotypes of genetic mouse models of autism

    PubMed Central

    Kazdoba, T. M.; Leach, P. T.; Crawley, J. N.

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. PMID:26403076

  9. Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17

    SciTech Connect

    Cheng, S.V.; Nadeau, J.H.; Tanzi, R.E.; Watkins, P.C.; Jagadesh, J.; Taylor, B.A.; Haines, J.L.; Sacchi, N.; Gusella, J.F. )

    1988-08-01

    Mouse trisomy 16 has been proposed as an animal model of Down syndrome (DS), since this chromosome contains homologues of several loci from the q22 band of human chromosome 21. The recent mapping of the defect causing familial Alzheimer disease (FAD) and the locus encoding the Alzheimer amyloid {beta} precursor protein (APP) to human chromosome 21 has prompted a more detailed examination of the extent of conservation of this linkage group between the two species. Using anonymous DNA probes and cloned genes from human chromosome 21 in a combination of recombinant inbred and interspecific mouse backcross analyses, the authors have established that the linkage group shared by mouse chromosome 16 includes not only the critical DS region of human chromosome 21 but also the APP gene and FAD-linked markers. Extending from the anonymous DNA locus D21S52 to ETS2, the linkage map of six loci spans 39% recombination in man but only 6.4% recombination in the mouse. A break in synteny occurs distal to ETS2, with the homologue of the human marker D21S56 mapping to mouse chromosome 17. Conservation of the linkage relationships of markers in the FAD region suggests that the murine homologue of the FAD locus probably maps to chromosome 16 and that detailed comparison of the corresponding region in both species could facilitate identification of the primary defect in this disorder. The break in synteny between the terminal portion of human chromosome 21 and mouse chromosome 16 indicates, however, that mouse trisomy 16 may not represent a complete model of DS.

  10. Development and testing of a mouse simulated space flight model

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1987-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occurs during space flight, and the carrying out of immunological experiments on animals undergoing space flight is examined. The mouse model developed was an antiorthostatic, hypokinetic, hypodynamic suspension model similar to one used with rats. The study was divided into two parts. The first involved determination of which immunological parameters should be observed on animals flown during space flight or studied in the suspension model. The second involved suspending mice and determining which of those immunological parameters were altered by the suspension. Rats that were actually flown in Space Shuttle SL-3 were used to test the hypotheses.

  11. Uterine disorders and pregnancy complications: insights from mouse models

    PubMed Central

    Lim, Hyunjung Jade; Wang, Haibin

    2010-01-01

    Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications. PMID:20364098

  12. Genomic responses in mouse models poorly mimic human inflammatory diseases

    PubMed Central

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  13. Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Altafaj, Xavier; Martín, Eduardo D; Ortiz-Abalia, Jon; Valderrama, Aitana; Lao-Peregrín, Cristina; Dierssen, Mara; Fillat, Cristina

    2013-04-01

    The cognitive dysfunctions of Down Syndrome (DS) individuals are the most disabling alterations caused by the trisomy of human chromosome 21 (HSA21). In trisomic Ts65Dn mice, a genetic model for DS, the overexpression of HSA21 homologous genes has been associated with strong visuo-spatial cognitive alterations, ascribed to hippocampal dysfunction. In the present study, we evaluated whether the normalization of the expression levels of Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), a candidate gene for DS, might correct hippocampal defects in Ts65Dn mice. In the hippocampus of 2 month-old Ts65Dn mice, such normalization was achieved through the stereotaxical injection of adeno-associated viruses containing a short hairpin RNA against Dyrk1A (AAV2/1-shDyrk1A) and a luciferase reporter gene. The injected hippocampi were efficiently transduced, as shown by bioluminescence in vivo imaging, luciferase activity quantification and immunohistochemical analysis. At the molecular level, viral infusion allowed the normalization of the targeted Dyrk1A expression, as well as of the key players of the MAPK/CREB pathway. The electrophysiological recordings of hippocampal slices from Ts65Dn mice injected with AAV2/1-shDyrk1A displayed attenuation of the synaptic plasticity defects of trisomic mice. In contrast, contralateral hippocampal injection with an AAV2/1 control virus containing a scrambled sequence, showed neither the normalization of Dyrk1A levels nor changes of synaptic plasticity. In the Morris water maze task, although long-term consolidation of the task was not achieved, treated Ts65Dn mice displayed initially a normalized thigmotactic behavior, similar to euploid littermates, indicating the partial improvement in their hippocampal-dependent search strategy. Taken together, these results show Dyrk1A as a critical player in the pathophysiology of DS and define Dyrk1A as a therapeutic target in adult trisomic mice. PMID:23220201

  14. Neuroprotective effects of VCP modulators in mouse models of glaucoma.

    PubMed

    Nakano, Noriko; Ikeda, Hanako Ohashi; Hasegawa, Tomoko; Muraoka, Yuki; Iwai, Sachiko; Tsuruyama, Tatsuaki; Nakano, Masaki; Fuchigami, Tomohiro; Shudo, Toshiyuki; Kakizuka, Akira; Yoshimura, Nagahisa

    2016-04-01

    Glaucoma is a major cause of adult blindness due to gradual death of retinal ganglion cells. Currently, no therapeutics are available for the protection of these cells from the cell death. We have recently succeeded in synthesizing novel compounds, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption by specifically inhibiting the ATPase activities of VCP, a major ATPase in the cell, and we have shown that KUSs could mitigate the disease progression of rd10, a mouse model of retinitis pigmentosa, without any apparent side effects. Here we show that KUSs (e.g. KUS121 and KUS187) can prevent antimycin- and oligomycin-induced ATP depletion, endoplasmic reticulum (ER) stress, and cell death in neuronally differentiated PC12 cells. Furthermore, KUSs manifest significant efficacies on several mouse models of glaucoma. KUS administration prevented or mitigated ER stress and subsequent apoptotic cell death of retinal ganglion cells in an acute injury mouse model of retinal ganglion cell loss, which was induced with N-methyl-D-aspartate. In a mouse model of glaucoma with high intraocular pressure, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. KUSs also preserved visual functions in GLAST knockout mice, a mouse model for chronic retinal ganglion cell loss. We propose "ATP maintenance" via inhibition of ATPase activities of VCP as a promising new neuroprotective strategy for currently incurable eye diseases, such as glaucoma. PMID:27441270

  15. Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges.

    PubMed

    Jiskoot, Wim; Kijanka, Grzegorz; Randolph, Theodore W; Carpenter, John F; Koulov, Atanas V; Mahler, Hanns-Christian; Joubert, Marisa K; Jawa, Vibha; Narhi, Linda O

    2016-05-01

    The success of clinical and commercial therapeutic proteins is rapidly increasing, but their potential immunogenicity is an ongoing concern. Most of the studies that have been conducted over the past few years to examine the importance of various product-related attributes (in particular several types of aggregates and particles) and treatment regimen (such as dose, dosing schedule, and route of administration) in the development of unwanted immune responses have utilized one of a variety of mouse models. In this review, we discuss the utility and drawbacks of different mouse models that have been used for this purpose. Moreover, we summarize the lessons these models have taught us and some of the challenges they present. Finally, we provide recommendations for future research utilizing mouse models to improve our understanding of critical factors that may contribute to protein immunogenicity. PMID:27044944

  16. Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

    SciTech Connect

    Mathews, K.D.; Rapisarda, D.; Bailey, H.L.

    1995-07-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD. 28 refs., 4 figs.

  17. Mouse models for understanding human developmental anomalies

    SciTech Connect

    Generoso, W.M.

    1989-01-01

    The mouse experimental system presents an opportunity for studying the nature of the underlying mutagenic damage and the molecular pathogenesis of this class of anomalies by virtue of the accessibility of the zygote and its descendant blastomeres. Such studies could contribute to the understanding of the etiology of certain sporadic but common human malformations. The vulnerability of the zygotes to mutagens as demonstrated in the studies described in this report should be a major consideration in chemical safety evaluation. It raises questions regarding the danger to human zygotes when the mother is exposed to drugs and environmental chemicals.

  18. Artificial rearing of mouse pups: development of a mouse pup in a cup model.

    PubMed

    Beierle, Elizabeth A; Chen, Mike K; Hartwich, Joseph E; Iyengar, Meera; Dai, Wei; Li, Nan; Demarco, Vince; Neu, Josef

    2004-08-01

    Artificial rearing of rat pups has been used in the investigation of the neonatal gut. We propose to adapt the model of artificially rearing rat pups for use in mouse pups, thereby allowing the use of transgenic animals for our research. We hypothesized that gastrostomy catheters may be placed successfully into neonatal mouse pups and that the pups may be artificially reared without significant alterations in their growth or intestinal development. Gastrostomy tubes are placed into 5-d-old mouse pups [artificially reared (AR); n = 32], and the mice are fed rodent milk substitute. Littermate pups [maternally reared (MR); n = 22] are used as controls. After 5 d, pups are killed and their organs are harvested. Intestinal villus measurements, protein content, and DNA content are determined. Data are reported as mean +/- SEM, compared with appropriate statistical methods, and significance is determined at P < 0.05. Initial weights and lengths are not different between the two groups, but after 5 d, MR pups weigh more than their AR counterparts (5.0 +/- 0.13 versus 4.1 +/- 0.14 g, MR versus AR; P < 0.01). However, the pups' length and the intestinal villus height-to-width ratios, protein, and DNA content are not different between the MR and AR pups. To our knowledge, this is the first report of artificially rearing mouse pups. Development of this technique will permit nutritional manipulation in neonatal mice, a mammalian model wherein the genome is sequenced and transgenic mutants are available.

  19. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  20. Generating Transgenic Mouse Models for Studying Celiac Disease.

    PubMed

    Ju, Josephine M; Marietta, Eric V; Murray, Joseph A

    2015-01-01

    This chapter provides a brief overview of current animal models for studying celiac disease, with a focus on generating HLA transgenic mouse models. Human Leukocyte Antigen class II molecules have been a particular target for transgenic mice due to their tight association with celiac disease, and a number of murine models have been developed which had the endogenous MHC class II genes replaced with insertions of disease susceptible HLA class II alleles DQ2 or DQ8. Additionally, transgenic mice that overexpress interleukin-15 (IL-15), a key player in the inflammatory cascade that leads to celiac disease, have also been generated to model a state of chronic inflammation. To explore the contribution of specific bacteria in gluten-sensitive enteropathy, the nude mouse and rat models have been studied in germ-free facilities. These reductionist mouse models allow us to address single factors thought to have crucial roles in celiac disease. No single model has incorporated all of the multiple factors that make up celiac disease. Rather, these mouse models can allow the functional interrogation of specific components of the many stages of, and contributions to, the pathogenic mechanisms that will lead to gluten-dependent enteropathy. Overall, the tools for animal studies in celiac disease are many and varied, and provide ample space for further creativity as well as to characterize the complete and complex pathogenesis of celiac disease.

  1. Mouse ataxin-3 functional knock-out model.

    PubMed

    Switonski, Pawel M; Fiszer, Agnieszka; Kazmierska, Katarzyna; Kurpisz, Maciej; Krzyzosiak, Wlodzimierz J; Figiel, Maciej

    2011-03-01

    Spinocerebellar ataxia 3 (SCA3) is a genetic disorder resulting from the expansion of the CAG repeats in the ATXN3 gene. The pathogenesis of SCA3 is based on the toxic function of the mutant ataxin-3 protein, but the exact mechanism of the disease remains elusive. Various types of transgenic mouse models explore different aspects of SCA3 pathogenesis, but a knock-in humanized mouse has not yet been created. The initial aim of this study was to generate an ataxin-3 humanized mouse model using a knock-in strategy. The human cDNA for ataxin-3 containing 69 CAG repeats was cloned from SCA3 patient and introduced into the mouse ataxin-3 locus at exon 2, deleting it along with exon 3 and intron 2. Although the human transgene was inserted correctly, the resulting mice acquired the knock-out properties and did not express ataxin-3 protein in any analyzed tissues, as confirmed by western blot and immunohistochemistry. Analyses of RNA expression revealed that the entire locus consisting of human and mouse exons was expressed and alternatively spliced. We detected mRNA isoforms composed of exon 1 spliced with mouse exon 4 or with human exon 7. After applying 37 PCR cycles, we also detected a very low level of the correct exon 1/exon 2 isoform. Additionally, we confirmed by bioinformatic analysis that the structure and power of the splicing site between mouse intron 1 and human exon 2 (the targeted locus) was not changed compared with the native mouse locus. We hypothesized that these splicing aberrations result from the deletion of further splicing sites and the presence of a strong splicing site in exon 4, which was confirmed by bioinformatic analysis. In summary, we created a functional ataxin-3 knock-out mouse model that is viable and fertile and does not present a reduced life span. Our work provides new insights into the splicing characteristics of the Atxn3 gene and provides useful information for future attempts to create knock-in SCA3 models.

  2. Foot Pad Skin Biopsy in Mouse Models of Hereditary Neuropathy

    PubMed Central

    Dacci, Patrizia; Dina, Giorgia; Cerri, Federica; Previtali, Stefano Carlo; Lopez, Ignazio Diego; Lauria, Giuseppe; Feltri, Maria Laura; Bolino, Alessandra; Comi, Giancarlo; Wrabetz, Lawrence; Quattrini, Angelo

    2010-01-01

    Numerous transgenic and knockout mouse models of human hereditary neuropathies have become available over the past decade. We describe a simple, reproducible, and safe biopsy of mouse skin for histopathological evaluation of the peripheral nervous system (PNS) in models of hereditary neuropathies. We compared the diagnostic outcome between sciatic nerve and dermal nerves found in skin biopsy (SB) from the hind foot. A total of five animal models of different Charcot-Marie-Tooth neuropathies, and one model of congenital muscular dystrophy associated neuropathy were examined. In wild type mice, dermal nerve fibers were readily identified by immunohistochemistry, light, and electron microscopy and they appeared similar to myelinated fibers in sciatic nerve. In mutant mice, SB manifested myelin abnormalities similar to those observed in sciatic nerves, including hypomyelination, onion bulbs, myelin outfolding, redundant loops, and tomacula. In many strains, however, SB showed additional abnormalities—fiber loss, dense neurofilament packing with lower phosphorylation status, and axonal degeneration—undetected in sciatic nerve, possibly because SB samples distal nerves. SB, a reliable technique to investigate peripheral neuropathies in human beings, is also useful to investigate animal models of hereditary neuropathies. Our data indicate that SB may reveal distal axonal pathology in mouse models and permits sequential follow-up of the neuropathy in an individual mouse, thereby reducing the number of mice necessary to document pathology of the PNS. © 2010 Wiley-Liss, Inc. PMID:20878767

  3. From transplantation to transgenics: mouse models of developmental hematopoiesis.

    PubMed

    Schmitt, Christopher E; Lizama, Carlos O; Zovein, Ann C

    2014-08-01

    The mouse is integral to our understanding of hematopoietic biology. Serving as a mammalian model system, the mouse has allowed for the discovery of self-renewing multipotent stem cells, provided functional assays to establish hematopoietic stem cell identity and function, and has become a tool for understanding the differentiation capacity of early hematopoietic progenitors. The advent of genetic technology has strengthened the use of mouse models for identifying critical pathways in hematopoiesis. Full genetic knockout models, tissue-specific gene deletion, and genetic overexpression models create a system for the dissection and identification of critical cellular and genetic processes underlying hematopoiesis. However, the murine model has also introduced perplexity in understanding developmental hematopoiesis. Requisite in utero development paired with circulation has historically made defining sites of origin and expansion in the murine hematopoietic system challenging. However, the genetic accessibility of the mouse as a mammalian system has identified key regulators of hematopoietic development. Technological advances continue to generate extremely powerful tools that when translated to the murine system provide refined in vivo spatial and temporal control of genetic deletion or overexpression. Future advancements may add the ability of reversible genetic manipulation. In this review, we describe the major contributions of the murine model to our understanding of hematopoiesis.

  4. A bovine model for polycystic ovary syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polycystic ovary syndrome (PCOS) results in the greatest single cause of anovulatory infertility in reproductive age women (affecting 5-10%). Previously, research groups have created animal models utilizing non-human primates and sheep to better understand the mechanisms involved in PCOS. However, c...

  5. Development and testing of a mouse simulated space flight model

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1985-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occur during space flight, and the carrying out of immunological flight experiments on animals was discussed. The mouse model is an antiorthostatic, hypokinetic, hypodynamic suspension model similar to the one used with rats. It is shown that this murine model yield similar results to the rat model of antiorthostatic suspension for simulating some aspects of weightlessness. It is also shown that mice suspended in this model have decreased interferon-alpha/beta production as compared to control, nonsuspended mice or to orthostatically suspended mice. It is suggested that the conditions occuring during space flight could possibly affect interferon production. The regulatory role of interferon in nonviral diseases is demonstrated including several bacterial and protozoan infections indicating the great significance of interferon in resistance to many types of infectious diseases.

  6. Genetically engineered humanized mouse models for preclinical antibody studies.

    PubMed

    Proetzel, Gabriele; Wiles, Michael V; Roopenian, Derry C

    2014-04-01

    The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies.

  7. Rat Model of Parkes Weber Syndrome

    PubMed Central

    Bojakowski, Krzysztof; Janusz, Gabriela; Grabowska, Iwona; Zegrocka-Stendel, Oliwia; Surowiecka-Pastewka, Agnieszka; Kowalewska, Magdalena; Maciejko, Dorota; Koziak, Katarzyna

    2015-01-01

    The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment. PMID:26217941

  8. Rat Model of Parkes Weber Syndrome.

    PubMed

    Bojakowski, Krzysztof; Janusz, Gabriela; Grabowska, Iwona; Zegrocka-Stendel, Oliwia; Surowiecka-Pastewka, Agnieszka; Kowalewska, Magdalena; Maciejko, Dorota; Koziak, Katarzyna

    2015-01-01

    The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment. PMID:26217941

  9. CHARACTERIZATION OF AEROMONAS VIRULENCE USING AN IMMUNOCOMPROMISED MOUSE MODEL

    EPA Science Inventory

    An immunocompromised mouse model was used to characterize Aeromonas strains for their ability to cause opportunistic, extraintestinal infections. A total of 34 isolates of Aeromonas (A. hydrophila [n = 12]), A. veronii biotype sobria [n = 7], A. caviae [n = 4], A. enchelia [n = 4...

  10. Exploration of West Nile Virus Infection in Mouse Models.

    PubMed

    Wang, Penghua

    2016-01-01

    West Nile virus (WNV) causes neurological diseases by penetrating the central nervous system (CNS)-an immune-privileged system. Although the CNS residential cells can produce antiviral immune responses, the blood leukocytes are required to contain virus spread. However, infiltrating leukocytes may also contribute to immunopathology if they overreact. Thus analyses of WNV infectivity and leukocyte numbers in the CNS are critical for understanding of WNV pathogenesis in experimental mouse models. Here I describe two basic assays for quantification of viral titers and infiltrating leukocytes in the mouse brain after WNV infection.

  11. Current State of Animal (Mouse) Modeling in Melanoma Research

    PubMed Central

    Kuzu, Omer F.; Nguyen, Felix D.; Noory, Mohammad A.; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID:26483610

  12. Current State of Animal (Mouse) Modeling in Melanoma Research.

    PubMed

    Kuzu, Omer F; Nguyen, Felix D; Noory, Mohammad A; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future.

  13. Comprehensive Neurocognitive Endophenotyping Strategies for Mouse Models of Genetic Disorders

    PubMed Central

    Hunsaker, Michael R.

    2012-01-01

    There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species. PMID:22266125

  14. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

    SciTech Connect

    Barnhoorn, Sander; Uittenboogaard, Lieneke M.; Jaarsma, Dick; Vermeij, Wilbert P.; Tresini, Maria; Weymaere, Michael; Menoni, Hervé; Brandt, Renata M. C.; de Waard, Monique C.; Botter, Sander M.; Sarker, Altaf H.; Jaspers, Nicolaas G. J.; van der Horst, Gijsbertus T. J.; Cooper, Priscilla K.; Hoeijmakers, Jan H. J.; van der Pluijm, Ingrid; Niedernhofer, Laura J.

    2014-10-09

    As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which—in a C57BL6/FVB F1 hybrid genetic background—displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.

  15. Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency

    PubMed Central

    Vermeij, Wilbert P.; Tresini, Maria; Weymaere, Michael; Menoni, Hervé; Brandt, Renata M. C.; de Waard, Monique C.; Botter, Sander M.; Sarker, Altaf H.; Jaspers, Nicolaas G. J.; van der Horst, Gijsbertus T. J.; Cooper, Priscilla K.; Hoeijmakers, Jan H. J.; van der Pluijm, Ingrid

    2014-01-01

    As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. PMID:25299392

  16. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

    DOE PAGES

    Barnhoorn, Sander; Uittenboogaard, Lieneke M.; Jaarsma, Dick; Vermeij, Wilbert P.; Tresini, Maria; Weymaere, Michael; Menoni, Hervé; Brandt, Renata M. C.; de Waard, Monique C.; Botter, Sander M.; et al

    2014-10-09

    As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which—in a C57BL6/FVB F1 hybrid genetic background—displays manymore » progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.« less

  17. Mouse models for the study of fungal pneumonia

    PubMed Central

    Muhammed, Maged; Feldmesser, Marta; Shubitz, Lisa F.; Lionakis, Michail S.; Sil, Anita; Wang, Yan; Glavis-Bloom, Justin; Lewis, Russell E.; Galgiani, John N.; Casadevall, Arturo; Kontoyiannis, Dimitrios P.; Mylonakis, Eleftherios

    2012-01-01

    Mouse models have facilitated the study of fungal pneumonia. In this report, we present the working protocols of groups that are working on the following pathogens: Aspergillus, Coccidioides, Cryptococcus, Fusarium, Histoplasma and Rhizopus. We describe the experimental procedures and the detailed methods that have been followed in the experienced laboratories to study pulmonary fungal infection; we also discuss the anticipated results and technical notes, and provide the practical advices that will help the users of these models. PMID:22546902

  18. Non-invasive mouse models of post-traumatic osteoarthritis.

    PubMed

    Christiansen, B A; Guilak, F; Lockwood, K A; Olson, S A; Pitsillides, A A; Sandell, L J; Silva, M J; van der Meulen, M C H; Haudenschild, D R

    2015-10-01

    Animal models of osteoarthritis (OA) are essential tools for investigating the development of the disease on a more rapid timeline than human OA. Mice are particularly useful due to the plethora of genetically modified or inbred mouse strains available. The majority of available mouse models of OA use a joint injury or other acute insult to initiate joint degeneration, representing post-traumatic osteoarthritis (PTOA). However, no consensus exists on which injury methods are most translatable to human OA. Currently, surgical injury methods are most commonly used for studies of OA in mice; however, these methods may have confounding effects due to the surgical/invasive injury procedure itself, rather than the targeted joint injury. Non-invasive injury methods avoid this complication by mechanically inducing a joint injury externally, without breaking the skin or disrupting the joint. In this regard, non-invasive injury models may be crucial for investigating early adaptive processes initiated at the time of injury, and may be more representative of human OA in which injury is induced mechanically. A small number of non-invasive mouse models of PTOA have been described within the last few years, including intra-articular fracture of tibial subchondral bone, cyclic tibial compression loading of articular cartilage, and anterior cruciate ligament (ACL) rupture via tibial compression overload. This review describes the methods used to induce joint injury in each of these non-invasive models, and presents the findings of studies utilizing these models. Altogether, these non-invasive mouse models represent a unique and important spectrum of animal models for studying different aspects of PTOA. PMID:26003950

  19. Intracytoplasmic sperm injection experiments using the mouse as a model.

    PubMed

    Yanagimachi, R

    1998-04-01

    Due to the existence of ample background information on its reproduction, embryology and genetics, the mouse is potentially an excellent animal model for intracytoplasmic sperm injection (ICSI). Normal fertile mouse offspring have been obtained by ICSI using not only mature (epididymal) and immature (testicular) spermatozoa, but also round spermatids and secondary spermatocytes. This suggests that genomic imprinting of male germ cells is complete before spermiogenesis. Mature mouse spermatozoa carry one or more factors that activate oocytes. This sperm-borne oocyte-activating factor is present in testicular spermatozoa, but not in round spermatids. Thus, at least in the mouse, it seems to appear (or become active) during spermiogenesis. Part of the factor seems to be associated with the perinuclear materials because, when freed from plasma and acrosomal membranes as well as all acrosome components, spermatozoa remain fully capable of activating oocytes by ICSI. Spermatozoa with grossly misshapen heads (e.g. those from the BALB/c mouse) are unable to fertilize oocytes under ordinary in-vivo and in-vitro conditions. However, by ICSI they can fertilize the oocytes, and the zygotes develop into fertile offspring. Inherently poorly motile spermatozoa (of male mice carrying two t haplotypes) are unable to fertilize, but through ICSI they can participate in normal fertilization and embryonic development. Examination of human sperm chromosomes after sperm injection into mouse oocytes revealed that spermatozoa with abnormal head morphology have a significantly higher incidence of chromosome abnormality than those with normal heads, yet the majority of the abnormal spermatozoa have normal chromosomal constitutions. These findings suggest that spermatozoa with aberrant morphology and/or motility are not necessarily genomically abnormal.

  20. Practical use of advanced mouse models for lung cancer.

    PubMed

    Safari, Roghaiyeh; Meuwissen, Ralph

    2015-01-01

    To date a variety of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) mouse models have been developed that mimic human lung cancer. Chemically induced or spontaneous lung cancer in susceptible inbred strains has been widely used, but the more recent genetically engineered somatic mouse models recapitulate much better the genotype-phenotype correlations found in human lung cancer. Additionally, improved orthotopic transplantation of primary human cancer tissue fragments or cells into lungs of immune-compromised mice can be valuable tools for preclinical research such as antitumor drug tests. Here we give a short overview of most somatic mouse models for lung cancer that are currently in use. We accompany each different model with a description of its practical use and application for all major lung tumor types, as well as the intratracheal injection or direct injection of fresh or freeze-thawed tumor cells or tumor cell lines into lung parenchyma of recipient mice. All here presented somatic mouse models are based on the ability to (in) activate specific alleles at a time, and in a tissue-specific cell type, of choice. This spatial-temporal controlled induction of genetic lesions allows the selective introduction of main genetic lesions in an adult mouse lung as found in human lung cancer. The resulting conditional somatic mouse models can be used as versatile powerful tools in basic lung cancer research and preclinical translational studies alike. These distinctively advanced lung cancer models permit us to investigate initiation (cell of origin) and progression of lung cancer, along with response and resistance to drug therapy. Cre/lox or FLP/frt recombinase-mediated methods are now well-used techniques to develop tissue-restricted lung cancer in mice with tumor-suppressor gene and/or oncogene (in)activation. Intranasal or intratracheal administration of engineered adenovirus-Cre or lentivirus-Cre has been optimized for introducing Cre

  1. Mouse models of liver cancer: Progress and recommendations

    PubMed Central

    He, Li; Tian, De-An; Li, Pei-Yuan; He, Xing-Xing

    2015-01-01

    To clarify the pathogenesis of hepatocellular carcinoma (HCC) and investigate the effects of potential therapies, a number of mouse models have been developed. Subcutaneous xenograft models are widely used in the past decades. Yet, with the advent of in vivo imaging technology, investigators are more and more concerned with the orthotopic models nowadays. Genetically engineered mouse models (GEM) have greatly facilitated studies of gene function in HCC development. Recently, GEM of miR-122 and miR-221 provided new approaches for better understanding of the in vivo functions of microRNA in hepatocarcinogenesis. Chemically induced liver tumors in animals share many of the morphological, histogenic, and biochemical features of human HCC. Yet, the complicated and obscure genomic alternation restricts their applications. In this review, we highlight both the frequently used mouse models and some emerging ones with emphasis on their merits or defects, and give advises for investigators to chose a “best-fit” animal model in HCC research. PMID:26259234

  2. MRI as a tool to study brain structure from mouse models for mental retardation

    NASA Astrophysics Data System (ADS)

    Verhoye, Marleen; Sijbers, Jan; Kooy, R. F.; Reyniers, E.; Fransen, E.; Oostra, B. A.; Willems, Peter; Van der Linden, Anne-Marie

    1998-07-01

    Nowadays, transgenic mice are a common tool to study brain abnormalities in neurological disorders. These studies usually rely on neuropathological examinations, which have a number of drawbacks, including the risk of artefacts introduced by fixation and dehydration procedures. Here we present 3D Fast Spin Echo Magnetic Resonance Imaging (MRI) in combination with 2D and 3D segmentation techniques as a powerful tool to study brain anatomy. We set up MRI of the brain in mouse models for the fragile X syndrome (FMR1 knockout) and Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH) syndrome (L1CAM knockout). Our major goal was to determine qualitative and quantitative differences in specific brain structures. MRI of the brain of fragile X and CRASH patients has revealed alterations in the size of specific brain structures, including the cerebellar vermis and the ventricular system. In the present MRI study of the brain from fragile X knockout mice, we have measured the size of the brain, cerebellum and 4th ventricle, which were reported as abnormal in human fragile X patients, but found no evidence for altered brain regions in the mouse model. In CRASH syndrome, the most specific brain abnormalities are vermis hypoplasia and abnormalities of the ventricular system with some degree of hydrocephalus. With the MRI study of L1CAM knockout mice we found vermis hypoplasia, abnormalities of the ventricular system including dilatation of the lateral and the 4th ventricles. These subtle abnormalities were not detected upon standard neuropathological examination. Here we proved that this sensitive MRI technique allows to measure small differences which can not always be detected by means of pathology.

  3. Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain.

    PubMed

    Bailus, Barbara J; Pyles, Benjamin; McAlister, Michelle M; O'Geen, Henriette; Lockwood, Sarah H; Adams, Alexa N; Nguyen, Jennifer Trang T; Yu, Abigail; Berman, Robert F; Segal, David J

    2016-03-01

    Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders. PMID:26727042

  4. Oxidative Stress in Genetic Mouse Models of Parkinson's Disease

    PubMed Central

    Varçin, Mustafa; Bentea, Eduard; Michotte, Yvette; Sarre, Sophie

    2012-01-01

    There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, gene-environment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease. PMID:22829959

  5. Neuroanatomical changes in a mouse model of early life neglect.

    PubMed

    Duque, Alvaro; Coman, Daniel; Carlyle, Becky C; Bordner, Kelly A; George, Elizabeth D; Papademetris, Xenophon; Hyder, Fahmeed; Simen, Arthur A

    2012-04-01

    Using a novel mouse model of early life neglect and abuse (ENA) based on maternal separation with early weaning, George et al. (BMC Neurosci 11:123, 2010) demonstrated behavioral abnormalities in adult mice, and Bordner et al. (Front Psychiatry 2(18):1-18, 2011) described concomitant changes in mRNA and protein expression. Using the same model, here we report neuroanatomical changes that include smaller brain size and abnormal inter-hemispheric asymmetry, decreases in cortical thickness, abnormalities in subcortical structures, and white matter disorganization and atrophy most severely affecting the left hemisphere. Because of the similarities between the neuroanatomical changes observed in our mouse model and those described in human survivors of ENA, this novel animal model is potentially useful for studies of human ENA too costly or cumbersome to be carried out in primates. Moreover, our current knowledge of the mouse genome makes this model particularly suited for targeted anatomical, molecular, and pharmacological experimentation not yet possible in other species. PMID:21984312

  6. Behavioral phenotyping of mouse models of Parkinson's Disease

    PubMed Central

    Taylor, Tonya N.; Greene, James G.; Miller, Gary W.

    2010-01-01

    Parkinson's disease (PD) is a common neurodegenerative movement disorder afflicting millions of people in the United States. The advent of transgenic technologies has contributed to the development of several new mouse models, many of which recapitulate some aspects of the disease; however, no model has been demonstrated to faithfully reproduce the full constellation of symptoms seen in human PD. This may be due in part to the narrow focus on the dopamine-mediated motor deficits. As current research continues to unmask PD as a multi-system disorder, animal models should similarly evolve to include the non-motor features of the disease. This requires that typically cited behavioral test batteries be expanded. The major non-motor symptoms observed in PD patients include hyposmia, sleep disturbances, gastrointestinal dysfunction, autonomic dysfunction, anxiety, depression, and cognitive decline. Mouse behavioral tests exist for all of these symptoms and while some models have begun to be reassessed for the prevalence of this broader behavioral phenotype, the majority has not. Moreover, all behavioral paradigms should be tested for their responsiveness to L-DOPA so these data can be compared to patient response and help elucidate which symptoms are likely not dopamine-mediated. Here, we suggest an extensive, yet feasible, battery of behavioral tests for mouse models of PD aimed to better assess both non-motor and motor deficits associated with the disease. PMID:20211655

  7. CCDC88A mutations cause PEHO-like syndrome in humans and mouse

    PubMed Central

    Nahorski, Michael S.; Asai, Masato; Wakeling, Emma; Parker, Alasdair; Asai, Naoya; Canham, Natalie; Holder, Susan E.; Chen, Ya-Chun; Dyer, Joshua

    2016-01-01

    Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with ‘early infantile epileptic encephalopathy’. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediate