Near-infrared imaging of enamel hypomineralization due to developmental defects.

PubMed

Lee, Robert C; Jang, Andrew; Fried, Daniel

2017-01-28

The increasing prevalence of mild hypomineralization due to developmental defects on tooth surfaces poses a challenge for caries detection and caries risk assessment and reliable methods need to be developed to discriminate such lesions from active caries lesions that need intervention. Previous studies have demonstrated that areas of hypomineralization are typically covered with a relatively thick surface layer of highly mineralized and transparent enamel similar to arrested lesions. Seventy-six extracted human teeth with mild to moderate degrees of suspicious fluorosis were imaged using near-infrared reflectance and transillumination. Enamel hypomineralization was clearly visible in both modalities. However, it was difficult to distinguish hypomineralization due to developmental defects from caries lesions with contrast measurements alone. The location of the lesion on tooth coronal surface (i.e. generalized vs. localized) seems to be the most important indicator for the presence of enamel hypomineralization due to developmental defects.

Association between developmental defects of enamel and dental caries: A systematic review and meta-analysis.

PubMed

Vargas-Ferreira, F; Salas, M M S; Nascimento, G G; Tarquinio, S B C; Faggion, C M; Peres, M A; Thomson, W M; Demarco, F F

2015-06-01

Dental caries is the main problem oral health and it is not well established in the literature if the enamel defects are a risk factor for its development. Studies have reported a potential association between developmental defects enamel (DDE) and dental caries occurrence. We investigated the association between DDE and caries in permanent dentition of children and teenagers. A systematic review was carried out using four databases (Pubmed, Web of Science, Embase, and Science Direct), which were searched from their earliest records until December 31, 2014. Population-based studies assessing differences in dental caries experience according to the presence of enamel defects (and their types) were included. PRISMA guidelines for reporting systematic reviews were followed. Meta-analysis was performed to assess the pooled effect, and meta-regression was carried out to identify heterogeneity sources. From the 2558 initially identified papers, nine studies fulfilled all inclusion criteria after checking the titles, abstracts, references, and complete reading. Seven of them were included in the meta-analysis with random model. A positive association between enamel defects and dental caries was identified; meta-analysis showed that individuals with DDE had higher pooled odds of having dental caries experience [OR 2.21 (95% CI 1.3; 3.54)]. Meta-regression analysis demonstrated that adjustment for sociodemographic factors, countries' socioeconomic status, and bias (quality of studies) explained the high heterogeneity observed. A higher chance of dental caries should be expected among individuals with enamel defects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim

2014-01-15

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairmentmore » of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.« less

Reproduction Symposium: developmental programming of reproductive and metabolic health.

PubMed

Padmanabhan, V; Veiga-Lopez, A

2014-08-01

Inappropriate programming of the reproductive system by developmental exposure to excess steroid hormones is of concern. Sheep are well suited for investigating developmental origin of reproductive and metabolic disorders. The developmental time line of female sheep (approximately 5 mo gestation and approximately 7 mo to puberty) is ideal for conducting sequential studies of the progression of metabolic and/or reproductive disruption from the developmental insult to manifestation of adult consequences. Major benefits of using sheep include knowledge of established critical periods to target adult defects, a rich understanding of reproductive neuroendocrine regulation, availability of noninvasive approaches to monitor follicular dynamics, established surgical approaches to obtain hypophyseal portal blood for measurement of hypothalamic hormones, and the ability to perform studies in natural setting thereby keeping behavioral interactions intact. Of importance is the ability to chronically instrument fetus and mother for determining early endocrine perturbations. Prenatal exposure of the female to excess testosterone (T) leads to an array of adult reproductive disorders that include LH excess, functional hyperandrogenism, neuroendocrine defects, multifollicular ovarian morphology, and corpus luteum dysfunction culminating in early reproductive failure. At the neuroendocrine level, all 3 feedback systems are compromised. At the pituitary level, gonadotrope (LH secretion) sensitivity to GnRH is increased. Multifollicular ovarian morphology stems from persistence of follicles as well as enhanced follicular recruitment. These defects culminate in progressive loss of cyclicity and reduced fecundity. Prenatal T excess also leads to fetal growth retardation, an early marker of adult reproductive and metabolic diseases, insulin resistance, hypertension, and behavioral deficits. Collectively, the reproductive and metabolic deficits of prenatal T-treated sheep provide proof of concept for the developmental origin of fertility and metabolic disorders. Studies with the environmental endocrine disruptor bisphenol A (BPA) show that reproductive disruptions found in prenatal BPA-treated sheep are similar to those seen in prenatal T-treated sheep. The ubiquitous exposure to endocrine disrupting compounds with steroidogenic potential via the environment and food sources calls for studies addressing the impact of developmental exposure to environmental steroid mimics on reproductive function.

Developmental programming of reproductive and metabolic health1,2

PubMed Central

Padmanabhan, V.; Veiga-Lopez, A.

2014-01-01

The inappropriate programming of the reproductive system by developmental exposure to excess steroid hormones is of concern. Sheep are well suited for investigating developmental origin of reproductive and metabolic disorders. The developmental time line of female sheep (~5 mo gestation and ~7 mo to puberty) is ideal for conducting sequential studies of the progression of metabolic and (or) reproductive disruption from the developmental insult to manifestation of adult consequences. Major benefits of using sheep include knowledge of established critical periods to target adult defects, a rich understanding of reproductive neuroendocrine regulation, availability of non-invasive approaches to monitor follicular dynamics, established surgical approaches to obtain hypophyseal portal blood for measurement of hypothalamic hormones, and the ability to perform studies in natural setting keeping behavioral interactions intact. Of importance is the ability to chronically instrument fetus and mother for determining early endocrine perturbations. Prenatal exposure of the female to excess testosterone (T) leads to an array of adult reproductive disorders that include LH excess, functional hyperandrogenism, neuroendocrine defects, multifollicular ovarian morphology, and corpus luteum dysfunction culminating in early reproductive failure. At the neuroendocrine level all three feedback systems are compromised. At the pituitary level, gonadotrope (LH secretion) sensitivity to GnRH is increased. Multifollicular ovarian morphology stems from persistence of follicles, as well as enhanced follicular recruitment. These defects culminate in progressive loss of cyclicity and reduced fecundity. Prenatal T excess also leads to fetal growth retardation, an early marker of adult reproductive/metabolic diseases, insulin resistance, hypertension and behavioral deficits. Collectively, the reproductive and metabolic deficits of prenatal T-treated sheep provide proof of concept for the developmental origin of fertility and metabolic disorders. Studies with the environmental endocrine disruptor, bisphenol-A (BPA), show that reproductive disruptions found in prenatal BPA-treated sheep are similar to those seen in prenatal T-treated sheep. The ubiquitous exposure to endocrine disrupting compounds (EDC) with steroidogenic potential via the environment and food sources, calls for studies addressing the impact of developmental exposure to environmental steroid mimics on reproductive function. PMID:25074449

Genetic and flow anomalies in congenital heart disease.

PubMed

Rugonyi, Sandra

2016-01-01

Congenital heart defects are the most common malformations in humans, affecting approximately 1% of newborn babies. While genetic causes of congenital heart disease have been studied, only less than 20% of human cases are clearly linked to genetic anomalies. The cause for the majority of the cases remains unknown. Heart formation is a finely orchestrated developmental process and slight disruptions of it can lead to severe malformations. Dysregulation of developmental processes leading to heart malformations are caused by genetic anomalies but also environmental factors including blood flow. Intra-cardiac blood flow dynamics plays a significant role regulating heart development and perturbations of blood flow lead to congenital heart defects in animal models. Defects that result from hemodynamic alterations, however, recapitulate those observed in human babies, even those due to genetic anomalies and toxic teratogen exposure. Because important cardiac developmental events, such as valve formation and septation, occur under blood flow conditions while the heart is pumping, blood flow regulation of cardiac formation might be a critical factor determining cardiac phenotype. The contribution of flow to cardiac phenotype, however, is frequently ignored. More research is needed to determine how blood flow influences cardiac development and the extent to which flow may determine cardiac phenotype.

Developmental Defects of Caenorhabditis elegans Lacking Branched-chain α-Ketoacid Dehydrogenase Are Mainly Caused by Monomethyl Branched-chain Fatty Acid Deficiency.

PubMed

Jia, Fan; Cui, Mingxue; Than, Minh T; Han, Min

2016-02-05

Branched-chain α-ketoacid dehydrogenase (BCKDH) catalyzes the critical step in the branched-chain amino acid (BCAA) catabolic pathway and has been the focus of extensive studies. Mutations in the complex disrupt many fundamental metabolic pathways and cause multiple human diseases including maple syrup urine disease (MSUD), autism, and other related neurological disorders. BCKDH may also be required for the synthesis of monomethyl branched-chain fatty acids (mmBCFAs) from BCAAs. The pathology of MSUD has been attributed mainly to BCAA accumulation, but the role of mmBCFA has not been evaluated. Here we show that disrupting BCKDH in Caenorhabditis elegans causes mmBCFA deficiency, in addition to BCAA accumulation. Worms with deficiency in BCKDH function manifest larval arrest and embryonic lethal phenotypes, and mmBCFA supplementation suppressed both without correcting BCAA levels. The majority of developmental defects caused by BCKDH deficiency may thus be attributed to lacking mmBCFAs in worms. Tissue-specific analysis shows that restoration of BCKDH function in multiple tissues can rescue the defects, but is especially effective in neurons. Taken together, we conclude that mmBCFA deficiency is largely responsible for the developmental defects in the worm and conceivably might also be a critical contributor to the pathology of human MSUD. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Developmental and Post-Eruptive Defects in Molar Enamel of Free-Ranging Eastern Grey Kangaroos (Macropus giganteus) Exposed to High Environmental Levels of Fluoride

PubMed Central

Kierdorf, Uwe; Death, Clare; Hufschmid, Jasmin; Witzel, Carsten; Kierdorf, Horst

2016-01-01

Dental fluorosis has recently been diagnosed in wild marsupials inhabiting a high-fluoride area in Victoria, Australia. Information on the histopathology of fluorotic marsupial enamel has thus far not been available. This study analyzed the developmental and post-eruptive defects in fluorotic molar enamel of eastern grey kangaroos (Macropus giganteus) from the same high-fluoride area using light microscopy and backscattered electron imaging in the scanning electron microscope. The fluorotic enamel exhibited a brownish to blackish discolouration due to post-eruptive infiltration of stains from the oral cavity and was less resistant to wear than normally mineralized enamel of kangaroos from low-fluoride areas. Developmental defects of enamel included enamel hypoplasia and a pronounced hypomineralization of the outer (sub-surface) enamel underneath a thin rim of well-mineralized surface enamel. While the hypoplastic defects denote a disturbance of ameloblast function during the secretory stage of amelogenesis, the hypomineralization is attributed to an impairment of enamel maturation. In addition to hypoplastic defects, the fluorotic molars also exhibited numerous post-eruptive enamel defects due to the flaking-off of portions of the outer, hypomineralized enamel layer during mastication. The macroscopic and histopathological lesions in fluorotic enamel of M. giganteus match those previously described for placental mammals. It is therefore concluded that there exist no principal differences in the pathogenic mechanisms of dental fluorosis between marsupial and placental mammals. The regular occurrence of hypomineralized, opaque outer enamel in the teeth of M. giganteus and other macropodids must be considered in the differential diagnosis of dental fluorosis in these species. PMID:26895178

Macondo crude oil from the Deepwater Horizon oil spill disrupts specific developmental processes during zebrafish embryogenesis

PubMed Central

2012-01-01

Background The Deepwater Horizon disaster was the largest marine oil spill in history, and total vertical exposure of oil to the water column suggests it could impact an enormous diversity of ecosystems. The most vulnerable organisms are those encountering these pollutants during their early life stages. Water-soluble components of crude oil and specific polycyclic aromatic hydrocarbons have been shown to cause defects in cardiovascular and craniofacial development in a variety of teleost species, but the developmental origins of these defects have yet to be determined. We have adopted zebrafish, Danio rerio, as a model to test whether water accumulated fractions (WAF) of the Deepwater Horizon oil could impact specific embryonic developmental processes. While not a native species to the Gulf waters, the developmental biology of zebrafish has been well characterized and makes it a powerful model system to reveal the cellular and molecular mechanisms behind Macondo crude toxicity. Results WAF of Macondo crude oil sampled during the oil spill was used to treat zebrafish throughout embryonic and larval development. Our results indicate that the Macondo crude oil causes a variety of significant defects in zebrafish embryogenesis, but these defects have specific developmental origins. WAF treatments caused defects in craniofacial development and circulatory function similar to previous reports, but we extend these results to show they are likely derived from an earlier defect in neural crest cell development. Moreover, we demonstrate that exposure to WAFs causes a variety of novel deformations in specific developmental processes, including programmed cell death, locomotor behavior, sensory and motor axon pathfinding, somitogenesis and muscle patterning. Interestingly, the severity of cell death and muscle phenotypes decreased over several months of repeated analysis, which was correlated with a rapid drop-off in the aromatic and alkane hydrocarbon components of the oil. Conclusions Whether these teratogenic effects are unique to the oil from the Deepwater Horizon oil spill or generalizable for most crude oil types remains to be determined. This work establishes a model for further investigation into the molecular mechanisms behind crude oil mediated deformations. In addition, due to the high conservation of genetic and cellular processes between zebrafish and other vertebrates, our work also provides a platform for more focused assessment of the impact that the Deepwater Horizon oil spill has had on the early life stages of native fish species in the Gulf of Mexico and the Atlantic Ocean. PMID:22559716

Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis.

PubMed

Lovely, Charles Ben; Fernandes, Yohaan; Eberhart, Johann K

2016-10-01

Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects, including craniofacial dysmorphology and cognitive impairments. It affects ∼1 in 100 children born in the United States each year. Due to the pleiotropic effects of ethanol, animal models have proven critical in characterizing the mechanisms of ethanol teratogenesis. In this review, we focus on the utility of zebrafish in characterizing ethanol-induced developmental defects. A growing number of laboratories have focused on using zebrafish to examine ethanol-induced defects in craniofacial, cardiac, ocular, and neural development, as well as cognitive and behavioral impairments. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects, yet little is understood about these gene-ethanol interactions. With a high degree of genetic amenability, zebrafish is at the forefront of identifying and characterizing the gene-ethanol interactions that underlie FASD. Because of the conservation of gene function between zebrafish and humans, these studies will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

EXPERIMENTAL MODELS FOR THE STUDY OF ORAL CLEFTS

EPA Science Inventory

Toxicology and teratology studies routinely utilize animal models to determine the potential for chemical and physical agents to produce reproductive and developmental toxicity, including birth defects such as cleft palate. The standardized teratology screen typically tests co...

Oral Health Characteristics and Dental Rehabilitation of Children with Global Developmental Delay.

PubMed

Kumar, Saurabh; Pai, Deepika; Saran, Runki

2017-01-01

Global developmental delay (GDD) is a chronic neurological disturbance which includes defects in one or more developmental domains. The developmental domain can be motor, cognitive, daily activities, speech or language, and social or personal development. The etiology for GDD can be prenatal, perinatal, or postnatal. It can be diagnosed early in childhood as the delay or absence of one or more developmental milestones. Hence the role of pedodontist and pediatricians becomes more crucial in identifying this condition. The diagnosis of GDD requires a detailed history including family history and environmental risk factors followed by physical and neurological examinations. Investigations for GDD include diagnostic laboratory tests, brain imaging, and other evidence-based evaluations. GDD affects multiple developmental domains that not only have direct bearing on maintenance of oral health, but also require additional behavior management techniques to deliver optimal dental care. This paper describes two different spectra of children with GDD. Since the severity of GDD can vary, this paper also discusses the different behavior management techniques that were applied to provide dental treatment in such children.

Color masking of developmental enamel defects: a case series.

PubMed

Torres, C R G; Borges, A B

2015-01-01

Developmental defects involving color alteration of enamel frequently compromise the esthetic appearance of the tooth. The resin infiltration technique represents an alternative treatment for color masking of these lesions and uniformization of tooth color. This technique is considered relatively simple and microinvasive, since only a minimal portion of enamel is removed. This article illustrates the color-masking effect with resin infiltration of fluorosis and traumatic hypomineralization lesions with a case series. The final esthetic outcomes demonstrated the ability of the resin infiltrant to mask the color of white developmental defect lesions, resulting in satisfactory clinical esthetic improvements. However, in more severe cases, the color-masking effect was not complete.

The Sterol Methyltransferases SMT1, SMT2, and SMT3 Influence Arabidopsis Development through Nonbrassinosteroid Products1[W][OA

PubMed Central

Carland, Francine; Fujioka, Shozo; Nelson, Timothy

2010-01-01

Plant sterols are structural components of cell membranes that provide rigidity, permeability, and regional identity to membranes. Sterols are also the precursors to the brassinosteroid signaling molecules. Evidence is accumulating that specific sterols have roles in pattern formation during development. COTYLEDON VASCULAR PATTERNING1 (CVP1) encodes C-24 STEROL METHYLTRANSFERASE2 (SMT2), one of three SMTs in Arabidopsis (Arabidopsis thaliana). SMT2 and SMT3, which also encodes a C-24 SMT, catalyze the reaction that distinguishes the synthesis of structural sterols from signaling brassinosteroid derivatives and are highly regulated. The deficiency of SMT2 in the cvp1 mutant results in moderate developmental defects, including aberrant cotyledon vein patterning, serrated floral organs, and reduced stature, but plants are viable, suggesting that SMT3 activity can substitute for the loss of SMT2. To test the distinct developmental roles of SMT2 and SMT3, we identified a transcript null smt3 mutant. Although smt3 single mutants appear wild type, cvp1 smt3 double mutants show enhanced defects relative to cvp1 mutants, such as discontinuous cotyledon vein pattern, and produce novel phenotypes, including defective root growth, loss of apical dominance, sterility, and homeotic floral transformations. These phenotypes are correlated with major alterations in the profiles of specific sterols but without significant alterations to brassinosteroid profiles. The alterations to sterol profiles in cvp1 mutants affect auxin response, demonstrated by weak auxin insensitivity, enhanced axr1 auxin resistance, ectopically expressed DR5:β-glucuronidase in developing embryos, and defective response to auxin-inhibited PIN2-green fluorescent protein endocytosis. We discuss the developmental roles of sterols implied by these results. PMID:20421456

Teratology: from science to birth defects prevention.

PubMed

Rasmussen, Sonja A; Erickson, J David; Reef, Susan E; Ross, Danielle S

2009-01-01

One of the goals of birth defects research is to better understand risk or preventive factors for birth defects so that strategies for prevention can be developed. In this article, we have selected four areas of birth defects research that have led to the development of prevention strategies. These areas include rubella virus as a cause of congenital rubella syndrome, folic acid as a preventive factor for neural tube defects, cytomegalovirus infection as a cause of birth defects and developmental disabilities, and alcohol as a cause of fetal alcohol spectrum disorders. For each of these areas, we review key clinical and research findings that led to the identification of the risk or preventive factor, milestones in the development of prevention strategies, and the progress made thus far toward prevention.

Prenatal stress and development: beyond the single cause and effect paradigm.

PubMed

Hamlin, Heather J

2012-12-01

Our awareness of the causes of stress-induced developmental dysfunction has increased dramatically over the past decade, and it is becoming increasingly clear that a number of factors can have considerable impacts on the developing fetus. Although there is a tendency in investigations of developmental teratogens to attribute specific causes to adverse fetal outcomes, it is important we recognize that for most developmental dysfunctions it is unlikely a single cause, but yet a series of environmental insults combined with genetic predisposition that ultimately leads to a disease state. Nonetheless, a number of developmental teratogens, such as maternal psychological stress and chemical exposures, have been shown to increase the likelihood of developmental defects. These defects can manifest during development, leading to observable birth defects, or could become evident long after birth, even into adulthood. In addition, epigenetic mutations in the germline can alter the phenotype of successive generations through transgenerational inheritance, and in this way environmental factors can alter the developmental outcomes and disease predispositions of future generations. Understanding this complexity is essential to interpretations of causality in the studies of stress-induced developmental dysfunction and needs to be fully considered to more effectively interpret potential outcomes. Copyright © 2013 Wiley Periodicals, Inc.

Interstitial deletion of 8q21-->22 associated with minor anomalies, congenital heart defect, and Dandy-Walker variant.

PubMed

Donahue, M L; Ryan, R M

1995-03-13

We describe an infant with a deletion of 8q21-->22 who had distinct clinical manifestations including minor facial anomalies, a congenital heart defect, a Dandy-Walker variant, and mild to moderate developmental delay. Her facial characteristics included small, wide-spaced eyes, asymmetric bilateral epicanthal folds, a broad nasal bridge, a "carp-shaped" mouth, micrognathia, and prominent, apparently low-set ears. Three other reports describe children with larger proximal deletions of 8q that include 8q21 and q22. These four children all have similar facial appearance. Of the others reported, one had a congenital heart defect and one had craniosynostosis. This case, in addition to the previously noted three cases, helps in delineating a recognizable syndrome.

Near-infrared imaging of developmental defects in dental enamel.

PubMed

Hirasuna, Krista; Fried, Daniel; Darling, Cynthia L

2008-01-01

Polarization-sensitive optical coherence tomography (PS-OCT) and near-infrared (NIR) imaging are promising new technologies under development for monitoring early carious lesions. Fluorosis is a growing problem in the United States, and the more prevalent mild fluorosis can be visually mistaken for early enamel demineralization. Unfortunately, there is little quantitative information available regarding the differences in optical properties of sound enamel, enamel developmental defects, and caries. Thirty extracted human teeth with various degrees of suspected fluorosis were imaged using PS-OCT and NIR. An InGaAs camera and a NIR diode laser were used to measure the optical attenuation through transverse tooth sections (approximately 200 microm). A digital microradiography system was used to quantify the enamel defect severity by measurement of the relative mineral loss for comparison with optical scattering measurements. Developmental defects were clearly visible in the polarization-resolved OCT images, demonstrating that PS-OCT can be used to nondestructively measure the depth and possible severity of the defects. Enamel defects on whole teeth that could be imaged with high contrast with visible light were transparent in the NIR. This study suggests that PS-OCT and NIR methods may potentially be used as tools to assess the severity and extent of enamel defects.

The Endocytic Recycling Regulatory Protein EHD1 Is Required for Ocular Lens Development

PubMed Central

Arya, Priyanka; Rainey, Mark A.; Bhattacharyya, Sohinee; Mohapatra, Bhopal; George, Manju; Kuracha, Murali R; Storck, Matthew D.; Band, Vimla; Govindarajan, Venkatesh; Band, Hamid

2015-01-01

The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis. PMID:26455409

Scalp defects, polythelia, microcephaly, and developmental delay: a new syndrome with apparent autosomal dominant inheritance.

PubMed

Marble, Michael; Pridjian, Gabriella

2002-04-01

We report a family with apparent autosomal dominant inheritance of scalp defects, polythelia, microcephaly, and developmental delay. A review of the literature revealed no previous report of this combination of anomalies. We conclude that these patients have a new autosomal dominant syndrome. Copyright 2002 Wiley-Liss, Inc.

A novel ciliopathic skull defect arising from excess neural crest.

PubMed

Tabler, Jacqueline M; Rice, Christopher P; Liu, Karen J; Wallingford, John B

2016-09-01

The skull is essential for protecting the brain from damage, and birth defects involving disorganization of skull bones are common. However, the developmental trajectories and molecular etiologies by which many craniofacial phenotypes arise remain poorly understood. Here, we report a novel skull defect in ciliopathic Fuz mutant mice in which only a single bone pair encases the forebrain, instead of the usual paired frontal and parietal bones. Through genetic lineage analysis, we show that this defect stems from a massive expansion of the neural crest-derived frontal bone. This expansion occurs at the expense of the mesodermally-derived parietal bones, which are either severely reduced or absent. A similar, though less severe, phenotype was observed in Gli3 mutant mice, consistent with a role for Gli3 in cilia-mediated signaling. Excess crest has also been shown to drive defective palate morphogenesis in ciliopathic mice, and that defect is ameliorated by reduction of Fgf8 gene dosage. Strikingly, skull defects in Fuz mutant mice are also rescued by loss of one allele of fgf8, suggesting a potential route to therapy. In sum, this work is significant for revealing a novel skull defect with a previously un-described developmental etiology and for suggesting a common developmental origin for skull and palate defects in ciliopathies. Copyright © 2016 Elsevier Inc. All rights reserved.

Congenital Heart Defects and Receipt of Special Education Services.

PubMed

Riehle-Colarusso, Tiffany; Autry, Andrew; Razzaghi, Hilda; Boyle, Coleen A; Mahle, William T; Van Naarden Braun, Kim; Correa, Adolfo

2015-09-01

We investigated the prevalence of receipt of special education services among children with congenital heart defects (CHDs) compared with children without birth defects. Children born from 1982 to 2004 in metropolitan Atlanta with CHDs (n = 3744) were identified from a population-based birth defect surveillance program; children without birth defects (n = 860 715) were identified from birth certificates. Cohorts were linked to special education files for the 1992-2012 school years to identify special education services. Children with noncardiac defects or genetic syndromes were excluded; children with CHDs were classified by presence or absence of critical CHDs (ie, CHDs requiring intervention by age one year). We evaluated the prevalence of receipt of special education services and prevalence rate ratios using children without birth defects as a reference. Compared with children without birth defects, children with CHDs were 50% more likely to receive special education services overall (adjusted prevalence rate ratio [aPRR] = 1.5; 95% confidence interval [CI]: 1.4-1.7). Specifically, they had higher prevalence of several special education categories including: intellectual disability (aPRR = 3.8; 95% CI: 2.8-5.1), sensory impairment (aPRR = 3.0; 95% CI: 1.8-5.0), other health impairment (aPRR = 2.8; 95% CI: 2.2-3.5), significant developmental delay (aPRR = 1.9; 95% CI: 1.3-2.8), and specific learning disability (aPRR = 1.4; 95% CI: 1.1-1.7). For most special education services, the excess prevalence did not vary by presence of critical CHDs. Children with CHDs received special education services more often than children without birth defects. These findings highlight the need for special education services and the importance of developmental screening for all children with CHDs. Copyright © 2015 by the American Academy of Pediatrics.

Developmental and perinatal brain diseases.

PubMed

Adle-Biassette, Homa; Golden, Jeffery A; Harding, Brian

2017-01-01

This chapter briefly describes the normal development of the nervous system, the neuropathology and pathophysiology of acquired and secondary disorders affecting the embryo, fetus, and child. They include CNS manifestations of chromosomal change; forebrain patterning defects; disorders of the brain size; cell migration and specification disorders; cerebellum, hindbrain and spinal patterning defects; hydrocephalus; secondary malformations and destructive pathologies; vascular malformations; arachnoid cysts and infectious diseases. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Copyright © 2017 Elsevier B.V. All rights reserved.

The aristaless-like homeobox protein Alx3 as an etiopathogenic factor for diabetes mellitus.

PubMed

Vallejo, Mario

2011-01-01

Inactivation of the gene encoding the aristaless-related homeodomain transcription factor Alx3 results in islet cell apoptosis and impaired glucose homeostasis that worsens with age due to the appearance of insulin resistance. Alx3-deficient mice also show extrapancreatic developmental defects with variable penetrance. These include polydactyly, craniofacial midline defects, and neural tube closure defects. In humans, related congenital defects associated with mutations in ALX3 and other aristaless-related genes are being identified. Emerging evidence suggests that normal pancreatic function in humans may require the integrity of aristaless-related genes. Here, the proposal that ALX3 could be considered as a candidate gene for the etiopathogenesis of diabetes or its complications during embryonic or fetal development is discussed.

Axenfeld-Rieger syndrome.

PubMed

Seifi, M; Walter, M A

2018-06-01

Axenfeld-Rieger syndrome (ARS) is a clinically and genetically heterogeneous group of developmental disorders affecting primarily the anterior segment of the eye, often leading to secondary glaucoma. Patients with ARS may also present with systemic changes, including dental defects, mild craniofacial dysmorphism, and umbilical anomalies. ARS is inherited in an autosomal-dominant fashion; the underlying defect in 40% of patients is mutations in PITX2 or FOXC1. Here, an overview of the clinical spectrum of ARS is provided. As well, the known underlying genetic defects, clinical diagnostic possibilities, genetic counseling and treatments of ARS are discussed in detail. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development

PubMed Central

Takahashi, Takamune; Takahashi, Keiko; St. John, Patricia L.; Fleming, Paul A.; Tomemori, Takuya; Watanabe, Toshio; Abrahamson, Dale R.; Drake, Christopher J.; Shirasawa, Takuji; Daniel, Thomas O.

2003-01-01

Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTPη), participates in developmental vascularization. A mutant allele, CD148ΔCyGFP, was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions. PMID:12588999

Genetic and Cellular Mechanisms Regulating Anterior Foregut and Esophageal Development

PubMed Central

Jacobs, Ian J.; Ku, Wei-Yao; Que, Jianwen

2012-01-01

Separation of the single anterior foregut tube into the esophagus and trachea involves cell proliferation and differentiation, as well as dynamic changes in cell-cell adhesion and migration. These biological processes are regulated and coordinated at multiple levels through the interplay of the epithelium and mesenchyme. Genetic studies and in vitro modeling have shed light on relevant regulatory networks that include a number of transcription factors and signaling pathways. These signaling molecules exhibit unique expression patterns and play specific functions in their respective territories before the separation process occurs. Disruption of regulatory networks inevitably leads to defective separation and malformation of the trachea and esophagus and results in the formation of a relatively common birth defect, esophageal atresia with or without tracheoesophageal fistula (EA/TEF). Significantly, some of the signaling pathways and transcription factors involved in anterior foregut separation continue to play important roles in the morphogenesis of the individual organs. In this review, we will focus on new findings related to these different developmental processes and discuss them in the context of developmental disorders (or birth defects) commonly seen in clinics. PMID:22750256

Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects

PubMed Central

Khan, Kamron; Logan, Clare V.; McKibbin, Martin; Sheridan, Eamonn; Elçioglu, Nursel H.; Yenice, Ozlem; Parry, David A.; Fernandez-Fuentes, Narcis; Abdelhamed, Zakia I.A.; Al-Maskari, Ahmed; Poulter, James A.; Mohamed, Moin D.; Carr, Ian M.; Morgan, Joanne E.; Jafri, Hussain; Raashid, Yasmin; Taylor, Graham R.; Johnson, Colin A.; Inglehearn, Chris F.; Toomes, Carmel; Ali, Manir

2012-01-01

The atonal homolog 7 (ATOH7) gene encodes a transcription factor involved in determining the fate of retinal progenitor cells and is particularly required for optic nerve and ganglion cell development. Using a combination of autozygosity mapping and next generation sequencing, we have identified homozygous mutations in this gene, p.E49V and p.P18RfsX69, in two consanguineous families diagnosed with multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus. Most of these clinical features overlap with defects in the Norrin/β-catenin signalling pathway that is characterized by dysgenesis of the retinal and hyaloid vasculature. Our findings document Mendelian mutations within ATOH7 and imply a role for this molecule in the development of structures at the front as well as the back of the eye. This work also provides further insights into the function of ATOH7, especially its importance in retinal vascular development and hyaloid regression. PMID:22068589

Post-natal myogenic and adipogenic developmental

PubMed Central

Konings, Gonda; van Weeghel, Michel; van den Hoogenhof, Maarten MG; Gijbels, Marion; van Erk, Arie; Schoonderwoerd, Kees; van den Bosch, Bianca; Dahlmans, Vivian; Calis, Chantal; Houten, Sander M; Misteli, Tom

2011-01-01

A-type lamins are a major component of the nuclear lamina. Mutations in the LMNA gene, which encodes the A-type lamins A and C, cause a set of phenotypically diverse diseases collectively called laminopathies. While adult LMNA null mice show various symptoms typically associated with laminopathies, the effect of loss of lamin A/C on early post-natal development is poorly understood. Here we developed a novel LMNA null mouse (LMNAGT−/−) based on genetrap technology and analyzed its early post-natal development. We detect LMNA transcripts in heart, the outflow tract, dorsal aorta, liver and somites during early embryonic development. Loss of A-type lamins results in severe growth retardation and developmental defects of the heart, including impaired myocyte hypertrophy, skeletal muscle hypotrophy, decreased amounts of subcutaneous adipose tissue and impaired ex vivo adipogenic differentiation. These defects cause death at 2 to 3 weeks post partum associated with muscle weakness and metabolic complications, but without the occurrence of dilated cardiomyopathy or an obvious progeroid phenotype. Our results indicate that defective early post-natal development critically contributes to the disease phenotypes in adult laminopathies. PMID:21818413

Developmental toxicity in flounder embryos exposed to crude oils derived from different geographical regions.

PubMed

Jung, Jee-Hyun; Lee, Eun-Hee; Choi, Kwang-Min; Yim, Un Hyuk; Ha, Sung Yong; An, Joon Geon; Kim, Moonkoo

2017-06-01

Crude oils from distinct geographical regions have distinct chemical compositions, and, as a result, their toxicity may be different. However, developmental toxicity of crude oils derived from different geographical regions has not been extensively characterized. In this study, flounder embryos were separately exposed to effluents contaminated by three crude oils including: Basrah Light (BLO), Pyrenees (PCO), and Sakhalin Vityaz (SVO), in addition to a processed fuel oil (MFO-380), to measure developmental toxicity and for gene expressions. Each oil possessed a distinct chemical composition. Edema defect was highest in embryos exposed to PCO and MFO-380 that both have a greater fraction of three-ring PAHs (33% and 22%, respectively) compared to BLO and SVO. Observed caudal fin defects were higher in embryos exposed to SVO and MFO-380, which are both dominated by naphthalenes (81% and 52%, respectively). CYP1A gene expressions were also highest in embryos exposed to SVO and MFO-380. Higher incidence of cardiotoxicity and lower nkx 2.5 expression were detected in embryos exposed to PCO. Unique gene expression profiles were observed in embryos exposed to crude oils with distinct compositions. This study demonstrates that crude oils of different geographical origins with different compositional characteristics induce developmental toxicity to different degrees. Copyright © 2017 Elsevier Inc. All rights reserved.

Developmental transitions in C. elegans larval stages.

PubMed

Rougvie, Ann E; Moss, Eric G

2013-01-01

Molecular mechanisms control the timing, sequence, and synchrony of developmental events in multicellular organisms. In Caenorhabditis elegans, these mechanisms are revealed through the analysis of mutants with "heterochronic" defects: cell division or differentiation patterns that occur in the correct lineage, but simply at the wrong time. Subsets of cells in these mutants thus express temporal identities normally restricted to a different life stage. A seminal finding arising from studies of the heterochronic genes was the discovery of miRNAs; these tiny miRNAs are now a defining feature of the pathway. A series of sequentially expressed miRNAs guide larval transitions through stage-specific repression of key effector molecules. The wild-type lineage patterns are executed as discrete modules programmed between temporal borders imposed by the molting cycles. How these successive events are synchronized with the oscillatory molting cycle is just beginning to come to light. Progression through larval stages can be specifically, yet reversibly, halted in response to environmental cues, including nutrient availability. Here too, heterochronic genes and miRNAs play key roles. Remarkably, developmental arrest can, in some cases, either mask or reveal timing defects associated with mutations. In this chapter, we provide an overview of how the C. elegans heterochronic gene pathway guides developmental transitions during continuous and interrupted larval development. © 2013 Elsevier Inc. All rights reserved.

Interstitial deletion of 8q21{yields}22 associated with minor anomalies, congenital heart defect, and Dandy-Walker variant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donahue, M.L.; Ryan, R.M.

1995-03-13

We describe an infant with a deletion of 8q21{yields}22 who had distinct clinical manifestations including minor facial anomalies, a congenital heart defect, a Dandy-Walker variant, and mild to moderate developmental delay. Her facial characteristics included small, wide-spaced eyes, asymmetric bilateral epicanthal folds, a broad nasal bridge, a {open_quotes}carp-shaped{close_quotes} mouth, micrognathia, and prominent, apparently low-set ears. Three other reports describe children with larger proximal deletions of 8q that include 8q21 and q22. These four children all have similar facial appearance. Of the others reported, one had a congenital heart defect and one had craniosynostosis. This case, in addition to the previouslymore » noted three cases, helps in delineating a recognizable syndrome. 12 refs., 3 figs., 1 tab.« less

Defective pulmonary innervation and autonomic imbalance in congenital diaphragmatic hernia

PubMed Central

Lath, Nikesh R.; Galambos, Csaba; Rocha, Alejandro Best; Malek, Marcus; Gittes, George K.

2012-01-01

Congenital diaphragmatic hernia (CDH) is associated with significant mortality due to lung hypoplasia and pulmonary hypertension. The role of embryonic pulmonary innervation in normal lung development and lung maldevelopment in CDH has not been defined. We hypothesize that developmental defects of intrapulmonary innervation, in particular autonomic innervation, occur in CDH. This abnormal embryonic pulmonary innervation may contribute to lung developmental defects and postnatal physiological derangement in CDH. To define patterns of pulmonary innervation in CDH, human CDH and control lung autopsy specimens were stained with the pan-neural marker S-100. To further characterize patterns of overall and autonomic pulmonary innervation during lung development in CDH, the murine nitrofen model of CDH was utilized. Immunostaining for protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (a sympathetic marker), vesicular acetylcholine transporter (a parasympathetic marker), or VIP (a parasympathetic marker) was performed on lung whole mounts and analyzed via confocal microscopy and three-dimensional reconstruction. Peribronchial and perivascular neuronal staining pattern is less complex in human CDH than control lung. In mice, protein gene product 9.5 staining reveals less complex neuronal branching and decreased neural tissue in nitrofen-treated lungs from embryonic day 12.5 to 16.5 compared with controls. Furthermore, nitrofen-treated embryonic lungs exhibited altered autonomic innervation, with a relative increase in sympathetic nerve staining and a decrease in parasympathetic nerve staining compared with controls. These results suggest a primary defect in pulmonary neural developmental in CDH, resulting in less complex neural innervation and autonomic imbalance. Defective embryonic pulmonary innervation may contribute to lung developmental defects and postnatal physiological derangement in CDH. PMID:22114150

METROPOLITAN ATLANTA DEVELOPMENTAL DISABILITIES PROGRAM (MADDSP)

EPA Science Inventory

To address the problem of developmental disabilities among children, CDC, the former Division of Birth Defects and Developmental Disabilities, which was funded by the Agency for Toxic Substances and Disease Registry (ATSDR), and the Georgia Department of Human Resources, initiate...

Lower urinary tract development and disease

PubMed Central

Rasouly, Hila Milo; Lu, Weining

2013-01-01

Congenital Anomalies of the Lower Urinary Tract (CALUT) are a family of birth defects of the ureter, the bladder and the urethra. CALUT includes ureteral anomalies such as congenital abnormalities of the ureteropelvic junction (UPJ) and ureterovesical junction (UVJ), and birth defects of the bladder and the urethra such as bladder-exstrophy-epispadias complex (BEEC), prune belly syndrome (PBS), and posterior urethral valves (PUV). CALUT is one of the most common birth defects and is often associated with antenatal hydronephrosis, vesicoureteral reflux (VUR), urinary tract obstruction, urinary tract infections (UTI), chronic kidney disease and renal failure in children. Here, we discuss the current genetic and molecular knowledge about lower urinary tract development and genetic basis of CALUT in both human and mouse models. We provide an overview of the developmental processes leading to the formation of the ureter, bladder, and urethra, and different genes and signaling pathways controlling these developmental processes. Human genetic disorders that affect the ureter, bladder and urethra and associated gene mutations are also presented. As we are entering the post-genomic era of personalized medicine, information in this article may provide useful interpretation for the genetic and genomic test results collected from patients with lower urinary tract birth defects. With evidence-based interpretations, clinicians may provide more effective personalized therapies to patients and genetic counseling for their families. PMID:23408557

Zinc and Zinc Transporters: Novel Regulators of Ventricular Myocardial Development.

PubMed

Lin, Wen; Li, Deqiang

2018-06-01

Ventricular myocardial development is a well-orchestrated process involving different cardiac structures, multiple signal pathways, and myriad proteins. Dysregulation of this important developmental event can result in cardiomyopathies, such as left ventricle non-compaction, which affect the pediatric population and the adults. Human and mouse studies have shed light upon the etiology of some cardiomyopathy cases and highlighted the contribution of both genetic and environmental factors. However, the regulation of ventricular myocardial development remains incompletely understood. Zinc is an essential trace metal with structural, enzymatic, and signaling function. Perturbation of zinc homeostasis has resulted in developmental and physiological defects including cardiomyopathy. In this review, we summarize several mechanisms by which zinc and zinc transporters can impact the regulation of ventricular myocardial development. Based on our review, we propose that zinc deficiency and mutations of zinc transporters may underlie some cardiomyopathy cases especially those involving ventricular myocardial development defects.

High Fat Diet Induced Developmental Defects in the Mouse: Oocyte Meiotic Aneuploidy and Fetal Growth Retardation/Brain Defects

PubMed Central

Purcell, Scott H.; Chi, Maggie; Jimenez, Patricia T.; Grindler, Natalia; Schedl, Tim; Moley, Kelle H.

2012-01-01

Background Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. Methodology/Principal Findings We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. Conclusions/Significance Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes. PMID:23152876

A DNA damage checkpoint pathway coordinates the division of dikaryotic cells in the ink cap mushroom Coprinopsis cinerea.

PubMed

de Sena-Tomás, Carmen; Navarro-González, Mónica; Kües, Ursula; Pérez-Martín, José

2013-09-01

The fungal fruiting body or mushroom is a multicellular structure essential for sexual reproduction. It is composed of dikaryotic cells that contain one haploid nucleus from each mating partner sharing the same cytoplasm without undergoing nuclear fusion. In the mushroom, the pileus bears the hymenium, a layer of cells that includes the specialized basidia in which nuclear fusion, meiosis, and sporulation occur. Coprinopsis cinerea is a well-known model fungus used to study developmental processes associated with the formation of the fruiting body. Here we describe that knocking down the expression of Atr1 and Chk1, two kinases shown to be involved in the response to DNA damage in a number of eukaryotic organisms, dramatically impairs the ability to develop fruiting bodies in C. cinerea, as well as other developmental decisions such as sclerotia formation. These developmental defects correlated with the impairment in silenced strains to sustain an appropriated dikaryotic cell cycle. Dikaryotic cells in which chk1 or atr1 genes were silenced displayed a higher level of asynchronous mitosis and as a consequence aberrant cells carrying an unbalanced dose of nuclei. Since fruiting body initiation is dependent on the balanced mating-type regulator doses present in the dikaryon, we believe that the observed developmental defects were a consequence of the impaired cell cycle in the dikaryon. Our results suggest a connection between the DNA damage response cascade, cell cycle regulation, and developmental processes in this fungus.

Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia.

PubMed

Dinchuk, Joseph E; Focht, Richard J; Kelley, Jennifer A; Henderson, Nancy L; Zolotarjova, Nina I; Wynn, Richard; Neff, Nicola T; Link, John; Huber, Reid M; Burn, Timothy C; Rupar, Mark J; Cunningham, Mark R; Selling, Bernard H; Ma, Jianhong; Stern, Andrew A; Hollis, Gregory F; Stein, Robert B; Friedman, Paul A

2002-04-12

The BAH genomic locus encodes three distinct proteins: junctin, humbug, and BAH. All three proteins share common exons, but differ significantly based upon the use of alternative terminal exons. The biological roles of BAH and humbug and their functional relationship to junctin remain unclear. To evaluate the role of BAH in vivo, the catalytic domain of BAH was specifically targeted such that the coding regions of junctin and humbug remained undisturbed. BAH null mice lack measurable BAH protein in several tissues, lack aspartyl beta-hydroxylase activity in liver preparations, and exhibit no hydroxylation of the epidermal growth factor (EGF) domain of clotting Factor X. In addition to reduced fertility in females, BAH null mice display several developmental defects including syndactyly, facial dysmorphology, and a mild defect in hard palate formation. The developmental defects present in BAH null mice are similar to defects observed in knock-outs and hypomorphs of the Notch ligand Serrate-2. In this work, beta-hydroxylation of Asp residues in EGF domains is demonstrated for a soluble form of a Notch ligand, human Jagged-1. These results along with recent reports that another post-translational modification of EGF domains in Notch gene family members (glycosylation by Fringe) alters Notch pathway signaling, lends credence to the suggestion that aspartyl beta-hydroxylation may represent another post-translational modification of EGF domains that can modulate Notch pathway signaling. Previous work has demonstrated increased levels of BAH in certain tumor tissues and a role for BAH in tumorigenesis has been proposed. The role of hydroxylase in tumor formation was tested directly by crossing BAH KO mice with an intestinal tumor model, APCmin mice. Surprisingly, BAH null/APCmin mice show a statistically significant increase in both intestinal polyp size and number when compared with BAH wild-type/APCmin controls. These results suggest that, in contrast to expectations, loss of BAH catalytic activity may promote tumor formation.

Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects.

PubMed

Brennan, Marie-Luise; Adam, Margaret P; Seaver, Laurie H; Myers, Angela; Schelley, Susan; Zadeh, Neda; Hudgins, Louanne; Bernstein, Jonathan A

2015-01-01

The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity. © 2014 Wiley Periodicals, Inc.

MoSwi6, an APSES family transcription factor, interacts with MoMps1 and is required for hyphal and conidial morphogenesis, appressorial function, and pathogenicity of Magnaporthe oryzae

PubMed Central

Qi, Zhongqiang; Wang, Qi; Dou, Xianying; Wang, Wei; Zhao, Qian; Lv, Ruili; Zhang, Haifeng; Zheng, Xiaobo; Wang, Ping; Zhang, Zhengguang

2011-01-01

Magnaporthe oryzae MAPK MoMps1 plays a critical role in regulating various developmental processes including cell wall integrity, stress responses, and pathogenicity. To identify potential effectors of MoMps1, we characterized the function of MoSwi6, a homolog of Saccharomyces cerevisiae Swi6 downstream of MAPK Slt2 signaling. MoSwi6 interacted with MoMps1 both in vivo and in vitro, suggesting a possible functional link analogous to Swi6-Slt2 in S. cerevisiae. Targeted gene disruption of MoSWI6 resulted in multiple developmental defects, including reduced hyphal growth, abnormal formation of conidia and appressoria, and impaired appressorium function. The reduction in appressorial turgor pressure also contributed to an attenuation of pathogenicity. The ΔMoswi6 mutant also displayed a defect in cell wall integrity, was hypersensitive to the oxidative stress, and showed significant reduction in transcription and activities of extracellular enzymes including peroxidases and laccases. Collectively, these roles are similar to those of MoMps1, confirming that MoSwi6 functions in the MoMps1 pathway to govern growth, development, and full pathogenicity. PMID:22321443

Root gravitropism and root hair development constitute coupled developmental responses regulated by auxin homeostasis in the Arabidopsis root apex.

PubMed

Rigas, Stamatis; Ditengou, Franck Anicet; Ljung, Karin; Daras, Gerasimos; Tietz, Olaf; Palme, Klaus; Hatzopoulos, Polydefkis

2013-03-01

Active polar transport establishes directional auxin flow and the generation of local auxin gradients implicated in plant responses and development. Auxin modulates gravitropism at the root tip and root hair morphogenesis at the differentiation zone. Genetic and biochemical analyses provide evidence for defective basipetal auxin transport in trh1 roots. The trh1, pin2, axr2 and aux1 mutants, and transgenic plants overexpressing PIN1, all showing impaired gravity response and root hair development, revealed ectopic PIN1 localization. The auxin antagonist hypaphorine blocked root hair elongation and caused moderate agravitropic root growth, also leading to PIN1 mislocalization. These results suggest that auxin imbalance leads to proximal and distal developmental defects in Arabidopsis root apex, associated with agravitropic root growth and root hair phenotype, respectively, providing evidence that these two auxin-regulated processes are coupled. Cell-specific subcellular localization of TRH1-YFP in stele and epidermis supports TRH1 engagement in auxin transport, and hence impaired function in trh1 causes dual defects of auxin imbalance. The interplay between intrinsic cues determining root epidermal cell fate through the TTG/GL2 pathway and environmental cues including abiotic stresses modulates root hair morphogenesis. As a consequence of auxin imbalance in Arabidopsis root apex, ectopic PIN1 mislocalization could be a risk aversion mechanism to trigger root developmental responses ensuring root growth plasticity. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

[Semiotics of the Currarino syndrome].

PubMed

Pankevych, T L; Lóniushkin, O I; Sitkovskyĭ, M B; Kaplan, V M; Iurchenko, M I; Cherniienko, Iu L

1993-01-01

The main criteria for diagnosis of the Currarino syndrome have been defined. Roentgenologic investigation of the lumbar-sacral spine in direct projection is indicated to all the patients with anorectal developmental defects, in particular with congenital anorectal stenosis. In detection of a specific defect of the terminal vertebrae, the performance of computed tomography of the pelvic bottom and nuclear magnetic resonance tomography of the lumbar-sacral spine is necessary. This permits to assess the nature of a presacral tumour and degree of dysplasia of the external and sphincter. Timely diagnosis of the Currarino syndrome in children with the anorectal developmental defects permits to avoid severe septic and functional complications in surgical intervention.

LIMB DEFECTS INDUCED BY RETINOIC ACID SIGNALING ANTAGONISM AND SYNTHESIS INHIBITION ARE CONSISTENT WITH ETHANOL-INDUCED LIMB DEFECTS

EPA Science Inventory

Limb defects induced by retinoic acid signaling antagonism and synthesis inhibition are consistent with ethanol-induced limb defects

Johnson CS1, Sulik KK1,2, Hunter, ES III3
1Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, NC....

Drosophila Lin-52 Acts in Opposition to Repressive Components of the Myb-MuvB/dREAM Complex

PubMed Central

Lewis, Peter W.; Sahoo, Debashis; Geng, Cuiyun; Bell, Maren

2012-01-01

The Drosophila melanogaster Myb-MuvB/dREAM complex (MMB/dREAM) participates in both the activation and repression of developmentally regulated genes and origins of DNA replication. Mutants in MMB subunits exhibit diverse phenotypes, including lethality, eye defects, reduced fecundity, and sterility. Here, we used P-element excision to generate mutations in lin-52, which encodes the smallest subunit of the MMB/dREAM complex. lin-52 is required for viability, as null mutants die prior to pupariation. The generation of somatic and germ line mutant clones indicates that lin-52 is required for adult eye development and for early embryogenesis via maternal effects. Interestingly, the maternal-effect embryonic lethality, larval lethality, and adult eye defects could be suppressed by mutations in other subunits of the MMB/dREAM complex. These results suggest that a partial MMB/dREAM complex is responsible for the lethality and eye defects of lin-52 mutants. Furthermore, these findings support a model in which the Lin-52 and Myb proteins counteract the repressive activities of the other members of the MMB/dREAM complex at specific genomic loci in a developmentally controlled manner. PMID:22688510

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

PubMed Central

Whittaker, Danielle E.; Kasah, Sahrunizam; Donovan, Alex P. A.; Ellegood, Jacob; Riegman, Kimberley L. H.; Volk, Holger A.; McGonnell, Imelda; Lerch, Jason P.

2017-01-01

Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. PMID:29168327

Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism

PubMed Central

Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Imaki, Humi; Wegiel, Jarek; Ma, Shuang Yong; Azmitia, Efrain C.; Banerjee, Probal; Flory, Michael; Cohen, Ira L.; London, Eric; Brown, W. Ted; Hare, Carolyn Komich; Wisniewski, Thomas

2014-01-01

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects. PMID:23558308

Arabidopsis ribosomal proteins control vacuole trafficking and developmental programs through the regulation of lipid metabolism.

PubMed

Li, Ruixi; Sun, Ruobai; Hicks, Glenn R; Raikhel, Natasha V

2015-01-06

The vacuole is the most prominent compartment in plant cells and is important for ion and protein storage. In our effort to search for key regulators in the plant vacuole sorting pathway, ribosomal large subunit 4 (rpl4d) was identified as a translational mutant defective in both vacuole trafficking and normal development. Polysome profiling of the rpl4d mutant showed reduction in polysome-bound mRNA compared with wild-type, but no significant change in the general mRNA distribution pattern. Ribsomal profiling data indicated that genes in the lipid metabolism pathways were translationally down-regulated in the rpl4d mutant. Live imaging studies by Nile red staining suggested that both polar and nonpolar lipid accumulation was reduced in meristem tissues of rpl4d mutants. Pharmacological evidence showed that sterol and sphingolipid biosynthetic inhibitors can phenocopy the defects of the rpl4d mutant, including an altered vacuole trafficking pattern. Genetic evidence from lipid biosynthetic mutants indicates that alteration in the metabolism of either sterol or sphingolipid biosynthesis resulted in vacuole trafficking defects, similar to the rpl4d mutant. Tissue-specific complementation with key enzymes from lipid biosynthesis pathways can partially rescue both vacuole trafficking and auxin-related developmental defects in the rpl4d mutant. These results indicate that lipid metabolism modulates auxin-mediated tissue differentiation and endomembrane trafficking pathways downstream of ribosomal protein function.

Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics

NASA Astrophysics Data System (ADS)

Anderson, Gregory Arthur

Cardiovascular development is a process that involves the timing of multiple molecular events, and numerous subtle three-dimensional conformational changes. Traditional developmental biology techniques have provided large quantities of information as to how these complex organ systems develop. However, the major drawback of the majority of current developmental biological imaging is that they are two-dimensional in nature. It is now well recognized that circulation of blood is required for normal patterning and remodeling of blood vessels. Normal blood vessel formation is dependent upon a complex network of signaling pathways, and genetic mutations in these pathways leads to impaired vascular development, heart failure, and lethality. As such, it is not surprising that mutant mice with aberrant cardiovascular patterning are so common, since normal development requires proper coordination between three systems: the heart, the blood, and the vasculature. This thesis describes the implementation of a three-dimensional imaging technique, optical projection tomography (OPT), in conjunction with a computer-based registration algorithm to statistically analyze developmental differences in groups of wild-type mouse embryos. Embryos that differ by only a few hours' gestational time are shown to have developmental differences in blood vessel formation and heart development progression that can be discerned. This thesis describes how we analyzed mouse models of cardiovascular perturbation by OPT to detect morphological differences in embryonic development in both qualitative and quantitative ways. Both a blood vessel specific mutation and a cardiac specific mutation were analyzed, providing evidence that developmental defects of these types can be quantified. Finally, we describe the implementation of OPT imaging to identify statistically significant phenotypes from three different mouse models of cardiovascular perturbation across a range of developmental time points. Image registration methods, combined with intensity- and deformation-based analyses are described and utilized to fully characterize myosin light chain 2a (Mlc2a), delta-like ligand 4 (Dll4), and Endoglin (Eng) mutant mouse embryos. We show that Eng mutant embryos are statistically similar to the Mlc2a phenotype, confirming that these mouse mutants suffer from a primary cardiac developmental defect. Thus, a loss of hemodynamic force caused by defective pumping of the heart is the primary developmental defect affecting these mice.

CHEMICAL PRIORITIZATION FOR DEVELOPMENTAL TOXICITY USING LITERATURE MINING-BASED WEIGHTING OF TOXCAST ASSAYS

EPA Science Inventory

Defining a predictive model of developmental toxicity from in vitro and high-throughput screening (HTS) assays can be limited by the availability of developmental defects data. ToxRefDB (www.epa.gov/ncct/todrefdb) was built from animal studies on data-rich environmental chemicals...

Heparan Sulfate Expression in the Neural Crest is Essential for Mouse Cardiogenesis

PubMed Central

Pan, Yi; Carbe, Christian; Pickhinke, Ute; Kupich, Sabine; Ohlig, Stefanie; Frye, Maike; Seelige, Ruth; Pallerla, Srinivas R.; Moon, Anne M.; Lawrence, Roger; Esko, Jeffrey D.; Zhang, Xin; Grobe, Kay

2015-01-01

Impaired heparan sulfate (HS) synthesis in vertebrate development causes complex malformations due to the functional disruption of multiple HS-binding growth factors and morphogens. Here, we report developmental heart defects in mice bearing a targeted disruption of the HS-generating enzyme GlcNAc N-Deacetylase/GlcN N-Sulfotransferase 1 (NDST1), including ventricular septal defects (VSD), persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), and retroesophageal right subclavian artery (RERSC). These defects closely resemble cardiac anomalies observed in mice made deficient in the cardiogenic regulator fibroblast growth factor 8 (FGF8). Consistent with this, we show that HS-dependent FGF8/FGF-receptor2C assembly and FGF8-dependent ERK-phosphorylation are strongly reduced in NDST1−/− embryonic cells and tissues. Moreover, WNT1-Cre/LoxP-mediated conditional targeting of NDST function in neural crest cells (NCCs) revealed that their impaired HS-dependent development contributes strongly to the observed cardiac defects. These findings raise the possibility that defects in HS biosynthesis may contribute to congenital heart defects in humans that represent the most common type of birth defect. PMID:24200809

Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.

PubMed

Osborn, Daniel P S; Roccasecca, Rosa Maria; McMurray, Fiona; Hernandez-Hernandez, Victor; Mukherjee, Sriparna; Barroso, Inês; Stemple, Derek; Cox, Roger; Beales, Philip L; Christou-Savina, Sonia

2014-01-01

Common intronic variants in the Human fat mass and obesity-associated gene (FTO) are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish) and in vitro (Fto(-/-) MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+) pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.

The prevalence of Molar-Incisor Hypomineralisation (MIH) in Wainuiomata children.

PubMed

Mahoney, Erin K; Morrison, David G

2009-12-01

The aim of this study was to determine the prevalence of Molar-Incisor Hypomineralisation (MIH) in Wainuiomata children and describe differences in prevalence among Māori, Pacific Island and New Zealand European ethnic groups. Cross-sectional survey of developmental defects of enamel in a random sample of children attending primary school in Wainuiomata, Wellington. Study information and consent forms were sent to 850 7-to-10-year-old schoolchildren. Using the modified Developmental Defects of Enamel index, a single paediatric dentist examined students in the classroom. Dental caries experience was recorded as decayed, missing or filled primary and permanent teeth. Examinations were conducted on 522 children (participation rate 61.4%). The mean age of the children was 8.2 years (range 7 to 10 years). MIH prevalence was 14.9%. The prevalence ofhypomineralisation ofany tooth was 15.3%, and that for hypoplasia was 4.0%. There was no statistically significant ethnic difference in MIH prevalence. The mean DMFT was 0.16 (SD, 0.54) in those without a developmental defect, 0.54 (SD, 1.12) in those with hypomineralisation and 1.85 (SD, 1.85) in those with hypoplasia (p < 0.01). Approximately one in seven Wainuiomata children have MIH. Ethnicity is not a modifying factor in the occurrence of developmental defects of enamel. The presence of hypomineralisation and/or hypoplasia was associated with significantly greater caries experience in the permanent dentition.

Etiology and clinical presentation of birth defects: population based study

PubMed Central

Carey, John C; Byrne, Janice L B; Krikov, Sergey; Botto, Lorenzo D

2017-01-01

Objective To assess causation and clinical presentation of major birth defects. Design Population based case cohort. Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah’s population based surveillance system. All records underwent clinical re-review. Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias). Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects). Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology). Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis. PMID:28559234

A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway

PubMed Central

McClure, Kimberly D.; French, Rachael L.; Heberlein, Ulrike

2011-01-01

SUMMARY Prenatal exposure to ethanol in humans results in a wide range of developmental abnormalities, including growth deficiency, developmental delay, reduced brain size, permanent neurobehavioral abnormalities and fetal death. Here we describe the use of Drosophila melanogaster as a model for exploring the effects of ethanol exposure on development and behavior. We show that developmental ethanol exposure causes reduced viability, developmental delay and reduced adult body size. We find that flies reared on ethanol-containing food have smaller brains and imaginal discs, which is due to reduced cell division rather than increased apoptosis. Additionally, we show that, as in mammals, flies reared on ethanol have altered responses to ethanol vapor exposure as adults, including increased locomotor activation, resistance to the sedating effects of the drug and reduced tolerance development upon repeated ethanol exposure. We have found that the developmental and behavioral defects are largely due to the effects of ethanol on insulin signaling; specifically, a reduction in Drosophila insulin-like peptide (Dilp) and insulin receptor expression. Transgenic expression of Dilp proteins in the larval brain suppressed both the developmental and behavioral abnormalities displayed by ethanol-reared adult flies. Our results thus establish Drosophila as a useful model system to uncover the complex etiology of fetal alcohol syndrome. PMID:21303840

Concentration-dependent actions of piperidine alkaloids on the inhibition of fetal movement in day 40 pregnant goats and comparison to cell-based models

USDA-ARS?s Scientific Manuscript database

Anabasine and anabaseine are potent and effective agonists at nicotinic acetylcholine receptors (nAChR). Anabasine in livestock species is teratogenic and has been shown to cause developmental defects that include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis. We have postulated that...

Luna, a Drosophila KLF6/KLF7, Is Maternally Required for Synchronized Nuclear and Centrosome Cycles in the Preblastoderm Embryo

PubMed Central

Weber, Ursula; Rodriguez, Estefania; Martignetti, John; Mlodzik, Marek

2014-01-01

Krüppel like factors (KLFs) are conserved transcription factors that have been implicated in many developmental processes including differentiation, organ patterning, or regulation of stem cell pluripotency. We report the generation and analysis of loss-of-function mutants of Drosophila Klf6/7, the luna gene. We demonstrate that luna mutants are associated with very early embryonic defects prior to cellularization at the syncytial stage and cause DNA separation defects during the rapid mitotic cycles resulting in un-coupled DNA and centrosome cycles. These defects manifest themselves, both in animals that are maternally homozygous and heterozygous mutant. Surprisingly, luna is only required during the syncytial stages and not later in development, suggesting that the DNA segregation defect is linked to centrosomes, since centrosomes are dispensable for later cell divisions. PMID:24915236

Neural tube and other developmental anomalies in the guinea pig following maternal hyperthermia during early neural tube development.

PubMed

Cawdell-Smith, J; Upfold, J; Edwards, M; Smith, M

1992-01-01

Guinea pigs were exposed to hyperthermia for 1 hr once or twice on day 11, 12, 13, or 14 (E11-E14) of pregnancy. The mean rectal temperatures were elevated by 3.4 degrees C-4.0 degrees C. This treatment resulted in a marked elevation of rates of resorption and developmental defects in embryos examined at day E23. The defects observed were those affecting the neural tube (NTD) (exencephaly, encephaloceles, and microphthalmia), kyphosis/scoliosis, branchial arch defects, and pericardial edema. Embryos with NTD and kyphosis/scoliosis have not been found among newborn guinea pigs to date following maternal heat exposure on days E12-E14. It appears that embryos with these defects are filtered out by resorption or abortion by days E30-E35.

Novel adverse outcome pathways revealed by chemical genetics in a developing marine fish

PubMed Central

Sørhus, Elin; Incardona, John P; Furmanek, Tomasz; Goetz, Giles W; Scholz, Nathaniel L; Meier, Sonnich; Edvardsen, Rolf B; Jentoft, Sissel

2017-01-01

Crude oil spills are a worldwide ocean conservation threat. Fish are particularly vulnerable to the oiling of spawning habitats, and crude oil causes severe abnormalities in embryos and larvae. However, the underlying mechanisms for these developmental defects are not well understood. Here, we explore the transcriptional basis for four discrete crude oil injury phenotypes in the early life stages of the commercially important Atlantic haddock (Melanogrammus aeglefinus). These include defects in (1) cardiac form and function, (2) craniofacial development, (3) ionoregulation and fluid balance, and (4) cholesterol synthesis and homeostasis. Our findings suggest a key role for intracellular calcium cycling and excitation-transcription coupling in the dysregulation of heart and jaw morphogenesis. Moreover, the disruption of ionoregulatory pathways sheds new light on buoyancy control in marine fish embryos. Overall, our chemical-genetic approach identifies initiating events for distinct adverse outcome pathways and novel roles for individual genes in fundamental developmental processes. DOI: http://dx.doi.org/10.7554/eLife.20707.001 PMID:28117666

Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

PubMed

Anand, Deepti; Agrawal, Smriti A; Slavotinek, Anne; Lachke, Salil A

2018-04-01

Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases. © 2018 Wiley Periodicals, Inc.

Developmental Toxicity of Drinking Water Disinfection By-Products to Embryos of the African Clawed Frog (Xenopus laevis)

DTIC Science & Technology

2005-06-10

and as representatives of byproducts of different disinfection processes . Endpoints measured included embryo mortality (LC50), embryo malformation...chemicals were selected for testing based on their potential for human harm and as representatives of byproducts of different disinfection processes ...highest frequency include notochord maldevelopment, craniofacial defects, and cardiac edema. The EC50 for BDCM malformations (62-72 mg/L) was at a much

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colman, Joan; Rice, Glenn E., E-mail: rice.glenn@epa.gov; Wright, J. Michael

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmentalmore » effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.« less

l-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome

PubMed Central

Xu, Baoshan; Sowa, Nenja; Cardenas, Maria E.; Gerton, Jennifer L.

2015-01-01

Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS. PMID:25378554

L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.

PubMed

Xu, Baoshan; Sowa, Nenja; Cardenas, Maria E; Gerton, Jennifer L

2015-03-15

Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS. © The Author 2014. Published by Oxford University Press.

A-to-I RNA editing promotes developmental stage–specific gene and lncRNA expression

PubMed Central

Goldstein, Boaz; Agranat-Tamir, Lily; Light, Dean; Ben-Naim Zgayer, Orna; Fishman, Alla; Lamm, Ayelet T.

2017-01-01

A-to-I RNA editing is a conserved widespread phenomenon in which adenosine (A) is converted to inosine (I) by adenosine deaminases (ADARs) in double-stranded RNA regions, mainly noncoding. Mutations in ADAR enzymes in Caenorhabditis elegans cause defects in normal development but are not lethal as in human and mouse. Previous studies in C. elegans indicated competition between RNA interference (RNAi) and RNA editing mechanisms, based on the observation that worms that lack both mechanisms do not exhibit defects, in contrast to the developmental defects observed when only RNA editing is absent. To study the effects of RNA editing on gene expression and function, we established a novel screen that enabled us to identify thousands of RNA editing sites in nonrepetitive regions in the genome. These include dozens of genes that are edited at their 3′ UTR region. We found that these genes are mainly germline and neuronal genes, and that they are down-regulated in the absence of ADAR enzymes. Moreover, we discovered that almost half of these genes are edited in a developmental-specific manner, indicating that RNA editing is a highly regulated process. We found that many pseudogenes and other lncRNAs are also extensively down-regulated in the absence of ADARs in the embryo but not in the fourth larval (L4) stage. This down-regulation is not observed upon additional knockout of RNAi. Furthermore, levels of siRNAs aligned to pseudogenes in ADAR mutants are enhanced. Taken together, our results suggest a role for RNA editing in normal growth and development by regulating silencing via RNAi. PMID:28031250

Stage specific requirement of platelet-derived growth factor receptor-α in embryonic development.

PubMed

Qian, Chen; Wong, Carol Wing Yan; Wu, Zhongluan; He, Qiuming; Xia, Huimin; Tam, Paul Kwong Hang; Wong, Kenneth Kak Yuen; Lui, Vincent Chi Hang

2017-01-01

Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures. To address the temporal requirement of Pdgfra in embryonic development. We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies. Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives. Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.

Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.

PubMed

Blanchette, Cassandra R; Thackeray, Andrea; Perrat, Paola N; Hekimi, Siegfried; Bénard, Claire Y

2017-01-01

The regulation of cell migration is essential to animal development and physiology. Heparan sulfate proteoglycans shape the interactions of morphogens and guidance cues with their respective receptors to elicit appropriate cellular responses. Heparan sulfate proteoglycans consist of a protein core with attached heparan sulfate glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin (EXT) family. Abnormal HS chain synthesis results in pleiotropic consequences, including abnormal development and tumor formation. In humans, mutations in either of the exostosin genes EXT1 and EXT2 lead to osteosarcomas or multiple exostoses. Complete loss of any of the exostosin glycosyltransferases in mouse, fish, flies and worms leads to drastic morphogenetic defects and embryonic lethality. Here we identify and study previously unavailable viable hypomorphic mutations in the two C. elegans exostosin glycosyltransferases genes, rib-1 and rib-2. These partial loss-of-function mutations lead to a severe reduction of HS levels and result in profound but specific developmental defects, including abnormal cell and axonal migrations. We find that the expression pattern of the HS copolymerase is dynamic during embryonic and larval morphogenesis, and is sustained throughout life in specific cell types, consistent with HSPGs playing both developmental and post-developmental roles. Cell-type specific expression of the HS copolymerase shows that HS elongation is required in both the migrating neuron and neighboring cells to coordinate migration guidance. Our findings provide insights into general principles underlying HSPG function in development.

FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.

PubMed

Dai, H; Zhang, V W; El-Hattab, A W; Ficicioglu, C; Shinawi, M; Lines, M; Schulze, A; McNutt, M; Gotway, G; Tian, X; Chen, S; Wang, J; Craigen, W J; Wong, L-J

2017-04-01

Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in 10 new subjects with a total of 7 novel deleterious variants; 5 null and 2 missense substitutions. All patients exhibited congenital lactic acidemia, most of them with severe encephalopathic presentation, and global developmental delay. Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Blastogenetic associations: General considerations.

PubMed

Lubinsky, Mark

2015-11-01

Associations of anomalies, with VACTERL as the prototype, have been the source of much debate, including questions about the validity and definition of this category. Evidence is presented for a teratologic basis for associations involving interactions between disruptive events and specific vulnerabilities. Because the embryo is organized in time and space, differences in the timing, location, and severity of exposures will create variable sequelae for any specific vulnerability, creating associations. The blastogenetic stage of development involves distinct properties that affect the nature of associations arising during this time, including relatively undifferentiated developmental fields and causally nonspecific malformations. With this, single anomalies can be part of the spectrum of findings that comprise a specific association. A specific defect defines a subset of disturbances, biasing frequencies of other defects. Processes are basic, integrated, and general, so disruptions are often lethal, and can have multiple effects, accounting for high incidences of multiple anomalies, and overlaps between associations. Blastogenetic disturbances also do not affect the late "fine tuning" of minor anomalies, although pathogenetic sequences can occur. This model suggests that certain combinations of congenital anomalies can arise from causally nonspecific teratogenetic fields determined by timing, location, and vulnerabilities, rather than polytopic developmental fields. © 2015 Wiley Periodicals, Inc.

ETOILE Regulates Developmental Patterning in the Filamentous Brown Alga Ectocarpus siliculosus[W

PubMed Central

Le Bail, Aude; Billoud, Bernard; Le Panse, Sophie; Chenivesse, Sabine; Charrier, Bénédicte

2011-01-01

Brown algae are multicellular marine organisms evolutionarily distant from both metazoans and land plants. The molecular or cellular mechanisms that govern the developmental patterning in brown algae are poorly characterized. Here, we report the first morphogenetic mutant, étoile (etl), produced in the brown algal model Ectocarpus siliculosus. Genetic, cellular, and morphometric analyses showed that a single recessive locus, ETL, regulates cell differentiation: etl cells display thickening of the extracellular matrix (ECM), and the elongated, apical, and actively dividing E cells are underrepresented. As a result of this defect, the overrepresentation of round, branch-initiating R cells in the etl mutant leads to the rapid induction of the branching process at the expense of the uniaxial growth in the primary filament. Computational modeling allowed the simulation of the etl mutant phenotype by including a modified response to the neighborhood information in the division rules used to specify wild-type development. Microarray experiments supported the hypothesis of a defect in cell–cell communication, as primarily Lin-Notch-domain transmembrane proteins, which share similarities with metazoan Notch proteins involved in binary cell differentiation were repressed in etl. Thus, our study highlights the role of the ECM and of novel transmembrane proteins in cell–cell communication during the establishment of the developmental pattern in this brown alga. PMID:21478443

Bisphenol A induces otolith malformations during vertebrate embryogenesis

PubMed Central

2011-01-01

Background The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models. Results We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype. Conclusions The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor. PMID:21269433

Bisphenol A induces otolith malformations during vertebrate embryogenesis.

PubMed

Gibert, Yann; Sassi-Messai, Sana; Fini, Jean-Baptiste; Bernard, Laure; Zalko, Daniel; Cravedi, Jean-Pierre; Balaguer, Patrick; Andersson-Lendahl, Monika; Demeneix, Barbara; Laudet, Vincent

2011-01-26

The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models. We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype. The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.

PubMed

Whittaker, Danielle E; Kasah, Sahrunizam; Donovan, Alex P A; Ellegood, Jacob; Riegman, Kimberley L H; Volk, Holger A; McGonnell, Imelda; Lerch, Jason P; Basson, M Albert

2017-12-01

Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

Adaptor protein complex 2-mediated endocytosis is crucial for male reproductive organ development in Arabidopsis.

PubMed

Kim, Soo Youn; Xu, Zheng-Yi; Song, Kyungyoung; Kim, Dae Heon; Kang, Hyangju; Reichardt, Ilka; Sohn, Eun Ju; Friml, Jirí; Juergens, Gerd; Hwang, Inhwan

2013-08-01

Fertilization in flowering plants requires the temporal and spatial coordination of many developmental processes, including pollen production, anther dehiscence, ovule production, and pollen tube elongation. However, it remains elusive as to how this coordination occurs during reproduction. Here, we present evidence that endocytosis, involving heterotetrameric adaptor protein complex 2 (AP-2), plays a crucial role in fertilization. An Arabidopsis thaliana mutant ap2m displays multiple defects in pollen production and viability, as well as elongation of staminal filaments and pollen tubes, all of which are pivotal processes needed for fertilization. Of these abnormalities, the defects in elongation of staminal filaments and pollen tubes were partially rescued by exogenous auxin. Moreover, DR5rev:GFP (for green fluorescent protein) expression was greatly reduced in filaments and anthers in ap2m mutant plants. At the cellular level, ap2m mutants displayed defects in both endocytosis of N-(3-triethylammonium-propyl)-4-(4-diethylaminophenylhexatrienyl) pyridinium dibromide, a lypophilic dye used as an endocytosis marker, and polar localization of auxin-efflux carrier PIN FORMED2 (PIN2) in the stamen filaments. Moreover, these defects were phenocopied by treatment with Tyrphostin A23, an inhibitor of endocytosis. Based on these results, we propose that AP-2-dependent endocytosis plays a crucial role in coordinating the multiple developmental aspects of male reproductive organs by modulating cellular auxin level through the regulation of the amount and polarity of PINs.

Adaptor Protein Complex 2–Mediated Endocytosis Is Crucial for Male Reproductive Organ Development in Arabidopsis[W

PubMed Central

Kim, Soo Youn; Xu, Zheng-Yi; Song, Kyungyoung; Kim, Dae Heon; Kang, Hyangju; Reichardt, Ilka; Sohn, Eun Ju; Friml, Jiří; Juergens, Gerd; Hwang, Inhwan

2013-01-01

Fertilization in flowering plants requires the temporal and spatial coordination of many developmental processes, including pollen production, anther dehiscence, ovule production, and pollen tube elongation. However, it remains elusive as to how this coordination occurs during reproduction. Here, we present evidence that endocytosis, involving heterotetrameric adaptor protein complex 2 (AP-2), plays a crucial role in fertilization. An Arabidopsis thaliana mutant ap2m displays multiple defects in pollen production and viability, as well as elongation of staminal filaments and pollen tubes, all of which are pivotal processes needed for fertilization. Of these abnormalities, the defects in elongation of staminal filaments and pollen tubes were partially rescued by exogenous auxin. Moreover, DR5rev:GFP (for green fluorescent protein) expression was greatly reduced in filaments and anthers in ap2m mutant plants. At the cellular level, ap2m mutants displayed defects in both endocytosis of N-(3-triethylammonium-propyl)-4-(4-diethylaminophenylhexatrienyl) pyridinium dibromide, a lypophilic dye used as an endocytosis marker, and polar localization of auxin-efflux carrier PIN FORMED2 (PIN2) in the stamen filaments. Moreover, these defects were phenocopied by treatment with Tyrphostin A23, an inhibitor of endocytosis. Based on these results, we propose that AP-2–dependent endocytosis plays a crucial role in coordinating the multiple developmental aspects of male reproductive organs by modulating cellular auxin level through the regulation of the amount and polarity of PINs. PMID:23975898

Arabidopsis ribosomal proteins control vacuole trafficking and developmental programs through the regulation of lipid metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ruixi; Sun, Ruobai; Hicks, Glenn R.

The vacuole is the most prominent compartment in plant cells and is important for ion and protein storage. In our effort to search for key regulators in the plant vacuole sorting pathway, ribosomal large subunit 4 (rpl4d) was identified as a translational mutant defective in both vacuole trafficking and normal development. Polysome profiling of the rpl4d mutant showed reduction in polysome-bound mRNA compared with wild-type, but no significant change in the general mRNA distribution pattern. Ribsomal profiling data indicated that genes in the lipid metabolism pathways were translationally down-regulated in the rpl4d mutant. Live imaging studies by Nile red stainingmore » suggested that both polar and nonpolar lipid accumulation was reduced in meristem tissues of rpl4d mutants. Pharmacological evidence showed that sterol and sphingolipid biosynthetic inhibitors can phenocopy the defects of the rpl4d mutant, including an altered vacuole trafficking pattern. Genetic evidence from lipid biosynthetic mutants indicates that alteration in the metabolism of either sterol or sphingolipid biosynthesis resulted in vacuole trafficking defects, similar to the rpl4d mutant. Tissue-specific complementation with key enzymes from lipid biosynthesis pathways can partially rescue both vacuole trafficking and auxin-related developmental defects in the rpl4d mutant. These results indicate that lipid metabolism modulates auxin-mediated tissue differentiation and endomembrane trafficking pathways downstream of ribosomal protein function.« less

Arabidopsis ribosomal proteins control vacuole trafficking and developmental programs through the regulation of lipid metabolism

DOE PAGES

Li, Ruixi; Sun, Ruobai; Hicks, Glenn R.; ...

2014-12-22

The vacuole is the most prominent compartment in plant cells and is important for ion and protein storage. In our effort to search for key regulators in the plant vacuole sorting pathway, ribosomal large subunit 4 (rpl4d) was identified as a translational mutant defective in both vacuole trafficking and normal development. Polysome profiling of the rpl4d mutant showed reduction in polysome-bound mRNA compared with wild-type, but no significant change in the general mRNA distribution pattern. Ribsomal profiling data indicated that genes in the lipid metabolism pathways were translationally down-regulated in the rpl4d mutant. Live imaging studies by Nile red stainingmore » suggested that both polar and nonpolar lipid accumulation was reduced in meristem tissues of rpl4d mutants. Pharmacological evidence showed that sterol and sphingolipid biosynthetic inhibitors can phenocopy the defects of the rpl4d mutant, including an altered vacuole trafficking pattern. Genetic evidence from lipid biosynthetic mutants indicates that alteration in the metabolism of either sterol or sphingolipid biosynthesis resulted in vacuole trafficking defects, similar to the rpl4d mutant. Tissue-specific complementation with key enzymes from lipid biosynthesis pathways can partially rescue both vacuole trafficking and auxin-related developmental defects in the rpl4d mutant. These results indicate that lipid metabolism modulates auxin-mediated tissue differentiation and endomembrane trafficking pathways downstream of ribosomal protein function.« less

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development.

PubMed

Kimmel, Gary L; Kimmel, Carole A; Williams, Amy L; DeSesso, John M

2013-02-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission's 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10-500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose-response relationship. In the six rat studies (dose range: 30-3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy.

Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development

PubMed Central

Kimmel, Gary L.; Kimmel, Carole A.; Williams, Amy L.

2013-01-01

The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission’s 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10–500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose–response relationship. In the six rat studies (dose range: 30–3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy. PMID:23286529

Prevalence and Characteristics of Developmental Dental Anomalies in Iranian Orofacial Cleft Patients.

PubMed

Ajami, Shabnam; Pakshir, Hamidreza; Samady, Hedyeh

2017-09-01

Individuals with oral clefts exhibit considerably more dental anomalies than individuals without clefts. These problems could initially be among the symptoms of their disease and/or they may be the side effect of their treatments. Pushback palatoplasty could cause some interference during the development of teeth and result in tooth defects. The study was performed to assess the prevalence and characteristics of developmental dental anomalies in orofacial cleft patients who attended Shiraz Orthodontics Research Center-Cleft Lip and Palate Clinic. We managed to compare dental anomaly traits based on gender and cleft side. Eighty out of 121 cleft patients were included in this cross-sectional study. All the patients used pushback palatoplasty in their palate closure surgeries. Intraoral photographs, panoramic and intraoral radiographs, cone-beam computed tomography (CBCT) and dental and medical histories were examined and recorded by two observers. Data were analyzed using SPSS PC version 20.0. The differences in the side of cleft and dental anomalies were compared using the Mann-Whitney test. The mean age of patients was 14.27 years (SD=5.06). The most frequent cleft type was unilateral cleft lip and palate (50%) followed by bilateral cleft lip and palate (43.75%), cleft palate (2.5%) and cleft lip (1.25%). Male predominance (70%) was observed. 92.5 percent had at least one developmental dental anomaly. The most prevalent anomalies were hypodontia (71.25%) followed by microdontia (30%), root dilacerations (21.25%) and supernumerary teeth (15%). The most prevalent cleft types were unilateral and bilateral cleft lip and palate with male and left side predominance. Hypodontia, microdontia, dilacerations and supernumerary teeth were the most prevalent developmental dental anomalies among Iranian southwestern cleft patients. The surgical technique used to repair their cleft palate may have played a role in developmental dental defects.

A developmental and genetic classification for midbrain-hindbrain malformations

PubMed Central

Millen, Kathleen J.; Dobyns, William B.

2009-01-01

Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered. PMID:19933510

Genetic analysis of tachyzoite to bradyzoite differentiation mutants in Toxoplasma gondii reveals a hierarchy of gene induction.

PubMed

Singh, Upinder; Brewer, Jeremy L; Boothroyd, John C

2002-05-01

Developmental switching in Toxoplasma gondii, from the virulent tachyzoite to the relatively quiescent bradyzoite stage, is responsible for disease propagation and reactivation. We have generated tachyzoite to bradyzoite differentiation (Tbd-) mutants in T. gondii and used these in combination with a cDNA microarray to identify developmental pathways in bradyzoite formation. Four independently generated Tbd- mutants were analysed and had defects in bradyzoite development in response to multiple bradyzoite-inducing conditions, a stable phenotype after in vivo passages and a markedly reduced brain cyst burden in a murine model of chronic infection. Transcriptional profiles of mutant and wild-type parasites, growing under bradyzoite conditions, revealed a hierarchy of developmentally regulated genes, including many bradyzoite-induced genes whose transcripts were reduced in all mutants. A set of non-developmentally regulated genes whose transcripts were less abundant in Tbd- mutants were also identified. These may represent genes that mediate downstream effects and/or whose expression is dependent on the same transcription factors as the bradyzoite-induced set. Using these data, we have generated a model of transcription regulation during bradyzoite development in T. gondii. Our approach shows the utility of this system as a model to study developmental biology in single-celled eukaryotes including protozoa and fungi.

Developmental Toxicity of Louisiana Crude Oiled Sediment to Zebrafish

EPA Science Inventory

Embryonic exposures to polycyclic aromatic hydrocarbons (PAHs) and petroleum products cause a characteristic suite of developmental defects in a variety of fish species. We exposed zebrafish embryos to sediment mixed with laboratory weathered South Louisiana crude oil. Oiled sedi...

The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development

PubMed Central

Akhter, Shamima; Lam, Yung C.; Chang, Sandy; Legerski, Randy J.

2013-01-01

Summary Conserved metallo β-Lactamase and β-CASP (CPSF-Artemis-Snm1-Pso2) domain nuclease family member SNM1B/Apollo is a shelterin-associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end-to-end fusions. Deficiency of the nonhomologous end-joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo-deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ-mediated repair, which results in genomic instability and the consequent multi-organ developmental failure. Although Snm1B/Apollo-deficient MEFs exhibited high levels of apoptosis, abrogation of p53-dependent programmed cell death did not rescue the multi-organ developmental failure in the mice. PMID:20854421

Public Health Practice of Population-Based Birth Defects Surveillance Programs in the United States.

PubMed

Mai, Cara T; Kirby, Russell S; Correa, Adolfo; Rosenberg, Deborah; Petros, Michael; Fagen, Michael C

2016-01-01

Birth defects remain a leading cause of infant mortality in the United States and contribute substantially to health care costs and lifelong disabilities. State population-based surveillance systems have been established to monitor birth defects, yet no recent systematic examination of their efforts in the United States has been conducted. To understand the current population-based birth defects surveillance practices in the United States. The National Birth Defects Prevention Network conducted a survey of US population-based birth defects activities that included questions about operational status, case ascertainment methodology, program infrastructure, data collection and utilization, as well as priorities and challenges for surveillance programs. Birth defects contacts in the United States, including District of Columbia and Puerto Rico, received the survey via e-mail; follow-up reminders via e-mails and telephone were used to ensure a 100% response rate. Forty-three states perform population-based surveillance for birth defects, covering approximately 80% of the live births in the United States. Seventeen primarily use an active case-finding approach and 26 use a passive case-finding approach. These programs all monitor major structural malformations; however, passive case-finding programs more often monitor a broader list of conditions, including developmental conditions and newborn screening conditions. Active case-finding programs more often use clinical reviewers, cover broader pregnancy outcomes, and collect more extensive information, such as family history. More than half of the programs (24 of 43) reported an ability to conduct follow-up studies of children with birth defects. The breadth and depth of information collected at a population level by birth defects surveillance programs in the United States serve as an important data source to guide public health action. Collaborative efforts at the state and national levels can help harmonize data collection and increase utility of birth defects programs.

K-RasV14I recapitulates Noonan syndrome in mice

PubMed Central

Hernández-Porras, Isabel; Fabbiano, Salvatore; Schuhmacher, Alberto J.; Aicher, Alexandra; Cañamero, Marta; Cámara, Juan Antonio; Cussó, Lorena; Desco, Manuel; Heeschen, Christopher; Mulero, Francisca; Bustelo, Xosé R.; Guerra, Carmen; Barbacid, Mariano

2014-01-01

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-RasV14I, a recurrent KRAS mutation in NS patients. K-RasV14I–mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-RasV14I–mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome. PMID:25359213

An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Extract Reproductive Outcomes Executive Summary introduction and Conclusions.

DTIC Science & Technology

1992-08-31

Birth Defects and Developmental Anomalies Twelve specific birth defects (anencephaly, spina bifida, hydrocephalus, cleft palate , cleft lip / palate ...Selected Birth Defects Twelve birth defects (anencephaly, spina bifida, hydrocephalus, cleft palate , cleft lip / palate , esophageal atresia, anorectal... cleft palate after coadministration of retinoic acid and TCDD. Toxicology and Applied Pharmacology 99(2):287-301 25. Roberts, E. A., Vella, L. M., Golas

Psf2 plays important roles in normal eye development in Xenopus laevis

PubMed Central

Walter, Brian E.; Perry, Kimberly J.; Fukui, Lisa; Malloch, Erica L.; Wever, Jason

2008-01-01

Purpose Psf2 (partner of Sld5 2) represents a member of the GINS (go, ichi, ni, san) heterotetramer [1] and functions in DNA replication as a “sliding clamp.” Previous in situ hybridization analyses revealed that Psf2 is expressed during embryonic development in a tissue-specific manner, including the optic cup (retina) and the lens [2]. This article provides an analysis of Psf2 function during eye development in Xenopus laevis. Methods A morpholino targeted to Psf2 mRNA was designed to knockdown Psf2 translation and was injected into specific embryonic cells during early cleavage stages in the frog, Xenopus laevis. Injected embryos were assayed for specific defects in morphology, cell proliferation, and apoptosis. Synthetic Psf2 RNA was also co-injected with the morpholino to rescue morpholino-mediated developmental defects. It is well known that reciprocal inductive interactions control the development of the optic cup and lens. Therefore, control- and morpholino-injected embryos were used for reciprocal transplantation experiments to distinguish the intrinsic role of Psf2 in the development of the optic cup (retina) versus the lens. Results Morpholino-mediated knockdown of Psf2 expression resulted in dosage-dependent phenotypes, which included microphthalmia, incomplete closure of the ventral retinal fissure, and retinal and lens dysgenesis. Defects were also observed in other embryonic tissues that normally express Psf2 including the pharyngeal arches and the otic vesicle, although other tissues that express Psf2 were not found to be grossly defective. Eye defects could be rescued by co-injection of synthetic Psf2 RNA. Examination of cell proliferation via an antibody against phospho-histone H3 S10P revealed no significant differences in the retina and lens following Psf2 knockdown. However, there was a significant increase in the level of apoptosis in retinal as well as forebrain tissues, as revealed by TUNEL (terminal deoxynucleotide transferase dUTP nick end labeling) assay. Conclusions The results demonstrate intrinsic roles for Psf2 in both retinal and to a lesser extent, lens tissues. Observed lens defects can mainly be attributed to deficiencies in retinal development and consequently the late phase of lens induction, which involves instructive cues from the optic cup. Developmental defects were not observed in all tissues that express Psf2, which could be related to differences in the translation of Psf2 or redundant effects of related factors such as proliferating cell nuclear antigen (PCNA). PMID:18509549

A-to-I RNA editing promotes developmental stage-specific gene and lncRNA expression.

PubMed

Goldstein, Boaz; Agranat-Tamir, Lily; Light, Dean; Ben-Naim Zgayer, Orna; Fishman, Alla; Lamm, Ayelet T

2017-03-01

A-to-I RNA editing is a conserved widespread phenomenon in which adenosine (A) is converted to inosine (I) by adenosine deaminases (ADARs) in double-stranded RNA regions, mainly noncoding. Mutations in ADAR enzymes in Caenorhabditis elegans cause defects in normal development but are not lethal as in human and mouse. Previous studies in C. elegans indicated competition between RNA interference (RNAi) and RNA editing mechanisms, based on the observation that worms that lack both mechanisms do not exhibit defects, in contrast to the developmental defects observed when only RNA editing is absent. To study the effects of RNA editing on gene expression and function, we established a novel screen that enabled us to identify thousands of RNA editing sites in nonrepetitive regions in the genome. These include dozens of genes that are edited at their 3' UTR region. We found that these genes are mainly germline and neuronal genes, and that they are down-regulated in the absence of ADAR enzymes. Moreover, we discovered that almost half of these genes are edited in a developmental-specific manner, indicating that RNA editing is a highly regulated process. We found that many pseudogenes and other lncRNAs are also extensively down-regulated in the absence of ADARs in the embryo but not in the fourth larval (L4) stage. This down-regulation is not observed upon additional knockout of RNAi. Furthermore, levels of siRNAs aligned to pseudogenes in ADAR mutants are enhanced. Taken together, our results suggest a role for RNA editing in normal growth and development by regulating silencing via RNAi. © 2017 Goldstein et al.; Published by Cold Spring Harbor Laboratory Press.

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

PubMed

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-12-23

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

A Rare de novo Interstitial Duplication at 4p15.2 in a Boy with Severe Congenital Heart Defects, Limb Anomalies, Hypogonadism, and Global Developmental Delay.

PubMed

Liang, Liyang; Xie, Yingjun; Shen, Yiping; Yin, Qibin; Yuan, Haiming

2016-01-01

Proximal 4p deletion syndrome is a relatively rare genetic condition characterized by dysmorphic facial features, limb anomalies, minor congenital heart defects, hypogonadism, cafe-au-lait spots, developmental delay, tall and thin habitus, and intellectual disability. At present, over 20 cases of this syndrome have been published. However, duplication of the same region in proximal 4p has never been reported. Here, we describe a 2-year-5-month-old boy with severe congenital heart defects, limb anomalies, hypogonadism, distinctive facial features, pre- and postnatal developmental delay, and mild cognitive impairments. A de novo 4.5-Mb interstitial duplication at 4p15.2p15.1 was detected by chromosomal microarray analysis. Next-generation sequencing was employed and confirmed the duplication, but revealed no additional pathogenic variants. Several candidate genes in this interval responsible for the complex clinical phenotype were identified, such as RBPJ, STIM2, CCKAR, and LGI2. The results suggest a novel contiguous gene duplication syndrome. © 2016 S. Karger AG, Basel.

Pancreas and gallbladder agenesis in a newborn with semilobar holoprosencephaly, a case report.

PubMed

Hilbrands, Robert; Keymolen, Kathelijn; Michotte, Alex; Marichal, Miriam; Cools, Filip; Goossens, Anieta; Veld, Peter In't; De Schepper, Jean; Hattersley, Andrew; Heimberg, Harry

2017-05-19

Pancreatic agenesis is an extremely rare cause of neonatal diabetes mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development. We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder. Although the sequences of a selected set of genes related to pancreas agenesis or HPE were wild-type, the patient's phenotype suggests a genetic defect that emerges early in embryonic development of brain, gallbladder and pancreas. Developmental defects of the pancreas and brain can occur together. Identifying the genetic defect may identify a novel key regulator in beta cell development.

Esthetic perception and psychosocial impact of developmental enamel defects among Malaysian adolescents.

PubMed

Sujak, Sharol Lail; Abdul Kadir, Rahimah; Dom, Tuti Ningseh Mohd

2004-12-01

The aim of this study was to investigate the prevalence and psychosocial impact of enamel defects among 16-year-old school children on the island of Penang. The data were collected through a self-administered questionnaire survey and an oral examination, using the Modified Developmental Defects of Enamel Index (FDI, 1992). In all, 1024 subjects were selected using a multistage random sampling technique. About two-thirds of the sample (67.1%) had at least one tooth affected by enamel defects. Enamel opacities accounted for 85.6% of the total condition. Diffuse-type opacity predominated (63.5%). Among subjects who expressed dissatisfaction, 18.8% reported covering their mouths when smiling, 8.7% avoided going out with friends and 39.1% had consulted their dentists. About 17% of the subjects reported that their parents had complained about the color of their front teeth but only 5.7% had experienced being teased by their friends about the problem. Two-thirds of the subjects were affected by enamel defects involving at least one tooth; however, the esthetic perception and psychosocial impact of those affected were minor.

The VIRTUAL EMBRYO. A Computational Framework for Developmental Toxicity

EPA Science Inventory

EPA’s ‘Virtual Embryo Project’ (v-Embryo™) is focused on the predictive toxicology of children’s health and developmental defects following prenatal exposure to environmental chemicals. The research is motivated by scientific principles in systems biology as a framework for the g...

Mechanistic modeling of developmental defects through computational embryology (WC10th)

EPA Science Inventory

Abstract: An important consideration for 3Rs is to identify developmental hazards utilizing mechanism-based in vitro assays (e.g., ToxCast) and in silico predictive models. Steady progress has been made with agent-based models that recapitulate morphogenetic drivers for angiogen...

Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome.

PubMed

Bacrot, Séverine; Doyard, Mathilde; Huber, Céline; Alibeu, Olivier; Feldhahn, Niklas; Lehalle, Daphné; Lacombe, Didier; Marlin, Sandrine; Nitschke, Patrick; Petit, Florence; Vazquez, Marie-Paule; Munnich, Arnold; Cormier-Daire, Valérie

2015-02-01

Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations. © 2014 WILEY PERIODICALS, INC.

Nitric Oxide Regulates Protein Methylation during Stress Responses in Plants.

PubMed

Hu, Jiliang; Yang, Huanjie; Mu, Jinye; Lu, Tiancong; Peng, Juli; Deng, Xian; Kong, Zhaosheng; Bao, Shilai; Cao, Xiaofeng; Zuo, Jianru

2017-08-17

Methylation and nitric oxide (NO)-based S-nitrosylation are highly conserved protein posttranslational modifications that regulate diverse biological processes. In higher eukaryotes, PRMT5 catalyzes Arg symmetric dimethylation, including key components of the spliceosome. The Arabidopsis prmt5 mutant shows severe developmental defects and impaired stress responses. However, little is known about the mechanisms regulating the PRMT5 activity. Here, we report that NO positively regulates the PRMT5 activity through S-nitrosylation at Cys-125 during stress responses. In prmt5-1 plants, a PRMT5 C125S transgene, carrying a non-nitrosylatable mutation at Cys-125, fully rescues the developmental defects, but not the stress hypersensitive phenotype and the responsiveness to NO during stress responses. Moreover, the salt-induced Arg symmetric dimethylation is abolished in PRMT5 C125S /prmt5-1 plants, correlated to aberrant splicing of pre-mRNA derived from a stress-related gene. These findings define a mechanism by which plants transduce stress-triggered NO signal to protein methylation machinery through S-nitrosylation of PRMT5 in response to environmental alterations. Copyright © 2017 Elsevier Inc. All rights reserved.

Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism

PubMed Central

Jiang, Xi; Hu, Haiyang; Guijarro, Patricia; Mitchell, Amanda; Ely, John J.; Sherwood, Chet C.; Hof, Patrick R.; Qiu, Zilong; Pääbo, Svante; Akbarian, Schahram; Khaitovich, Philipp

2016-01-01

Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans. PMID:27685936

Systems Biology and Birth Defects Prevention: Blockade of the Glucocorticoid Receptor Prevents Arsenic-Induced Birth Defects

PubMed Central

Ahir, Bhavesh K.; Sanders, Alison P.; Rager, Julia E.

2013-01-01

Background: The biological mechanisms by which environmental metals are associated with birth defects are largely unknown. Systems biology–based approaches may help to identify key pathways that mediate metal-induced birth defects as well as potential targets for prevention. Objectives: First, we applied a novel computational approach to identify a prioritized biological pathway that associates metals with birth defects. Second, in a laboratory setting, we sought to determine whether inhibition of the identified pathway prevents developmental defects. Methods: Seven environmental metals were selected for inclusion in the computational analysis: arsenic, cadmium, chromium, lead, mercury, nickel, and selenium. We used an in silico strategy to predict genes and pathways associated with both metal exposure and developmental defects. The most significant pathway was identified and tested using an in ovo whole chick embryo culture assay. We further evaluated the role of the pathway as a mediator of metal-induced toxicity using the in vitro midbrain micromass culture assay. Results: The glucocorticoid receptor pathway was computationally predicted to be a key mediator of multiple metal-induced birth defects. In the chick embryo model, structural malformations induced by inorganic arsenic (iAs) were prevented when signaling of the glucocorticoid receptor pathway was inhibited. Further, glucocorticoid receptor inhibition demonstrated partial to complete protection from both iAs- and cadmium-induced neurodevelopmental toxicity in vitro. Conclusions: Our findings highlight a novel approach to computationally identify a targeted biological pathway for examining birth defects prevention. PMID:23458687

Applying standard perikymata profiles to Pongo pygmaeus canines to estimate perikymata counts between linear enamel hypoplasias.

PubMed

O'Hara, Mackie

2017-05-01

Recently, studies have interpreted regular spacing and average number of perikymata between dental enamel defects in orangutans to reflect seasonal episodes of physiological stress. To estimate the amount of time between developmental defects (enamel hypoplasia), studies have relied on perikymata counts. Unfortunately, perikymata are frequently not continuously visible between defects, significantly reducing data sets. A method is presented here for estimating the number of perikymata between defects using standard perikymata profiles (SPP) that allow the number of perikymata between all pairs of defects across a tooth to be analyzed. The SPP method should allow the entire complement of defects to be analyzed within the context of an individual's crown formation time. The average number of perikymata were established per decile and charted to create male and female Pongo pygmaeus SPPs. The position of the beginning of each defect was recorded for lower canines from males (n = 6) and females (n = 17). The number of perikymata between defects estimated by the SPP was compared to the actual count (where perikymata were continuously visible). The number of perikymata between defects estimated by the SPPs was accurate within three perikymata and highly correlated with the actual counts, significantly increasing the number of analyzable defect pairs. SPPs allow all defect pairs to be included in studies of defect timing, not just those with continuously visible perikymata. Establishing an individual's entire complement of dental defects makes it possible to calculate the regularity (and potential seasonality) of defects. © 2017 Wiley Periodicals, Inc.

in vitro Models if Human Embryonic Mesenchymal Transitions in Morphogenesis

EPA Science Inventory

Our ability to predict human developmental consequences produced by exposure to environmental chemicals is limited by the current experimental and computational models.Human heart defects are among the most common type of birth defects and affect 1% of children (~40,000 children)...

Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shao, Xue; Hu, Zhengtao; Hu, Chunyan

Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using {sup 1}H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed amore » more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use. Highlights: ► Metabonomics findings. ► Abnormal development. ► Dysregulations of key proteins.« less

The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development.

PubMed

Akhter, Shamima; Lam, Yung C; Chang, Sandy; Legerski, Randy J

2010-12-01

Conserved metallo β-Lactamase and β-CASP (CPSF-Artemis-Snm1-Pso2) domain nuclease family member SNM1B/Apollo is a shelterin-associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end-to-end fusions. Deficiency of the nonhomologous end-joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo-deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ-mediated repair, which results in genomic instability and the consequent multi-organ developmental failure. Although Snm1B/Apollo-deficient MEFs exhibited high levels of apoptosis, abrogation of p53-dependent programmed cell death did not rescue the multi-organ developmental failure in the mice. © 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Wnt signaling in caudal dysgenesis and diabetic embryopathy

PubMed Central

Pavlinkova, Gabriela; Salbaum, J. Michael; Kappen, Claudia

2010-01-01

Congenital defects are a major complication of diabetic pregnancy, and the leading cause of infant death in the first year of life. Caudal dysgenesis, occurring up to 200-fold more frequently in children born to diabetic mothers, is a hallmark of diabetic pregnancy. Given that there is also an at least 3-fold higher risk for heart defects and neural tube defects, it is important to identify the underlying molecular mechanisms for aberrant embryonic development. We have investigated gene expression in a transgenic mouse model of caudal dysgenesis, and in a pharmacological model using situ hybridization and quantitative real-time PCR. We identify altered expression of several molecules that control developmental processes and embryonic growth. The results from our models point towards major implication of altered Wnt signaling in the pathogenesis of developmental anomalies associated with embryonic exposure to maternal diabetes. PMID:18937363

Shared molecular networks in orofacial and neural tube development.

PubMed

Kousa, Youssef A; Mansour, Tamer A; Seada, Haitham; Matoo, Samaneh; Schutte, Brian C

2017-01-30

Single genetic variants can affect multiple tissues during development. Thus it is possible that disruption of shared gene regulatory networks might underlie syndromic presentations. In this study, we explore this idea through examination of two critical developmental programs that control orofacial and neural tube development and identify shared regulatory factors and networks. Identification of these networks has the potential to yield additional candidate genes for poorly understood developmental disorders and assist in modeling and perhaps managing risk factors to prevent morbidly and mortality. We reviewed the literature to identify genes common between orofacial and neural tube defects and development. We then conducted a bioinformatic analysis to identify shared molecular targets and pathways in the development of these tissues. Finally, we examine publicly available RNA-Seq data to identify which of these genes are expressed in both tissues during development. We identify common regulatory factors in orofacial and neural tube development. Pathway enrichment analysis shows that folate, cancer and hedgehog signaling pathways are shared in neural tube and orofacial development. Developing neural tissues differentially express mouse exencephaly and cleft palate genes, whereas developing orofacial tissues were enriched for both clefting and neural tube defect genes. These data suggest that key developmental factors and pathways are shared between orofacial and neural tube defects. We conclude that it might be most beneficial to focus on common regulatory factors and pathways to better understand pathology and develop preventative measures for these birth defects. Birth Defects Research 109:169-179, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Computational Modeling and Simulation of Developmental Toxicity. What can we learn from a virtual embryo? (FDA-CFSAN workshop)

EPA Science Inventory

SYNOPSIS: The question of how tissues and organs are shaped during development is crucial for understanding human birth defects. Data from high-throughput screening assays on human stem cells may be utilized predict developmental toxicity with reasonable accuracy. Other types of ...

Developmental Patterning: Putting the Squeeze on Mis-specified Cells.

PubMed

Nakajima, Yu-Ichiro; Gibson, Matthew C

2016-03-07

Widely implicated in human disease, abnormal cellular cysts reflect dramatic defects in the maintenance of epithelial integrity. A new study reports that epithelial cysts may arise as a surprisingly general consequence of clonal defects in the specification of cell identity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Duplication of the pituitary gland associated with multiple blastogenesis defects: Duplication of the pituitary gland (DPG)-plus syndrome. Case report and review of literature.

PubMed

Manjila, Sunil; Miller, Erin A; Vadera, Sumeet; Goel, Rishi K; Khan, Fahd R; Crowe, Carol; Geertman, Robert T

2012-01-01

Duplication of the pituitary gland (DPG) is a rare craniofacial developmental anomaly occurring during blastogenesis with postulated etiology such as incomplete twinning, teratogens, median cleft face syndrome or splitting of the notochord. The complex craniocaudal spectrum of blastogenesis defects associated with DPG is examined with an illustrative case. We report for the first time in the medical literature some unique associations with DPG, such as a clival encephalocele, third cerebral peduncle, duplicate odontoid process and a double tongue with independent volitional control. This patient also has the previously reported common associations such as duplicated sella, cleft palate, hypertelorism, callosal agenesis, hypothalamic enlargement, nasopharyngeal teratoma, fenestrated basilar artery and supernumerary teeth. This study also reviews 37 cases of DPG identified through MEDLINE literature search from 1880 to 2011. It provides a detailed analysis of the current case through physical examination and imaging. The authors propose that the developmental deformities associated with duplication of pituitary gland (DPG) occur as part of a developmental continuum, not as chance associations. Considering the fact that DPG is uniquely and certainly present throughout the spectrum of these blastogenesis defects, we suggest the term DPG-plus syndrome.

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

PubMed Central

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-01-01

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

A practical guide to the management of anophthalmia and microphthalmia.

PubMed

Ragge, N K; Subak-Sharpe, I D; Collin, J R O

2007-10-01

Congenital anophthalmia and microphthalmia are rare developmental defects of the globe. They often arise in conjunction with other ocular defects such as coloboma and orbital cyst. They may also be part of more generalised syndromes, such as CHARGE syndrome. Anophthalmia, microphthalmia, and coloboma are likely to be caused by disturbances of the morphogenetic pathway that controls eye development, either as a result of primary genetic defect, or external gestational factors, including infection or drugs that can influence the smooth processes of morphogenesis. The ophthalmologist is often the primary carer for children with anophthalmia and microphthalmia, and as such can coordinate the multidisciplinary input needed to offer optimal care for these individuals, including vision and family support services. They are able to assess the vision and maximise the visual potential of the child and they can also ensure that the cosmetic and social impact of anophthalmia or microphthalmia is minimised by starting socket expansion or referring to a specialist oculoplastics and prosthetics unit. A coordinated approach with paediatrics is necessary to manage any associated conditions. Genetic diagnosis and investigations can greatly assist in providing a diagnosis and informed genetic counselling.

[Risk factors for teeth aplasia and hypoplasia in cleft lip and palate children].

PubMed

Korolenkova, M V; Starikova, N V; Ageeva, L V

2016-01-01

The aim of the study was to assess the significance of environmental risk factors for teeth aplasia and hypoplasia in cleft lip and palate children. Two hundred and forty-seven cleft lip and palate (CLP) children were enrolled in the study including 105 (42.5%) with bilateral CLP and 57.5% with unilateral CLP. The mean age was 11.2±4.9 years. Teeth condition was assessed clinically and radiologically. The impact of risk factors for teeth anomalies was analyzed by retrospective data obtained from computer database (absence of preoperative orthopedic treatment, palatal defects after primary palatoplasty and type of primary procedures). Surgical trauma by early periosteoplasty (at the age of 3-4 months), excessive scarring and tissue traction due to absence of early orthopedic treatment and palatal defect were associated with significantly higher incidence of incisors hypoplasia (both developmental enamel defects and microdentia) and aplasia of central incisors not seen in the other study subgroups. Incisors aplasia and hypoplasia in CLP patients do not always have disembryogenic origin but may depend on external environmental factors, including surgical trauma.

Overexpression of a truncated CTF7 construct leads to pleiotropic defects in reproduction and vegetative growth in Arabidopsis.

PubMed

Liu, Desheng; Makaroff, Christopher A

2015-03-05

Eco1/Ctf7 is essential for the establishment of sister chromatid cohesion during S phase of the cell cycle. Inactivation of Ctf7/Eco1 leads to a lethal phenotype in most organisms. Altering Eco1/Ctf7 levels or point mutations in the gene can lead to alterations in nuclear division as well as a wide range of developmental defects. Inactivation of Arabidopsis CTF7 (AtCTF7) results in severe defects in reproduction and vegetative growth. To further investigate the function(s) of AtCTF7, a tagged version of AtCTF7 and several AtCTF7 deletion constructs were created and transformed into wild type or ctf7 +/- plants. Transgenic plants expressing 35S:NTAP:AtCTF7∆299-345 (AtCTF7∆B) displayed a wide range of phenotypic alterations in reproduction and vegetative growth. Male meiocytes exhibited chromosome fragmentation and uneven chromosome segregation. Mutant ovules contained abnormal megasporocyte-like cells during pre-meiosis, megaspores experienced elongated meiosis and megagametogenesis, and defective megaspores/embryo sacs were produced at various stages. The transgenic plants also exhibited a broad range of vegetative defects, including meristem disruption and dwarfism that were inherited in a non-Mendelian fashion. Transcripts for epigenetically regulated transposable elements (TEs) were elevated in transgenic plants. Transgenic plants expressing 35S:AtCTF7∆B displayed similar vegetative defects, suggesting the defects in 35S:NTAP:AtCTF7∆B plants are caused by high-level expression of AtCTF7∆B. High level expression of AtCTF7∆B disrupts megasporogenesis, megagametogenesis and male meiosis, as well as causing a broad range of vegetative defects, including dwarfism that are inherited in a non-Mendelian fashion.

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

PubMed

Schwörer, Simon; Becker, Friedrich; Feller, Christian; Baig, Ali H; Köber, Ute; Henze, Henriette; Kraus, Johann M; Xin, Beibei; Lechel, André; Lipka, Daniel B; Varghese, Christy S; Schmidt, Manuel; Rohs, Remo; Aebersold, Ruedi; Medina, Kay L; Kestler, Hans A; Neri, Francesco; von Maltzahn, Julia; Tümpel, Stefan; Rudolph, K Lenhard

2016-12-15

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux.

PubMed

Fujita, Atsushi; Isidor, Bertrand; Piloquet, Hugues; Corre, Pierre; Okamoto, Nobuhiko; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Miyake, Noriko; Matsumoto, Naomichi

2016-09-01

MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect.

Suppressed production of methyl farnesoid hormones yields developmental defects and lethality in Drosophila larvae

USDA-ARS?s Scientific Manuscript database

A long-unresolved question in the developmental biology of Drosophila melanogaster has been whether methyl farnesoid hormones secreted by the ring gland are necessary for larval maturation and metamorphosis. In this study, we have used RNAi techniques to inhibit 3-Hydroxy-3-Methylglutaryl CoA Reduct...

Prevalence and Characteristics of Developmental Dental Anomalies in Iranian Orofacial Cleft Patients

PubMed Central

Ajami, Shabnam; Pakshir, Hamidreza; Samady, Hedyeh

2017-01-01

Statement of the Problem: Individuals with oral clefts exhibit considerably more dental anomalies than individuals without clefts. These problems could initially be among the symptoms of their disease and/or they may be the side effect of their treatments. Pushback palatoplasty could cause some interference during the development of teeth and result in tooth defects. Purpose: The study was performed to assess the prevalence and characteristics of developmental dental anomalies in orofacial cleft patients who attended Shiraz Orthodontics Research Center-Cleft Lip and Palate Clinic. We managed to compare dental anomaly traits based on gender and cleft side. Materials and Method: Eighty out of 121 cleft patients were included in this cross-sectional study. All the patients used pushback palatoplasty in their palate closure surgeries. Intraoral photographs, panoramic and intraoral radiographs, cone-beam computed tomography (CBCT) and dental and medical histories were examined and recorded by two observers. Data were analyzed using SPSS PC version 20.0. The differences in the side of cleft and dental anomalies were compared using the Mann-Whitney test. Results: The mean age of patients was 14.27 years (SD=5.06). The most frequent cleft type was unilateral cleft lip and palate (50%) followed by bilateral cleft lip and palate (43.75%), cleft palate (2.5%) and cleft lip (1.25%). Male predominance (70%) was observed. 92.5 percent had at least one developmental dental anomaly. The most prevalent anomalies were hypodontia (71.25%) followed by microdontia (30%), root dilacerations (21.25%) and supernumerary teeth (15%). Conclusion: The most prevalent cleft types were unilateral and bilateral cleft lip and palate with male and left side predominance. Hypodontia, microdontia, dilacerations and supernumerary teeth were the most prevalent developmental dental anomalies among Iranian southwestern cleft patients. The surgical technique used to repair their cleft palate may have played a role in developmental dental defects. PMID:29034274

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report

PubMed Central

Alshenqiti, Abduljabbar; Nashabat, Marwan; AlGhoraibi, Hissah; Tamimi, Omar; Alfadhel, Majid

2017-01-01

Incontinentia pigmenti (IP; Bloch–Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case. PMID:28533687

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report.

PubMed

Alshenqiti, Abduljabbar; Nashabat, Marwan; AlGhoraibi, Hissah; Tamimi, Omar; Alfadhel, Majid

2017-01-01

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case.

The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity.

PubMed

Muth-Köhne, Elke; Wichmann, Arne; Delov, Vera; Fenske, Martina

2012-07-01

Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC₅₀). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC₅₀ values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures. Copyright © 2012 Elsevier Inc. All rights reserved.

CHEMICAL PRIORITIZATION FOR DEVELOPMENTAL ...

EPA Pesticide Factsheets

Defining a predictive model of developmental toxicity from in vitro and high-throughput screening (HTS) assays can be limited by the availability of developmental defects data. ToxRefDB (www.epa.gov/ncct/todrefdb) was built from animal studies on data-rich environmental chemicals, and has been used as an anchor for predictive modeling of ToxCast™ data. Scaling to thousands of untested chemicals requires another approach. ToxPlorer™ was developed as a tool to query and extract specific facts about defined biological entities from the open scientific literature and to coherently synthesize relevant knowledge about relationships, pathways and processes in toxicity. Here, we investigated the specific application of ToxPlorer to weighting HTS assay targets for relevance to developmental defects as defined in the literature. First, we systemically analyzed 88,193 Pubmed abstracts selected by bulk query using harmonized terminology for 862 developmental endpoints (www.devtox.net) and 364,334 dictionary term entities in our VT-KB (virtual tissues knowledgebase). We specifically focused on entities corresponding to genes/proteins mapped across of >500 ToxCast HTS assays. The 88,193 devtox abstracts mentioned 244 gene/protein entities in an aggregated total of ~8,000 occurrences. Each of the 244 assays was scored and weighted by the number of devtox articles and relevance to developmental processes. This score was used as a feature for chemical prioritization by Toxic

Dissection of the complex genetic basis of craniofacial anomalies using haploid genetics and interspecies hybrids in Nasonia wasps

PubMed Central

Werren, John H.; Cohen, Lorna B.; Gadau, Juergen; Ponce, Rita; Baudry, Emmanuelle; Lynch, Jeremy A.

2016-01-01

The animal head is a complex structure where numerous sensory, structural and alimentary structures are concentrated and integrated, and its ontogeny requires precise and delicate interactions among genes, cells, and tissues. Thus, it is perhaps unsurprising that craniofacial abnormalities are among the most common birth defects in people, or that these defects have a complex genetic basis involving interactions among multiple loci. Developmental processes that depend on such epistatic interactions become exponentially more difficult to study in diploid organisms as the number of genes involved increases. Here, we present hybrid haploid males of the wasp species pair Nasonia vitripennis and Nasonia giraulti, which have distinct male head morphologies, as a genetic model of craniofacial development that possesses the genetic advantages of haploidy, along with many powerful genomic tools. Viable, fertile hybrids can be made between the species, and quantitative trail loci related to shape differences have been identified. In addition, a subset of hybrid males show head abnormalities, including clefting at the midline and asymmetries. Crucially, epistatic interactions among multiple loci underlie several developmental differences and defects observed in the F2 hybrid males. Furthermore, we demonstrate an introgression of a chromosomal region from N. giraulti into N. vitripennis that shows an abnormality in relative eye size, which maps to a region containing a major QTL for this trait. Therefore, the genetic sources of head morphology can, in principle, be identified by positional cloning. Thus, Nasonia is well positioned to be a uniquely powerful model invertebrate system with which to probe both development and complex genetics of craniofacial patterning and defects. PMID:26721604

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways.

PubMed

Geoffroy, Andréa; Kerek, Racha; Pourié, Grégory; Helle, Déborah; Guéant, Jean-Louis; Daval, Jean-Luc; Bossenmeyer-Pourié, Carine

2017-09-01

The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid. However, the question about the duration and periodicity of supplementation remains. We therefore tested maternal supply (3 mg/kg/day) during the last third of gestation from embryonic days (E) 13 to 20. Methyl donor deficiency-related developmental disorders at E20, including cerebellar and interhemispheric suture defects and atrophy of selective cerebral layers, were associated with increased brain expression (by 2.5-fold) of let-7a and miR-34a, with subsequent downregulation of their regulatory targets such as Trim71 and Notch signaling partners, respectively. These processes could be reversed by siRNA strategy in differentiating neuroprogenitors lacking folate, with improvement of their morphological characteristics. While folic acid supplementation helped restoring the levels of let-7a and miR-34a and their downstream targets, it led to a reduction of structural and functional defects taking place during the perinatal period. Our data outline the potential role of let-7 and miR-34 and their related signaling pathways in the developmental defects following gestational methyl donor deficiency and support the likely usefulness of late folate supplementation in at risk women.

Constitutional Epi/Genetic Conditions: Genetic, Epigenetic, and Environmental Factors

PubMed Central

Schenkel, Laila C.; Rodenhiser, David; Siu, Victoria; McCready, Elizabeth; Ainsworth, Peter; Sadikovic, Bekim

2016-01-01

There are more than 4,000 phenotypes for which the molecular basis is at least partly known. Though defects in primary DNA structure constitute a major cause of these disorders, epigenetic disruption is emerging as an important alternative mechanism in the etiology of a broad range of congenital and developmental conditions. These include epigenetic defects caused by either localized (in cis) genetic alterations or more distant (in trans) genetic events but can also include environmental effects. Emerging evidence suggests interplay between genetic and environmental factors in the epigenetic etiology of several constitutional “epi/genetic” conditions. This review summarizes our broadening understanding of how epigenetics contributes to pediatric disease by exploring different classes of epigenomic disorders. It further challenges the simplistic dogma of “DNA encodes RNA encodes protein” to best understand the spectrum of factors that can influence genetic traits in a pediatric population. PMID:28180025

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PubMed

Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PubMed Central

Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W.

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects. PMID:28575130

The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3.

PubMed

Albert, Mareike; Schmitz, Sandra U; Kooistra, Susanne M; Malatesta, Martina; Morales Torres, Cristina; Rekling, Jens C; Johansen, Jens V; Abarrategui, Iratxe; Helin, Kristian

2013-04-01

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications.

The Histone Demethylase Jarid1b Ensures Faithful Mouse Development by Protecting Developmental Genes from Aberrant H3K4me3

PubMed Central

Kooistra, Susanne M.; Malatesta, Martina; Morales Torres, Cristina; Rekling, Jens C.; Johansen, Jens V.; Abarrategui, Iratxe; Helin, Kristian

2013-01-01

Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications. PMID:23637629

Association between developmental enamel defects in the primary and permanent dentitions.

PubMed

Casanova-Rosado, A J; Medina-Solís, C E; Casanova-Rosado, J F; Vallejos-Sánchez, A A; Martinez-Mier, E A; Loyola-Rodríguez, J P; Islas-Márquez, A J; Maupomé, G

2011-09-01

To determine if the presence of developmental enamel defects (DED) in the primary dentition is a risk indicator for the presence of DED in the permanent dentition in children with mixed dentition, as well as others factors. A cross-sectional study was undertaken in 1296 school children ages six to 72 years. The DED [FDI; 1982] in both dentitions were identified by means of an oral exam scoring enamel opacities [classified as demarcated or diffused], and enamel hypoplasia. Sociodemographic and socioeconomic variables were collected through a questionnaire. Socioeconomic status (SES) was determined based on the occupation and maximum level of education of parents. Statistical analysis included logistic regression. Mean age of participants was 8.40 +/- 1.68; 51.6% were boys. DED prevalence was 7.5% in the permanent dentition and 10.0% in the primary dentition. The logistic regression model, adjusting for sociodemographic and socioeconomic variables, showed that for each primary tooth with DED, the odds of observing DED in the permanent dentition increased 7.38 times [95% CI = 1.17-1.64; p < 0.001]. An association between DED presence in both permanent and primary dentitions was observed. Further studies are necessary to fully characterise such relationship.

Dental caries and developmental defects of enamel in relation to fluoride levels in drinking water in an arid area of Sri Lanka.

PubMed

Ekanayake, L; van der Hoek, W

2002-01-01

The study was conducted to assess caries and developmental defects of enamel in relation to fluoride levels in drinking water and the association between caries experience and the severity of diffuse opacities in children living in Uda Walawe, an area with varying concentrations of fluoride in drinking water in Sri Lanka. A total of 518 14-year-old children who were lifelong residents in this area were examined for dental caries and developmental defects of enamel. But the present analysis is confined to 486 children from whom drinking water samples were collected. The prevalence of enamel defects and diffuse opacities ranged from 27 to 57% while the prevalence of caries ranged from 18 to 29% in the different fluoride exposure groups. The prevalence of enamel defects increased significantly with the increase in the fluoride level in drinking water. Both the caries prevalence and the mean caries experience were significantly higher in children with diffuse opacities than in those without in the group consuming water containing >0.70 mg/l of fluoride. The association between dental caries and the severity of diffuse opacities was also significant only in this group. Children with the mildest form of opacities (DDE scores 3 and 4) had the lowest DMFS (0.25 +/- 0.7), and the highest DMFS (1.1 +/- 1.7) was found in those with the most severe form of opacities (DDE score 6). In conclusion, the relationship that was observed in this study between fluoride levels in drinking water, diffuse opacities and caries suggests that the appropriate level of fluoride in drinking water for arid areas of Sri Lanka is around 0.3 mg/l. Also individuals with severe forms of enamel defects in high-fluoride areas are susceptible to dental caries. Copyright 2002 S. Karger AG, Basel

Periodontal cosmetic surgery.

PubMed

Oringer, R J; Iacono, V J

1999-07-01

Periodontal plastic procedures are performed to prevent or correct anatomical, developmental, traumatic, or plaque induced defects of the gingiva, alveolar mucosa, or bone. The majority of these procedures are performed in combination with restorative and/or orthodontic therapy with the primary goal of enhancing aesthetics. In this review some of the more prominent techniques currently available to address mucogingival deficiencies including pedicle grafts, free soft tissue grafts, and combination grafts are illustrated. In addition, potential complications associated with periodontal plastic procedures are discussed.

The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth

PubMed Central

Lynch, Sally Ann; Foulds, Nicola; Thuresson, Ann-Charlotte; Collins, Amanda L; Annerén, Göran; Hedberg, Bernt-Oves; Delaney, Carol A; Iremonger, James; Murray, Caroline M; Crolla, John A; Costigan, Colm; Lam, Wayne; Fitzpatrick, David R; Regan, Regina; Ennis, Sean; Sharkey, Freddie

2011-01-01

We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism. PMID:21267005

Homozygosity Mapping and Candidate Prioritization Identify Mutations, Missed by Whole-Exome Sequencing, in SMOC2, Causing Major Dental Developmental Defects

PubMed Central

Bloch-Zupan, Agnès; Jamet, Xavier; Etard, Christelle; Laugel, Virginie; Muller, Jean; Geoffroy, Véronique; Strauss, Jean-Pierre; Pelletier, Valérie; Marion, Vincent; Poch, Olivier; Strahle, Uwe; Stoetzel, Corinne; Dollfus, Hélène

2011-01-01

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2. PMID:22152679

Numerical Estimation in Adults with and without Developmental Dyscalculia

ERIC Educational Resources Information Center

Mejias, Sandrine; Gregoire, Jacques; Noel, Marie-Pascale

2012-01-01

It has been hypothesized that developmental dyscalculia (DD) is either due to a defect of the approximate number system (ANS) or to an impaired access between that system and symbolic numbers. Several studies have tested these two hypotheses in children with DD but none has dealt with adults who had experienced DD as children. This study aimed to…

Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes with Different Cognitive Profiles and Deficits

ERIC Educational Resources Information Center

Skagerlund, Kenny; Träff, Ulf

2016-01-01

This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with…

Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1

PubMed Central

Balmus, Gabriel; Zhu, Min; Mukherjee, Sucheta; Lyndaker, Amy M.; Hume, Kelly R.; Lee, Jaesung; Riccio, Mark L.; Reeves, Anthony P.; Sutter, Nathan B.; Noden, Drew M.; Peters, Rachel M.; Weiss, Robert S.

2012-01-01

The human genomic instability syndrome ataxia telangiectasia (A-T), caused by mutations in the gene encoding the DNA damage checkpoint kinase ATM, is characterized by multisystem defects including neurodegeneration, immunodeficiency and increased cancer predisposition. ATM is central to a pathway that responds to double-strand DNA breaks, whereas the related kinase ATR leads a parallel signaling cascade that is activated by replication stress. To dissect the physiological relationship between the ATM and ATR pathways, we generated mice defective for both. Because complete ATR pathway inactivation causes embryonic lethality, we weakened the ATR mechanism to different degrees by impairing HUS1, a member of the 911 complex that is required for efficient ATR signaling. Notably, simultaneous ATM and HUS1 defects caused synthetic lethality. Atm/Hus1 double-mutant embryos showed widespread apoptosis and died mid-gestationally. Despite the underlying DNA damage checkpoint defects, increased DNA damage signaling was observed, as evidenced by H2AX phosphorylation and p53 accumulation. A less severe Hus1 defect together with Atm loss resulted in partial embryonic lethality, with the surviving double-mutant mice showing synergistic increases in genomic instability and specific developmental defects, including dwarfism, craniofacial abnormalities and brachymesophalangy, phenotypes that are observed in several human genomic instability disorders. In addition to identifying tissue-specific consequences of checkpoint dysfunction, these data highlight a robust, cooperative configuration for the mammalian DNA damage response network and further suggest HUS1 and related genes in the ATR pathway as candidate modifiers of disease severity in A-T patients. PMID:22575700

ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS

EPA Science Inventory

Altered RA Signaling in the Genesis of Ethanol-Induced Limb Defects

Johnson CS(1), Sulik KK(1,2) Hunter, ES III(3)
(1) Dept of Cell and Developmental Biology, UNC-Chapel Hill (2) Bowles Center for Alcohol Studies, UNC-CH (3) NHEERL, ORD, US EPA, RTP, NC

Administr...

Evidence of Early Childhood Defects Due to Prenatal Over-Exposure to Vitamin A: A Case Study

ERIC Educational Resources Information Center

Naude, H.; Marx, J.; Pretorius, E.; Hislop-Esterhuyzen, N.

2007-01-01

One of the important nutrients during pregnancy is vitamin A or related compounds called retinoids. Although it is well-known that vitamin A deficiency may be detrimental to foetal development, overdosage of retinoids might cause developmental defects, particularly affecting the central nervous system development of the foetus, causing hindbrain…

Duplication of the pituitary gland associated with multiple blastogenesis defects: Duplication of the pituitary gland (DPG)-plus syndrome. Case report and review of literature

PubMed Central

Manjila, Sunil; Miller, Erin A.; Vadera, Sumeet; Goel, Rishi K.; Khan, Fahd R.; Crowe, Carol; Geertman, Robert T.

2012-01-01

Background: Duplication of the pituitary gland (DPG) is a rare craniofacial developmental anomaly occurring during blastogenesis with postulated etiology such as incomplete twinning, teratogens, median cleft face syndrome or splitting of the notochord. The complex craniocaudal spectrum of blastogenesis defects associated with DPG is examined with an illustrative case. Case Description: We report for the first time in the medical literature some unique associations with DPG, such as a clival encephalocele, third cerebral peduncle, duplicate odontoid process and a double tongue with independent volitional control. This patient also has the previously reported common associations such as duplicated sella, cleft palate, hypertelorism, callosal agenesis, hypothalamic enlargement, nasopharyngeal teratoma, fenestrated basilar artery and supernumerary teeth. This study also reviews 37 cases of DPG identified through MEDLINE literature search from 1880 to 2011. It provides a detailed analysis of the current case through physical examination and imaging. Conclusion: The authors propose that the developmental deformities associated with duplication of pituitary gland (DPG) occur as part of a developmental continuum, not as chance associations. Considering the fact that DPG is uniquely and certainly present throughout the spectrum of these blastogenesis defects, we suggest the term DPG-plus syndrome. PMID:22439114

Epidermal wound repair is regulated by the planar cell polarity signaling pathway.

PubMed

Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A; Murdoch, Jennifer N; Humbert, Patrick O; Parekh, Vishwas; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M; Jane, Stephen M

2010-07-20

The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects, and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3(-)(/-) mice, we identified RhoGEF19, a homolog of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerization, cellular polarity, and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling and broadly implicate this pathway in epidermal repair. (c) 2010 Elsevier Inc. All rights reserved.

Epidermal wound repair is regulated by the planar cell polarity signaling pathway

PubMed Central

Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B.; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A.; Murdoch, Jennifer N.; Humbert, Patrick O.; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M.; Jane, Stephen M.

2010-01-01

SUMMARY The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3−/− mice, we identified RhoGEF19, a homologue of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerisation, cellular polarity and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling, and broadly implicate this pathway in epidermal repair. PMID:20643356

A Clonal Genetic Screen for Mutants Causing Defects in Larval Tracheal Morphogenesis in Drosophila

PubMed Central

Baer, Magdalena M.; Bilstein, Andreas; Leptin, Maria

2007-01-01

The initial establishment of the tracheal network in the Drosophila embryo is beginning to be understood in great detail, both in its genetic control cascades and in its cell biological events. By contrast, the vast expansion of the system during larval growth, with its extensive ramification of preexisting tracheal branches, has been analyzed less well. The mutant phenotypes of many genes involved in this process are probably not easy to reveal, as these genes may be required for other functions at earlier developmental stages. We therefore conducted a screen for defects in individual clonal homozygous mutant cells in the tracheal network of heterozygous larvae using the mosaic analysis with a repressible cell marker (MARCM) system to generate marked, recombinant mitotic clones. We describe the identification of a set of mutants with distinct phenotypic effects. In particular we found a range of defects in terminal cells, including failure in lumen formation and reduced or extensive branching. Other mutations affect cell growth, cell shape, and cell migration. PMID:17603107

The Bicoid Class Homeodomain Factors ceh-36/OTX and unc-30/PITX Cooperate in C. elegans Embryonic Progenitor Cells to Regulate Robust Development

PubMed Central

Walton, Travis; Preston, Elicia; Nair, Gautham; Zacharias, Amanda L.; Raj, Arjun; Murray, John Isaac

2015-01-01

While many transcriptional regulators of pluripotent and terminally differentiated states have been identified, regulation of intermediate progenitor states is less well understood. Previous high throughput cellular resolution expression studies identified dozens of transcription factors with lineage-specific expression patterns in C. elegans embryos that could regulate progenitor identity. In this study we identified a broad embryonic role for the C. elegans OTX transcription factor ceh-36, which was previously shown to be required for the terminal specification of four neurons. ceh-36 is expressed in progenitors of over 30% of embryonic cells, yet is not required for embryonic viability. Quantitative phenotyping by computational analysis of time-lapse movies of ceh-36 mutant embryos identified cell cycle or cell migration defects in over 100 of these cells, but most defects were low-penetrance, suggesting redundancy. Expression of ceh-36 partially overlaps with that of the PITX transcription factor unc-30. unc-30 single mutants are viable but loss of both ceh-36 and unc-30 causes 100% lethality, and double mutants have significantly higher frequencies of cellular developmental defects in the cells where their expression normally overlaps. These factors are also required for robust expression of the downstream developmental regulator mls-2/HMX. This work provides the first example of genetic redundancy between the related yet evolutionarily distant OTX and PITX families of bicoid class homeodomain factors and demonstrates the power of quantitative developmental phenotyping in C. elegans to identify developmental regulators acting in progenitor cells. PMID:25738873

Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA)

EPA Science Inventory

(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research pro...

Rethinking developmental toxicity testing: Evolution or revolution?

PubMed

Scialli, Anthony R; Daston, George; Chen, Connie; Coder, Prägati S; Euling, Susan Y; Foreman, Jennifer; Hoberman, Alan M; Hui, Julia; Knudsen, Thomas; Makris, Susan L; Morford, LaRonda; Piersma, Aldert H; Stanislaus, Dinesh; Thompson, Kary E

2018-06-01

Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis-driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one-protocol-fits-all approach. Central to the idea of hypothesis-driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach. © 2018 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.

PubMed

Tang, Guomei; Gudsnuk, Kathryn; Kuo, Sheng-Han; Cotrina, Marisa L; Rosoklija, Gorazd; Sosunov, Alexander; Sonders, Mark S; Kanter, Ellen; Castagna, Candace; Yamamoto, Ai; Yue, Zhenyu; Arancio, Ottavio; Peterson, Bradley S; Champagne, Frances; Dwork, Andrew J; Goldman, James; Sulzer, David

2014-09-03

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR. Copyright © 2014 Elsevier Inc. All rights reserved.

Live dynamic imaging and analysis of developmental cardiac defects in mouse models with optical coherence tomography

NASA Astrophysics Data System (ADS)

Lopez, Andrew L.; Wang, Shang; Garcia, Monica; Valladolid, Christian; Larin, Kirill V.; Larina, Irina V.

2015-03-01

Understanding mouse embryonic development is an invaluable resource for our interpretation of normal human embryology and congenital defects. Our research focuses on developing methods for live imaging and dynamic characterization of early embryonic development in mouse models of human diseases. Using multidisciplinary methods: optical coherence tomography (OCT), live mouse embryo manipulations and static embryo culture, molecular biology, advanced image processing and computational modeling we aim to understand developmental processes. We have developed an OCT based approach to image live early mouse embryos (E8.5 - E9.5) cultured on an imaging stage and visualize developmental events with a spatial resolution of a few micrometers (less than the size of an individual cell) and a frame rate of up to hundreds of frames per second and reconstruct cardiodynamics in 4D (3D+time). We are now using these methods to study how specific embryonic lethal mutations affect cardiac morphology and function during early development.

The very-long-chain hydroxy fatty acyl-CoA dehydratase PASTICCINO2 is essential and limiting for plant development

PubMed Central

Bach, Liên; Michaelson, Louise V.; Haslam, Richard; Bellec, Yannick; Gissot, Lionel; Marion, Jessica; Da Costa, Marco; Boutin, Jean-Pierre; Miquel, Martine; Tellier, Frédérique; Domergue, Frederic; Markham, Jonathan E.; Beaudoin, Frederic; Napier, Johnathan A.; Faure, Jean-Denis

2008-01-01

Very-long-chain fatty acids (VLCFAs) are synthesized as acyl-CoAs by the endoplasmic reticulum-localized elongase multiprotein complex. Two Arabidopsis genes are putative homologues of the recently identified yeast 3-hydroxy-acyl-CoA dehydratase (PHS1), the third enzyme of the elongase complex. We showed that Arabidopsis PASTICCINO2 (PAS2) was able to restore phs1 cytokinesis defects and sphingolipid long chain base overaccumulation. Conversely, the expression of PHS1 was able to complement the developmental defects and the accumulation of long chain bases of the pas2–1 mutant. The pas2–1 mutant was characterized by a general reduction of VLCFA pools in seed storage triacylglycerols, cuticular waxes, and complex sphingolipids. Most strikingly, the defective elongation cycle resulted in the accumulation of 3-hydroxy-acyl-CoA intermediates, indicating premature termination of fatty acid elongation and confirming the role of PAS2 in this process. We demonstrated by in vivo bimolecular fluorescence complementation that PAS2 was specifically associated in the endoplasmic reticulum with the enoyl-CoA reductase CER10, the fourth enzyme of the elongase complex. Finally, complete loss of PAS2 function is embryo lethal, and the ectopic expression of PHS1 led to enhanced levels of VLCFAs associated with severe developmental defects. Altogether these results demonstrate that the plant 3-hydroxy-acyl-CoA dehydratase PASTICCINO2 is an essential and limiting enzyme in VLCFA synthesis but also that PAS2-derived VLCFA homeostasis is required for specific developmental processes. PMID:18799749

Nbn and atm cooperate in a tissue and developmental stage-specific manner to prevent double strand breaks and apoptosis in developing brain and eye.

PubMed

Rodrigues, Paulo M G; Grigaravicius, Paulius; Remus, Martina; Cavalheiro, Gabriel R; Gomes, Anielle L; Rocha-Martins, Maurício; Martins, Mauricio R; Frappart, Lucien; Reuss, David; McKinnon, Peter J; von Deimling, Andreas; Martins, Rodrigo A P; Frappart, Pierre-Olivier

2013-01-01

Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.

HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans.

PubMed

Kinet, Maxime J; Malin, Jennifer A; Abraham, Mary C; Blum, Elyse S; Silverman, Melanie R; Lu, Yun; Shaham, Shai

2016-03-08

Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

Williams Syndrome Transcription Factor is critical for neural crest cell function in Xenopus laevis

PubMed Central

Barnett, Chris; Yazgan, Oya; Kuo, Hui-Ching; Malakar, Sreepurna; Thomas, Trevor; Fitzgerald, Amanda; Harbour, Billy; Henry, Jonathan J.; Krebs, Jocelyn E.

2012-01-01

Williams Syndrome Transcription Factor (WSTF) is one of ~25 haplodeficient genes in patients with the complex developmental disorder Williams Syndrome (WS). WS results in visual/spatial processing defects, cognitive impairment, unique behavioral phenotypes, characteristic “elfin” facial features, low muscle tone and heart defects. WSTF exists in several chromatin remodeling complexes and has roles in transcription, replication, and repair. Chromatin remodeling is essential during embryogenesis, but WSTF’s role in vertebrate development is poorly characterized. To investigate the developmental role of WSTF, we knocked down WSTF in Xenopus laevis embryos using a morpholino that targets WSTF mRNA. BMP4 shows markedly increased and spatially aberrant expression in WSTF-deficient embryos, while SHH, MRF4, PAX2, EPHA4 and SOX2 expression are severely reduced, coupled with defects in a number of developing embryonic structures and organs. WSTF-deficient embryos display defects in anterior neural development. Induction of the neural crest, measured by expression of the neural crest-specific genes SNAIL and SLUG, is unaffected by WSTF depletion. However, at subsequent stages WSTF knockdown results in a severe defect in neural crest migration and/or maintenance. Consistent with a maintenance defect, WSTF knockdowns display a specific pattern of increased apoptosis at the tailbud stage in regions corresponding to the path of cranial neural crest migration. Our work is the first to describe a role for WSTF in proper neural crest function, and suggests that neural crest defects resulting from WSTF haploinsufficiency may be a major contributor to the pathoembryology of WS. PMID:22691402

Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis.

PubMed

Harel, Itamar; Maezawa, Yoshiro; Avraham, Roi; Rinon, Ariel; Ma, Hsiao-Yen; Cross, Joe W; Leviatan, Noam; Hegesh, Julius; Roy, Achira; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Carvajal, Jaime; Tole, Shubha; Kioussi, Chrissa; Quaggin, Susan; Tzahor, Eldad

2012-11-13

The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

PubMed

Makris, Susan L; Scott, Cheryl Siegel; Fox, John; Knudsen, Thomas B; Hotchkiss, Andrew K; Arzuaga, Xabier; Euling, Susan Y; Powers, Christina M; Jinot, Jennifer; Hogan, Karen A; Abbott, Barbara D; Hunter, E Sidney; Narotsky, Michael G

2016-10-01

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties. Published by Elsevier Inc.

Toxicity and developmental defects of different sizes and shape nickel nanoparticles in zebrafish

PubMed Central

Ispas, Cristina; Andreescu, Daniel; Patel, Avni; Goia, Dan V.; Andreescu, Silvana; Wallace, Kenneth N.

2009-01-01

Metallic nanoparticles such as nickel are used in catalytic, sensing and electronic applications, but health and environmental affects have not been fully investigated. While some metal nanoparticles result in toxicity, it is also important to determine whether nanoparticles of the same metal but of different size and shape changes toxicity. Three different size nickel nanoparticle (Ni NPs) of 30, 60, and 100 nm and larger particle clusters of aggregated 60 nm entities with a dendritic structure were synthesized and exposed to zebrafish embryos assessing mortality and developmental defects. Ni NPs exposure was compared to soluble nickel salts. All three 30, 60, and 100 nm Ni NPs are equal to or less toxic than soluble nickel while dendritic clusters were more toxic. With each Ni NP exposure, thinning of the intestinal epithelium first occurs around the LD10 continuing into the LD50. LD50 exposure also results in skeletal muscle fiber separation. Exposure to soluble nickel does not cause intestinal defects while skeletal muscle separation occurs at concentrations well over LD50. These results suggest that configuration of nanoparticles may affect toxicity more than size and defects from Ni NPs exposure occur by different biological mechanisms than soluble nickel. PMID:19746736

Social complementation and growth advantages promote socially defective bacterial isolates.

PubMed

Kraemer, Susanne A; Velicer, Gregory J

2014-04-22

Social interactions among diverse individuals that encounter one another in nature have often been studied among animals but rarely among microbes. For example, the evolutionary forces that determine natural frequencies of bacteria that express cooperative behaviours at low levels remain poorly understood. Natural isolates of the soil bacterium Myxococcus xanthus sampled from the same fruiting body often vary in social phenotypes, such as group swarming and multicellular development. Here, we tested whether genotypes highly proficient at swarming or development might promote the persistence of less socially proficient genotypes from the same fruiting body. Fast-swarming strains complemented slower isolates, allowing the latter to keep pace with faster strains in mixed groups. During development, one low-sporulating strain was antagonized by high sporulators, whereas others with severe developmental defects had those defects partially complemented by high-sporulating strains. Despite declining in frequency overall during competition experiments spanning multiple cycles of development, developmentally defective strains exhibited advantages during the growth phases of competitions. These results suggest that microbes with low-sociality phenotypes often benefit from interacting with more socially proficient strains. Such complementation may combine with advantages at other traits to increase equilibrium frequencies of low-sociality genotypes in natural populations.

Evolutionary developmental pathology and anthropology: A new field linking development, comparative anatomy, human evolution, morphological variations and defects, and medicine.

PubMed

Diogo, Rui; Smith, Christopher M; Ziermann, Janine M

2015-11-01

We introduce a new subfield of the recently created field of Evolutionary-Developmental-Anthropology (Evo-Devo-Anth): Evolutionary-Developmental-Pathology-and-Anthropology (Evo-Devo-P'Anth). This subfield combines experimental and developmental studies of nonhuman model organisms, biological anthropology, chordate comparative anatomy and evolution, and the study of normal and pathological human development. Instead of focusing on other organisms to try to better understand human development, evolution, anatomy, and pathology, it places humans as the central case study, i.e., as truly model organism themselves. We summarize the results of our recent Evo-Devo-P'Anth studies and discuss long-standing questions in each of the broader biological fields combined in this subfield, paying special attention to the links between: (1) Human anomalies and variations, nonpentadactyly, homeotic transformations, and "nearest neighbor" vs. "find and seek" muscle-skeleton associations in limb+facial muscles vs. other head muscles; (2) Developmental constraints, the notion of "phylotypic stage," internalism vs. externalism, and the "logic of monsters" vs. "lack of homeostasis" views about human birth defects; (3) Human evolution, reversions, atavisms, paedomorphosis, and peromorphosis; (4) Scala naturae, Haeckelian recapitulation, von Baer's laws, and parallelism between phylogeny and development, here formally defined as "Phylo-Devo parallelism"; and (5) Patau, Edwards, and Down syndrome (trisomies 13, 18, 21), atavisms, apoptosis, heart malformations, and medical implications. © 2015 Wiley Periodicals, Inc.

[Multiplex Ligation - dependent Probe Amplification (MLPA) as a screening test in children with developmental defects and intellectual disability of unknown etiology].

PubMed

Laczmańska, Izabela; Jakubiak, Aleksandra; Slęzak, Ryszard; Pesz, Karolina; Stembalska, Agnieszka; Laczmański, Lukasz; Sąsiadek, Maria M; Smigiel, Robert

2011-01-01

Developmental delay and intellectual disability are significant medical and social problems which concern 1-3% of population. The etiology remains unknown in over half of the cases. To evaluate the efficiency of MLPA (Multiplex Ligation-dependent Probe Amplification) as a screening test in diagnosis of patients with developmental delay and/or intellectual disability. 313 MLPA tests were performed in 256 patients with developmental delay and/ or intellectual disability with unknown etiology. MLPA test was made after exclusion of genetic disorders possible to diagnose by dysmorphological examination or using specifi c genetic tests. Positive results were confirmed by FISH analysis with appropriate probes. Chromosomal microaberrations were identifi ed in 15 patients (4,8%): deletions of 1p36 in 4 cases, in one case deletion of 22q11.21, 22q13.33, SNRPN1, 4ptel, 6qtel, 7q11.23, 16ptel, 18qtel as well as one ca se of deletion 3ptel/duplication 15qtel; deletion 18qtel/duplication Xqtel, and also duplication 7q11.23. Detail clinical analysis was performed in patients with diagnosed microaberrations in MLPA test. The molecular MLPA test, screening for chromosomal microaberration syndromes, should be performed in each patient with developmental delay and/or intellectual disability of unknown etiology and normal cytogenetic analysis, even if congenital defects and positive familial history do not exist.

Location negative priming effects in children with developmental dyslexia: An event-related potential study.

PubMed

Ma, Yujun; Wang, Enguo; Yuan, Tian; Zhao, Guo Xiang

2016-08-01

As the reading process is inseparable from working memory, inhibition, and other higher cognitive processes, the deep cognitive processing defects that are associated with dyslexia may be due to defective distraction inhibition systems. In this study, we used event-related potential technology to explore the source of negative priming effects in children with developmental dyslexia and in a group of healthy children for comparison. We found that the changes in the average response times in the negative priming and control conditions were consistent across the two groups, while the negative priming effects differed significantly between the groups. The magnitude of the negative priming effect was significantly different between the two groups, with the magnitude being significantly higher in the control group than it was in the developmental dyslexia group. These results indicate that there are deficits in distraction inhibition in children with developmental dyslexia. In terms of the time course of processing, inhibition deficits in the dyslexia group appeared during early-stage cognition selection and lasted through the response selection phase. Regarding the cerebral cortex locations, early-stage cognition selection was mainly located in the parietal region, while late-stage response selection was mainly located in the frontal and central regions. The results of our study may help further our understanding of the intrinsic causes of developmental dyslexia. Copyright © 2016 Elsevier Ltd. All rights reserved.

IFT46 plays an essential role in cilia development

PubMed Central

Lee, Mi-Sun; Hwang, Kyu-Seok; Oh, Hyun-Woo; Ji-Ae, Kim; Kim, Hyun-Taek; Cho, Hyun-Soo; Lee, Jeong-Ju; Ko, Je Yeong; Choi, Jung-Hwa; Jeong, Yun-Mi; You, Kwan-Hee; Kim, Joon; Park, Doo-Sang; Nam, Ki-Hoan; Aizawa, Shinichi; Kiyonari, Hiroshi; Shioi, Go; Park, Jong-Hoon; Zhou, Weibin; Kim, Nam-Soon; Kim, Cheol-Hee

2015-01-01

Cilia are microtubule-based structures that project into the extracellular space. Ciliary defects are associated with several human diseases, including polycystic kidney disease, primary ciliary dyskinesia, left-right axis patterning, hydrocephalus and retinal degeneration. However, the genetic and cellular biological control of ciliogenesis remains poorly understood. The IFT46 is one of the highly conserved intraflagellar transport complex B proteins. In zebrafish, ift46 is expressed in various ciliated tissues such as Kupffer’s vesicle, pronephric ducts, ears and spinal cord. We show that ift46 is localized to the basal body. Knockdown of ift46 gene results in multiple phenotypes associated with various ciliopathies including kidney cysts, pericardial edema and ventral axis curvature. In ift46 morphants, cilia in kidney and spinal canal are shortened and abnormal. Similar ciliary defects are observed in otic vesicles, lateral line hair cells, olfactory pits, but not in Kupffer’s vesicle. To explore the functions of Ift46 during mouse development, we have generated Ift46 knock-out mice. The Ift46 mutants have developmental defects in brain, neural tube and heart. In particular Ift46(−/−) homozygotes displays randomization of the embryo heart looping, which is a hallmark of defective left-right (L/R) axis patterning. Taken together, our results demonstrated that IFT46 has an essential role in vertebrate ciliary development. PMID:25722189

The Application of a Chemical Determination of N-Homocysteinylation Levels in Developing Mouse Embryos: Implication for Folate Responsive Birth Defects

PubMed Central

Fathe, Kristin; Person, Maria D.; Finnell, Richard H.

2014-01-01

Elevated homocysteine levels have long been associated with various disease states, including cardiovascular disease and birth defects, including neural tube defects (NTDs). One hypothesis regarding the strong correlation between these various disorders and high levels of homocysteine is that a reactive form of this small molecule can attach to mammalian proteins in a phenomenon known as homocysteinylation. These posttranslational modifications may become antigenic, or may even directly disrupt certain protein function. It remains to be determined whether dietary influences that can cause globally increased levels of circulating homocysteine confer negative effects maternally, or may otherwise negatively and materially impact the metabolic balance in developing embryos. Herein we present the application of a chemical method of determination of N-homocysteinylation to a set of neural tube closure stage mouse embryos and their mothers. We explore the uses of this newly-described technique to investigate levels of maternal and embryonic N-homocysteinylation using dietary manipulations of onecarbon metabolism with two known folate responsive neural tube defect mouse models. The data presented reveals that although diet appeared to have significant effects on the maternal metabolic status, those effects did not directly correlate to the embryonic folate or N-homocysteinylation status. Our studies indicate that maternal diet and embryonic genotype most significantly affected the embryonic developmental outcome. PMID:25620692

Magnetic resonance microscopy-based analyses of the neuroanatomical effects of gestational day 9 ethanol exposure in mice

PubMed Central

Parnell, Scott E.; Holloway, Hunter T.; O’Leary-Moore, Shonagh K.; Dehart, Deborah B.; Paniaqua, Beatriz; Oguz, Ipek; Budin, Francois; Styner, Martin A.; Johnson, G. Allan; Sulik, Kathleen K.

2013-01-01

Animal model-based studies have shown that ethanol exposure during early gestation induces developmental stage-specific abnormalities of the face and brain. The exposure time-dependent variability in ethanol’s teratogenic outcomes is expected to contribute significantly to the wide spectrum of effects observed in humans with fetal alcohol spectrum disorder (FASD). The work presented here employs a mouse FASD model and magnetic resonance microscopy (MRM; high resolution magnetic resonance imaging) in studies designed to further our understanding of the developmental stage-specific defects of the brain that are induced by ethanol. At neurulation stages, i.e. at the beginning of gestational day (GD) 9 and again 4 hours later, time-mated C57Bl/6J dams were intraperitoneally administered 2.9 g/kg ethanol or vehicle. Ethanol-exposed fetuses were collected on GD 17, processed for MRM analysis, and results compared to comparably staged controls. Linear and volume measurements as well as shape changes for numerous individual brain regions were determined. GD 9 ethanol exposure resulted in significantly increased septal region width, reduction of cerebellar volume, and enlargement of all of the ventricles. Additionally, the results of shape analyses showed that many areas of the ethanol-exposed brains including the cerebral cortex, hippocampus and right striatum were significantly misshapen. These data demonstrate that ethanol can induce dysmorphology that may not be obvious based on volumetric analyses alone, highlight the asymmetric aspects of ethanol-induced defects, and add to our understanding of ethanol’s developmental stage-dependent neuroteratogenesis. PMID:23911654

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

PubMed Central

Ouyang, Qing; Nakayama, Tojo; Baytas, Ozan; Davidson, Shawn M.; Yang, Chendong; Schmidt, Michael; Lizarraga, Sofia B.; Mishra, Sasmita; EI-Quessny, Malak; Niaz, Saima; Gul Butt, Mirrat; Imran Murtaza, Syed; Javed, Afzal; Chaudhry, Haroon Rashid; Vaughan, Dylan J.; Hill, R. Sean; Partlow, Jennifer N.; Yoo, Seung-Yun; Lam, Anh-Thu N.; Nasir, Ramzi; Al-Saffar, Muna; Barkovich, A. James; Schwede, Matthew; Nagpal, Shailender; Rajab, Anna; DeBerardinis, Ralph J.; Housman, David E.; Mochida, Ganeshwaran H.; Morrow, Eric M.

2016-01-01

Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms. PMID:27601654

Enhancer of zeste acts as a major developmental regulator of Ciona intestinalis embryogenesis

PubMed Central

Le Goff, Emilie; Martinand-Mari, Camille; Martin, Marianne; Feuillard, Jérôme; Boublik, Yvan; Godefroy, Nelly; Mangeat, Paul; Baghdiguian, Stephen; Cavalli, Giacomo

2015-01-01

ABSTRACT The paradigm of developmental regulation by Polycomb group (PcG) proteins posits that they maintain silencing outside the spatial expression domains of their target genes, particularly of Hox genes, starting from mid embryogenesis. The Enhancer of zeste [E(z)] PcG protein is the catalytic subunit of the PRC2 complex, which silences its targets via deposition of the H3K27me3 mark. Here, we studied the ascidian Ciona intestinalis counterpart of E(z). Ci-E(z) is detected by immunohistochemistry as soon as the 2- and 4-cell stages as a cytoplasmic form and becomes exclusively nuclear thereafter, whereas the H3K27me3 mark is detected starting from the gastrula stage and later. Morpholino invalidation of Ci-E(z) leads to the total disappearance of both Ci-E(z) protein and its H3K27me3 mark. Ci-E(z) morphants display a severe phenotype. Strikingly, the earliest defects occur at the 4-cell stage with the dysregulation of cell positioning and mitotic impairment. At later stages, Ci-E(z)-deficient embryos are affected by terminal differentiation defects of neural, epidermal and muscle tissues, by the failure to form a notochord and by the absence of caudal nerve. These major phenotypic defects are specifically rescued by injection of a morpholino-resistant Ci-E(z) mRNA, which restores expression of Ci-E(z) protein and re-deposition of the H3K27me3 mark. As observed by qPCR analyses, Ci-E(z) invalidation leads to the early derepression of tissue-specific developmental genes, whereas late-acting developmental genes are generally down-regulated. Altogether, our results suggest that Ci-E(z) plays a major role during embryonic development in Ciona intestinalis by silencing early-acting developmental genes in a Hox-independent manner. PMID:26276097

Comparison of enamel defects in the primary and permanent dentitions of children from a low-fluoride District in Australia.

PubMed

Seow, W Kim; Ford, Daniel; Kazoullis, Stauros; Newman, Bruce; Holcombe, Trevor

2011-01-01

The purpose of this study was to compare developmental defects of enamel (DDE) in the primary and permanent dentitions of children from a low-fluoride district. A total of 517 healthy schoolchildren were examined using the modified DDE criteria. The prevalence of DDE in the primary and permanent dentition was 25% and 58%, respectively (P<.001). The mean number of teeth with enamel opacity per subject was approximately threefold compared to that affected by enamel hypoplasia (3.1±3.8 vs 0.8±1.4, P<.001 in the primary dentition and 3.6±4.7 vs 1.2±2.2, P<.001 in the permanent dentition). Demarcated opacities (83%) were predominant compared to diffuse opacities (17%), while missing enamel was the most common type of enamel hypoplasia (50%), followed by grooves (31%) and enamel pits (19%) (P=.04). In the permanent dentition, diffuse and demarcated opacities were equally frequent, while enamel grooves were the commonest type of hypoplasia (52%), followed by missing enamel (35%) and enamel pits (5%; P<.001). In a low-fluoride community, developmental defects of enamel were twice as common in the permanent dentition vs the primary dentition. In the primary dentition, the predominant defects were demarcated opacities and missing enamel, while in the permanent dentition, the defects were more variable.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

PubMed

Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel; Anderson, Blair R; Capone, Valentina P; Otto, Edgar A; Yan, Zhonghai; Mitrotti, Adele; Martino, Jeremiah; Steers, Nicholas J; Fasel, David A; Vukojevic, Katarina; Deng, Rong; Racedo, Silvia E; Liu, Qingxue; Werth, Max; Westland, Rik; Vivante, Asaf; Makar, Gabriel S; Bodria, Monica; Sampson, Matthew G; Gillies, Christopher E; Vega-Warner, Virginia; Maiorana, Mariarosa; Petrey, Donald S; Honig, Barry; Lozanovski, Vladimir J; Salomon, Rémi; Heidet, Laurence; Carpentier, Wassila; Gaillard, Dominique; Carrea, Alba; Gesualdo, Loreto; Cusi, Daniele; Izzi, Claudia; Scolari, Francesco; van Wijk, Joanna A E; Arapovic, Adela; Saraga-Babic, Mirna; Saraga, Marijan; Kunac, Nenad; Samii, Ali; McDonald-McGinn, Donna M; Crowley, Terrence B; Zackai, Elaine H; Drozdz, Dorota; Miklaszewska, Monika; Tkaczyk, Marcin; Sikora, Przemyslaw; Szczepanska, Maria; Mizerska-Wasiak, Malgorzata; Krzemien, Grazyna; Szmigielska, Agnieszka; Zaniew, Marcin; Darlow, John M; Puri, Prem; Barton, David; Casolari, Emilio; Furth, Susan L; Warady, Bradley A; Gucev, Zoran; Hakonarson, Hakon; Flogelova, Hana; Tasic, Velibor; Latos-Bielenska, Anna; Materna-Kiryluk, Anna; Allegri, Landino; Wong, Craig S; Drummond, Iain A; D'Agati, Vivette; Imamoto, Akira; Barasch, Jonathan M; Hildebrandt, Friedhelm; Kiryluk, Krzysztof; Lifton, Richard P; Morrow, Bernice E; Jeanpierre, Cecile; Papaioannou, Virginia E; Ghiggeri, Gian Marco; Gharavi, Ali G; Katsanis, Nicholas; Sanna-Cherchi, Simone

2017-02-23

The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10 -14 ). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions.

PubMed

Cardoso, Rodolfo C; Puttabyatappa, Muraly; Padmanabhan, Vasantha

2015-01-01

The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS. © 2015 S. Karger AG, Basel.

Teratology – past, present and future

PubMed Central

Mach, Mojmír; Navarová, Jana; Brucknerová, Ingrid; Dubovický, Michal

2012-01-01

Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development. The authors present an updated overview of the most important milestones and stages of the development of modern teratology. Development of knowledge and society led to the recognition that causes of congenital developmental disorders (CDDs) might be caused by various mechanical effects, foetal diseases, and retarded or arrested development of the embryo and foetus. Based on the analysis of the historical development of hypotheses and theories representing a decisive contribution to this field, we present a survey of the six Wilson′s fundamental principles of teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realise that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in CDDs. Moreover, the classical toxicologic monotonic dose-response paradigm recently has been challenged by the so-called “low dose-hypothesis”, particularly in the case of endocrine active substances. These include some pesticides, dioxins, polychlorobiphenyls (PCBs), and bisphenol A. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 65 to 70% of all congenital defects classified as having an unknown etiology. Today CDDs include any birth defect, either morphological, biochemical, or behavioural. PMID:23554558

Teratology - past, present and future.

PubMed

Ujházy, Eduard; Mach, Mojmír; Navarová, Jana; Brucknerová, Ingrid; Dubovický, Michal

2012-12-01

Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development. The authors present an updated overview of the most important milestones and stages of the development of modern teratology. Development of knowledge and society led to the recognition that causes of congenital developmental disorders (CDDs) might be caused by various mechanical effects, foetal diseases, and retarded or arrested development of the embryo and foetus. Based on the analysis of the historical development of hypotheses and theories representing a decisive contribution to this field, we present a survey of the six Wilson's fundamental principles of teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realise that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in CDDs. Moreover, the classical toxicologic monotonic dose-response paradigm recently has been challenged by the so-called "low dose-hypothesis", particularly in the case of endocrine active substances. These include some pesticides, dioxins, polychlorobiphenyls (PCBs), and bisphenol A. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 65 to 70% of all congenital defects classified as having an unknown etiology. Today CDDs include any birth defect, either morphological, biochemical, or behavioural.

Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.

PubMed

Liu, Wei; Zhou, Hui; Liu, Lei; Zhao, Chuntao; Deng, Yaqi; Chen, Lina; Wu, Laiman; Mandrycky, Nicole; McNabb, Christopher T; Peng, Yuanbo; Fuchs, Perry N; Lu, Jie; Sheen, Volney; Qiu, Mengsheng; Mao, Meng; Lu, Q Richard

2015-05-01

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21. Copyright © 2015 Elsevier Inc. All rights reserved.

Roles of mTOR Signaling in Brain Development.

PubMed

Lee, Da Yong

2015-09-01

mTOR is a serine/threonine kinase composed of multiple protein components. Intracellular signaling of mTOR complexes is involved in many of physiological functions including cell survival, proliferation and differentiation through the regulation of protein synthesis in multiple cell types. During brain development, mTOR-mediated signaling pathway plays a crucial role in the process of neuronal and glial differentiation and the maintenance of the stemness of neural stem cells. The abnormalities in the activity of mTOR and its downstream signaling molecules in neural stem cells result in severe defects of brain developmental processes causing a significant number of brain disorders, such as pediatric brain tumors, autism, seizure, learning disability and mental retardation. Understanding the implication of mTOR activity in neural stem cells would be able to provide an important clue in the development of future brain developmental disorder therapies.

Fused pulmonary lobes is a rat model of human Fraser syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiyozumi, Daiji; Nakano, Itsuko; Takahashi, Ken L.

Highlights: {yields} Fused pulmonary lobes (fpl) mutant rats exhibit similar phenotypes to Fraser syndrome. {yields} The fpl gene harbors a nonsense mutation in Fraser syndrome-associated gene Frem2. {yields} Fpl mutant is defined as a first model of human Fraser syndrome in rats. -- Abstract: Fused pulmonary lobes (fpl) is a mutant gene that is inherited in an autosomal recessive manner and causes various developmental defects, including fusion of pulmonary lobes, and eyelid and digit anomalies in rats. Since these developmental defects closely resemble those observed in patients with Fraser syndrome, a recessive multiorgan disorder, and its model animals, we investigatedmore » whether the abnormal phenotypes observed in fpl/fpl mutant rats are attributable to a genetic disorder similar to Fraser syndrome. At the epidermal basement membrane in fpl/fpl mutant neonates, the expression of QBRICK, a basement membrane protein whose expression is attenuated in Fraser syndrome model mice, was greatly diminished compared with control littermates. Quantitative RT-PCR analyses of Fraser syndrome-related genes revealed that Frem2 transcripts were markedly diminished in QBRICK-negative embryos. Genomic DNA sequencing of the fpl/fpl mutant identified a nonsense mutation that introduced a stop codon at serine 2005 in Frem2. These findings indicate that the fpl mutant is a rat model of human Fraser syndrome.« less

Stimulation of mTORC1 with L-leucine Rescues Defects Associated with Roberts Syndrome

PubMed Central

Xu, Baoshan; Lee, Kenneth K.; Zhang, Lily; Gerton, Jennifer L.

2013-01-01

Roberts syndrome (RBS) is a human disease characterized by defects in limb and craniofacial development and growth and mental retardation. RBS is caused by mutations in ESCO2, a gene which encodes an acetyltransferase for the cohesin complex. While the essential role of the cohesin complex in chromosome segregation has been well characterized, it plays additional roles in DNA damage repair, chromosome condensation, and gene expression. The developmental phenotypes of Roberts syndrome and other cohesinopathies suggest that gene expression is impaired during embryogenesis. It was previously reported that ribosomal RNA production and protein translation were impaired in immortalized RBS cells. It was speculated that cohesin binding at the rDNA was important for nucleolar form and function. We have explored the hypothesis that reduced ribosome function contributes to RBS in zebrafish models and human cells. Two key pathways that sense cellular stress are the p53 and mTOR pathways. We report that mTOR signaling is inhibited in human RBS cells based on the reduced phosphorylation of the downstream effectors S6K1, S6 and 4EBP1, and this correlates with p53 activation. Nucleoli, the sites of ribosome production, are highly fragmented in RBS cells. We tested the effect of inhibiting p53 or stimulating mTOR in RBS cells. The rescue provided by mTOR activation was more significant, with activation rescuing both cell division and cell death. To study this cohesinopathy in a whole animal model we used ESCO2-mutant and morphant zebrafish embryos, which have developmental defects mimicking RBS. Consistent with RBS patient cells, the ESCO2 mutant embryos show p53 activation and inhibition of the TOR pathway. Stimulation of the TOR pathway with L-leucine rescued many developmental defects of ESCO2-mutant embryos. Our data support the idea that RBS can be attributed in part to defects in ribosome biogenesis, and stimulation of the TOR pathway has therapeutic potential. PMID:24098154

Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.

PubMed

Xu, Baoshan; Lee, Kenneth K; Zhang, Lily; Gerton, Jennifer L

2013-01-01

Roberts syndrome (RBS) is a human disease characterized by defects in limb and craniofacial development and growth and mental retardation. RBS is caused by mutations in ESCO2, a gene which encodes an acetyltransferase for the cohesin complex. While the essential role of the cohesin complex in chromosome segregation has been well characterized, it plays additional roles in DNA damage repair, chromosome condensation, and gene expression. The developmental phenotypes of Roberts syndrome and other cohesinopathies suggest that gene expression is impaired during embryogenesis. It was previously reported that ribosomal RNA production and protein translation were impaired in immortalized RBS cells. It was speculated that cohesin binding at the rDNA was important for nucleolar form and function. We have explored the hypothesis that reduced ribosome function contributes to RBS in zebrafish models and human cells. Two key pathways that sense cellular stress are the p53 and mTOR pathways. We report that mTOR signaling is inhibited in human RBS cells based on the reduced phosphorylation of the downstream effectors S6K1, S6 and 4EBP1, and this correlates with p53 activation. Nucleoli, the sites of ribosome production, are highly fragmented in RBS cells. We tested the effect of inhibiting p53 or stimulating mTOR in RBS cells. The rescue provided by mTOR activation was more significant, with activation rescuing both cell division and cell death. To study this cohesinopathy in a whole animal model we used ESCO2-mutant and morphant zebrafish embryos, which have developmental defects mimicking RBS. Consistent with RBS patient cells, the ESCO2 mutant embryos show p53 activation and inhibition of the TOR pathway. Stimulation of the TOR pathway with L-leucine rescued many developmental defects of ESCO2-mutant embryos. Our data support the idea that RBS can be attributed in part to defects in ribosome biogenesis, and stimulation of the TOR pathway has therapeutic potential.

iPSC-derived cardiomyocytes reveal abnormal TGFβ signaling in left ventricular non-compaction cardiomyopathy

PubMed Central

Kodo, Kazuki; Ong, Sang-Ging; Jahanbani, Fereshteh; Termglinchan, Vittavat; Hirono, Keiichi; InanlooRahatloo, Kolsoum; Ebert, Antje D.; Shukla, Praveen; Abilez, Oscar J.; Churko, Jared M.; Karakikes, Ioannis; Jung, Gwanghyun; Ichida, Fukiko; Wu, Sean M.; Snyder, Michael P.; Bernstein, Daniel; Wu, Joseph C.

2016-01-01

Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and its pathogenesis has been associated with the developmental defect of the embryonic myocardium. We show that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in the cardiac transcription factor TBX20 recapitulate a key aspect of the pathological phenotype at the single-cell level and was associated with perturbed transforming growth factor beta (TGFβ) signaling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGFβ signaling. TBX20 regulates the expression of TGFβ signaling modifiers including a known genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGFβ signaling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype. Our study demonstrates that iPSC-CMs are a useful tool for the exploration of pathological mechanisms underlying poorly understood cardiomyopathies including LVNC. PMID:27642787

Exclusion of MYF5, GSC, RUNX2, and TCOF1 mutation in a case of cerebro-costo-mandibular syndrome.

PubMed

Su, Pen-Hua; Chen, Jia-Yuh; Chiang, Chin-Lung; Ng, Yan-Yan; Chen, Suh-Jen

2010-04-01

Cerebro-costo-mandibular syndrome (CCMS) is an uncommon multiple congenital anomaly syndrome characterized by severe micrognathia, posterior rib-gap defects, and developmental delay. The cause of CCMS is unknown. Genes hypothesized to have a causal role in CCMS, include myogenic factor 5 (MYF5), goosecoid homeobox (GSC) and runt-related transcription factor 2 (RUNX2) [formerly known as core-binding factor (CBFA1)]. We report an infant with typical features of CCMS who, on prenatal ultrasound, was found to have severe micrognathia. We present the first image by three-dimensional computed tomography of posterior rib-defect, and we exclude mutations of the MYF5, GSC, RUNX2, and TCOF1 genes in our patient. Further molecular studies are needed to evaluate the cause of CCMS.

Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling

PubMed Central

Iwao, Keiichiro; Inatani, Masaru; Matsumoto, Yoshihiro; Ogata-Iwao, Minako; Takihara, Yuji; Irie, Fumitoshi; Yamaguchi, Yu; Okinami, Satoshi; Tanihara, Hidenobu

2009-01-01

During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-β2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-β2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-β2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma. PMID:19509472

Prevalence of olfactory and other developmental anomalies in patients with central hypogonadotropic hypogonadism.

PubMed

Della Valle, Elisa; Vezzani, Silvia; Rochira, Vincenzo; Granata, Antonio Raffaele Michele; Madeo, Bruno; Genovese, Elisabetta; Pignatti, Elisa; Marino, Marco; Carani, Cesare; Simoni, Manuela

2013-01-01

Hypogonadotropic hypogonadism (HH) is a heterogeneous disease caused by mutations in several genes. Based on the presence of hyposmia/anosmia it is distinguished into Kallmann syndrome (KS) and isolated HH. The prevalence of other developmental anomalies is not well established. We studied 36 patients with HH (31 males, 5 females, mean age 41.5), 9 with familial and 27 with sporadic HH (33 congenital, 3 adult-onset), by physical examination, smell test (BSIT Sensonics), audiometry, renal ultrasound, and magnetic resonance imaging of the olfactory structures. Based on the smell test, patients were classified as normosmic (n = 21, 58.3%) and hypo/anosmic (n = 15, 41.6%). Hypoplasia/agenesis of olfactory bulbs was found in 40% of patients (10/25; 75% hypo/anosmic, 7.6% normosmic, p < 0.01, Fisher's test). Remarkably, olfactory structures were normal in two anosmic patients, while one normosmic patient presented a unilateral hypoplastic bulb. Fourteen of 33 patients (42.4%) presented neurosensorial hearing loss of various degrees (28.5% hypo/anosmic, 52.6% normosmic, p = NS). Renal ultrasound revealed 27.7% of cases with renal anomalies (26.6% hypo/anosmic, 28.5% normosmic, p = NS). At least one midline defect was found in 50% of the patients (53.3% hypo/anosmic, 47.6% normosmic, p = NS), including abnormal palate, dental anomalies, pectus excavatum, bimanual synkinesis, iris coloboma, and absent nasal cartilage. Anamnestically 4/31 patients reported cryptorchidism (25% hypo/anosmic, 5.2% normosmic, p = NS). Hypo/anosmia is significantly related to anatomical anomalies of the olfactory bulbs/tracts but the prevalence of other developmental anomalies, especially midline defects and neurosensorial hearing loss, is high both in HH and KS and independent of the presence of anosmia/hyposmia. From the clinical standpoint KS and normosmic HH should be considered as the same complex, developmental disease.

Prenatal Ablation of Nicotinic Receptor alpha7 Cell Lineages Produces Lumbosacral Spina Bifida the Severity of Which is Modified by Choline and Nicotine Exposure

PubMed Central

Rogers, Scott W; Tvrdik, Petr; Capecchi, Mario R; Gahring, Lorise C

2012-01-01

Lumbosacral spina bifida is a common debilitating birth defect whose multiple causes are poorly understood. Here, we provide the first genetic delineation of cholinergic nicotinic receptor alpha7 (Chrna7) expression and link the ablation of the Chrna7 cell lineage to this condition in the mouse. Using homologous recombination, an IRES-Cre bi-cistronic cassette was introduced into the 3′ noncoding region of Chrna7 (Chrna7:Cre) for identifying cell lineages expressing this gene. This lineage first appears at embryonic day E9.0 in rhombomeres 3 and 5 of the neural tube and extends to cell subsets in most tissues by E14.5. Ablation of the Chrna7:Cre cell lineage in embryos from crosses with conditionally expressed attenuated diphtheria toxin results in precise developmental defects including omphalocele (89%) and open spina bifida (SB; 80%). We hypothesized that like humans, this defect would be modified by environmental compounds not only folic acid or choline but also nicotine. Prenatal chronic oral nicotine administration substantially worsened the defect to often include the rostral neural tube. In contrast, supplementation of the maternal diet with 2% choline decreased SB prevalence to 38% and dramatically reduced the defect severity. Folic acid supplementation only trended towards a reduced SB frequency. The omphalocele was unaffected by these interventions. These studies identify the Chrna7 cell lineage as participating in posterior neuropore closure and present a novel model of lower SB that can be substantially modified by the prenatal environment. © 2012 Wiley Periodicals, Inc. PMID:22473653

Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences

PubMed Central

Basson, M. Albert; Wingate, Richard J.

2013-01-01

Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy–Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function. PMID:24027500

Bone development in laboratory mammals used in developmental toxicity studies.

PubMed

DeSesso, John M; Scialli, Anthony R

2018-06-19

Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. © 2018 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Variable developmental delays and characteristic facial features-A novel 7p22.3p22.2 microdeletion syndrome?

PubMed

Yu, Andrea C; Zambrano, Regina M; Cristian, Ingrid; Price, Sue; Bernhard, Birgitta; Zucker, Marc; Venkateswaran, Sunita; McGowan-Jordan, Jean; Armour, Christine M

2017-06-01

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation. © 2017 Wiley Periodicals, Inc.

Behavioral Teratogenesis in Drosophila melanogaster.

PubMed

Mishra, Monalisa; Barik, Bedanta Kumar

2018-01-01

Developmental biology is a fascinating branch of science which helps us to understand the mechanism of development, thus the findings are used in various therapeutic approach. Drosophila melanogaster served as a model to find the key molecules that initiate and regulate the mechanism of development. Various genes, transcription factors, and signaling pathways helping in development are identified in Drosophila. Many toxic compounds, which can affect the development, are also recognized using Drosophila model. These compounds, which can affect the development, are named as a teratogen. Many teratogens identified using Drosophila may also act as a teratogen for a human being since 75% of conservation exist between the disease genes present in Drosophila and human. There are certain teratogens, which do not cause developmental defect if exposed during pregnancy, however; behavioral defect appears in later part of development. Such compounds are named as a behavioral teratogen. Thus, it is worthy to identify the potential behavioral teratogen using Drosophila model. Drosophila behavior is well studied in various developmental stages. This chapter describes various methods which can be employed to test behavioral teratogenesis in Drosophila.

Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected].

PubMed

Busiah, Kanetee; Drunat, Séverine; Vaivre-Douret, Laurence; Bonnefond, Amélie; Simon, Albane; Flechtner, Isabelle; Gérard, Bénédicte; Pouvreau, Nathalie; Elie, Caroline; Nimri, Revital; De Vries, Liat; Tubiana-Rufi, Nadia; Metz, Chantal; Bertrand, Anne-Marie; Nivot-Adamiak, Sylvie; de Kerdanet, Marc; Stuckens, Chantal; Jennane, Farida; Souchon, Pierre-François; Le Tallec, Claire; Désirée, Christelle; Pereira, Sabrina; Dechaume, Aurélie; Robert, Jean-Jacques; Phillip, Moshe; Scharfmann, Raphaël; Czernichow, Paul; Froguel, Philippe; Vaxillaire, Martine; Polak, Michel; Cavé, Hélène

2013-11-01

Neonatal diabetes mellitus is a rare genetic form of pancreatic β-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without β-cell autoimmunity and with normal pancreas morphology. We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for β-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities. We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36). Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus. Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie. Copyright © 2013 Elsevier Ltd. All rights reserved.

Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.

PubMed

Stern, D; Cho, M T; Chikarmane, R; Willaert, R; Retterer, K; Kendall, F; Deardorff, M; Hopkins, S; Bedoukian, E; Slavotinek, A; Schrier Vergano, S; Spangler, B; McDonald, M; McConkie-Rosell, A; Burton, B K; Kim, K H; Oundjian, N; Kronn, D; Chandy, N; Baskin, B; Guillen Sacoto, M J; Wentzensen, I M; McLaughlin, H M; McKnight, D; Chung, W K

2017-08-01

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges

PubMed Central

Mishra, Swati; Choe, Youngshik; Pleasure, Samuel J.; Siegenthaler, Julie A.

2016-01-01

Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant’s complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations. PMID:27671872

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges.

PubMed

Mishra, Swati; Choe, Youngshik; Pleasure, Samuel J; Siegenthaler, Julie A

2016-12-01

Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant's complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations. Copyright © 2016 Elsevier Inc. All rights reserved.

Maternal characteristics and birth outcomes of pregnant women who had offspring with congenital ear abnormalities - a population-based case-control study.

PubMed

Paput, László; Bánhidy, Ferenc; Czeizel, Andrew E

2011-09-01

To describe the maternal characteristics and birth outcomes of newborn infants affected with isolated ear congenital abnormalities (IECA), mainly isolated anotia/microtia and unclassified multiple congenital abnormalities (CAs) including anotia/microtia (UMAM). Cases with IECA and UMAM were compared with their matched controls and all controls without any defect and malformed controls affected with other defects in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. The mothers of 354 cases with IECA did not show significant difference in age, but their mean birth order was higher while their socio-economic status based on the maternal employment status was lower compared to the figures of their matched controls. There was a male excess among cases with microtia and mainly with UMAM. The evaluation of birth outcomes of newborns affected with IECA indicated intrauterine fetal growth retardation. Newborn infants with isolated microtia had intrauterine growth retardation and the association of this developmental defect localized for a small region of head with the general fetal development raises interesting theoretical question.

Congenital hypothyroidism of dogs and cats: a review.

PubMed

Bojanic, K; Acke, E; Jones, B R

2011-05-01

Congenital hypothyroidism is a rare and underdiagnosed congenital endocrine disorder in dogs and cats and the true incidence is unknown. The disorder may cause a range of clinical signs depending on the primary defect, which affect production of thyroid hormones; some cases present when adult. Hallmark clinical signs of congenital hypothyroidism are mental impairment and skeletal developmental abnormalities, resulting in disproportionate dwarfism; goitre may or may not be present. Documented causes of congenital hypothyroidism in dogs include deficiency of, or unresponsiveness to, thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH), thyroid dysgenesis, dyshormonogenesis and iodine deficiency. In cats, TSH unresponsiveness, thyroid dysgenesis, dyshormonogenesis and iodine deficiency have been confirmed. Adequate replacement therapy results in a successful outcome in the majority of cases, especially when started early in life, as permanent developmental abnormalities can be prevented. This review describes reported cases in dogs and cats, diagnostic investigation, and recommendations for treatment.

Noonan syndrome and clinically related disorders

PubMed Central

Tartaglia, Marco; Gelb, Bruce D.; Zenker, Martin

2010-01-01

Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. PMID:21396583

Neural crest cells: from developmental biology to clinical interventions.

PubMed

Noisa, Parinya; Raivio, Taneli

2014-09-01

Neural crest cells are multipotent cells, which are specified in embryonic ectoderm in the border of neural plate and epiderm during early development by interconnection of extrinsic stimuli and intrinsic factors. Neural crest cells are capable of differentiating into various somatic cell types, including melanocytes, craniofacial cartilage and bone, smooth muscle, and peripheral nervous cells, which supports their promise for cell therapy. In this work, we provide a comprehensive review of wide aspects of neural crest cells from their developmental biology to applicability in medical research. We provide a simplified model of neural crest cell development and highlight the key external stimuli and intrinsic regulators that determine the neural crest cell fate. Defects of neural crest cell development leading to several human disorders are also mentioned, with the emphasis of using human induced pluripotent stem cells to model neurocristopathic syndromes. © 2014 Wiley Periodicals, Inc.

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

PubMed Central

Agochukwu, Nneamaka B.; Pineda-Alvarez, Daniel E.; Keaton, Amelia A.; Warren-Mora, Nicole; Raam, Manu S.; Kamat, Aparna; Chandrasekharappa, Settara C.; Solomon, Benjamin D.

2011-01-01

VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 – 35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high-density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size. PMID:21315191

Pre-mRNA Splicing in Plants: In Vivo Functions of RNA-Binding Proteins Implicated in the Splicing Process

PubMed Central

Meyer, Katja; Koester, Tino; Staiger, Dorothee

2015-01-01

Alternative pre-messenger RNA splicing in higher plants emerges as an important layer of regulation upon exposure to exogenous and endogenous cues. Accordingly, mutants defective in RNA-binding proteins predicted to function in the splicing process show severe phenotypic alterations. Among those are developmental defects, impaired responses to pathogen threat or abiotic stress factors, and misregulation of the circadian timing system. A suite of splicing factors has been identified in the model plant Arabidopsis thaliana. Here we summarize recent insights on how defects in these splicing factors impair plant performance. PMID:26213982

Excessive apoptosis and defective autophagy contribute to developmental testicular toxicity induced by fluoride.

PubMed

Zhang, Shun; Niu, Qiang; Gao, Hui; Ma, Rulin; Lei, Rongrong; Zhang, Cheng; Xia, Tao; Li, Pei; Xu, Chunyan; Wang, Chao; Chen, Jingwen; Dong, Lixing; Zhao, Qian; Wang, Aiguo

2016-05-01

Fluoride, a ubiquitous environmental contaminant, is known to impair testicular functions and fertility; however the underlying mechanisms remain obscure. In this study, we used a rat model to mimic human exposure and sought to investigate the roles of apoptosis and autophagy in testicular toxicity of fluoride. Sprague-Dawley rats were developmentally exposed to 25, 50, or 100 mg/L sodium fluoride (NaF) via drinking water from pre-pregnancy to post-puberty, and then the testes of offspring were excised on postnatal day 56. Our results demonstrated that developmental NaF exposure induced an enhanced testicular apoptosis, as manifested by a series of hallmarks such as caspase-3 activation, chromatin condensation and DNA fragmentation. Further study revealed that fluoride exposure elicited significant elevations in the levels of cell surface death receptor Fas with a parallel increase in cytoplasmic cytochrome c, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Intriguingly, fluoride treatment also simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II but not Beclin1. Unexpectedly, the expression of p62, a substrate that is degraded by autophagy, was also significantly elevated, suggesting that the accumulated autophagosomes resulted from impaired autophagy degradation rather than increased formation. Importantly, these were associated with marked histopathological lesions including spermatogenic failure and germ cell loss, along with severe ultrastructural abnormalities in testes. Taken together, our findings provide deeper insights into roles of excessive apoptosis and defective autophagy in the aggravation of testicular damage, which could contribute to a better understanding of fluoride-induced male reproductive toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel isoforms of Dlg are fundamental for neuronal development in Drosophila.

PubMed

Mendoza, Carolina; Olguín, Patricio; Lafferte, Gabriela; Thomas, Ulrich; Ebitsch, Susanne; Gundelfinger, Eckart D; Kukuljan, Manuel; Sierralta, Jimena

2003-03-15

Drosophila discs-large (dlg) mutants exhibit multiple developmental abnormalities, including severe defects in neuronal differentiation and synaptic structure and function. These defects have been ascribed to the loss of a single gene product, Dlg-A, a scaffold protein thought to be expressed in many cell types. Here, we describe that additional isoforms arise as a consequence of different transcription start points and alternative splicing of dlg. At least five different dlg gene products are predicted. We identified a subset of dlg-derived cDNAs that include novel exons encoding a peptide homologous to the N terminus of the mammalian protein SAP97/hDLG (S97N). Dlg isoforms containing the S97N domain are expressed at larval neuromuscular junctions and within the CNS of both embryos and larvae but are not detectable in epithelial tissues. Strong hypomorphic dlg alleles exhibit decreased expression of S97N, which may account for neural-specific aspects of the pleiomorphic dlg mutant phenotype. Selective inhibition of the expression of S97N-containing proteins in embryos by double-strand RNA leads to severe defects in neuronal differentiation and axon guidance, without overt perturbations in epithelia. These results indicate that the differential expression of dlg products correlates with distinct functions in non-neural and neural cells. During embryonic development, proteins that include the S97N domain are essential for proper neuronal differentiation and organization, acting through mechanisms that may include the adequate localization of cell fate determinants.

The Rachitic Tooth

PubMed Central

Nociti, Francisco H.; Somerman, Martha J.

2014-01-01

Teeth are mineralized organs composed of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of rickets, which traditionally referred to skeletal disease associated with vitamin D deficiency but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate-regulating endopeptidase homolog, X-linked, fibroblast growth factor 23, and dentin matrix protein 1. Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase are necessary for proper mineralization, where rickets can result from loss of activity of tissue nonspecific alkaline phosphatase. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the rachitic tooth will be revealed. PMID:23939820

Dental health of aboriginal pre-school children in Brisbane, Australia.

PubMed

Seow, W K; Amaratunge, A; Bennett, R; Bronsch, D; Lai, P Y

1996-06-01

This investigation studied the dental health status of a group of 184 Australian Aboriginal children with a mean age of 4.4 +/- 0.8 years, who were attending pre-schools in metropolitan Brisbane, a non-fluoridated state capital city. The DDE (Developmental Defects of Enamel) Index was used to chart enamel hypoplasia and enamel opacities. WHO criteria was used to diagnose dental caries. The results showed that 98% of children had at least one tooth showing developmental enamel defects. Each child had a mean of 3.8 +/- 1.7 teeth affected by enamel hypoplasia and another 1.1 +/- 0.8 teeth affected by enamel opacity. Seventy-eight percent of the children had dental caries. The mean number of decayed, missing, filled teeth (dmft) per child was 3.8 +/- 3.7. The decayed component constituted 3.5 (95%) of the mean dmft, indicating a high unmet restorative need in this group. The mean dmfs (decayed, missing, filled, surfaces) was 5.9 +/- 7.3. Maxillary anterior labial decay of at least one tooth affected 43 (23%) of the children. In this sub-group, the dmft and dmfs was 9.1 +/- 2.8 and 15.4 +/- 7.7 respectively. Oral debris was found in 98% of the children. It is hypothesized that the high levels of underlying developmental enamel defects, compounded by low fluoride exposure, poor oral hygiene and a diet high in refined sugars pose an important caries risk factor in this group of children.

Trim9 Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

PubMed Central

Winkle, Cortney C.; Olsen, Reid H. J.; Kim, Hyojin; Moy, Sheryl S.

2016-01-01

During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9−/− adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9−/− mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. SIGNIFICANCE STATEMENT Appropriate generation and incorporation of adult-born neurons in the dentate gyrus are critical for spatial learning and memory and other hippocampal functions. Here we identify the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of embryonic and adult hippocampal neuron shape acquisition and hippocampal-dependent behaviors. Genetic deletion of Trim9 elevated dendritic arborization of hippocampal neurons in vitro and in vivo. Adult-born dentate granule cells lacking Trim9 similarly exhibited excessive dendritic arborization and mislocalization of cell bodies in vivo. These cellular defects were associated with severe deficits in spatial learning and memory. PMID:27147649

Trim9 Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory.

PubMed

Winkle, Cortney C; Olsen, Reid H J; Kim, Hyojin; Moy, Sheryl S; Song, Juan; Gupton, Stephanie L

2016-05-04

During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9(-/-) adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9(-/-) mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. Appropriate generation and incorporation of adult-born neurons in the dentate gyrus are critical for spatial learning and memory and other hippocampal functions. Here we identify the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of embryonic and adult hippocampal neuron shape acquisition and hippocampal-dependent behaviors. Genetic deletion of Trim9 elevated dendritic arborization of hippocampal neurons in vitro and in vivo Adult-born dentate granule cells lacking Trim9 similarly exhibited excessive dendritic arborization and mislocalization of cell bodies in vivo These cellular defects were associated with severe deficits in spatial learning and memory. Copyright © 2016 the authors 0270-6474/16/364940-19$15.00/0.

Moving from Survival to Healthy Survival through Child Health Screening and Early Intervention Services Under Rashtriya Bal Swasthya Karyakram (RBSK).

PubMed

Singh, Arun K; Kumar, Rakesh; Mishra, C K; Khera, Ajay; Srivastava, Anubhav

2015-11-01

For negating the impact of early adversities on the development and ensuring a healthy, dynamic future for all children, Ministry of Health and Family Welfare in 2013 launched a programme for child health screening and early intervention services as Rashtriya Bal Swasthya Karyakram (RBSK) which aims to improve the quality of life with special focus on improving cognition and survival outcomes for "at risk" children. It has a systemic approach of prevention, early identification and management of 30 health conditions distributed under 4Ds: Defects at birth, Diseases, Deficiencies and Developmental delays including Disabilities spread over birth to 18 y of age in a holistic manner. There is a dedicated 4 member Mobile Health team for community screening and a dedicated 14 member team at District Early Intervention Center (DEIC) for comprehensive management. Existing health infrastructure and personnel are also integrated and utilized in this endeavor. Defects at birth are screened at Delivery points, home visits by accredited social health activist (ASHA), Anganwadi centers and at schools. Developmental delays are evaluated at DEIC through a multidisciplinary team with interdisciplinary approach. Five thousand four hundred eighteen dedicated Mobile Health teams have screened a total of 12.19 crore children till Dec.14. From April to Dec. 2014, 4.20 crore children were screened, of which birth to 6-y-old children were 2.13 crore while 2.07 crore were from 6 to 18 y. 17.7 lakh children were referred to tertiary centers and 6.2 lakh availed tertiary care. 50.7 lakhs were found positive for 4Ds; 1.35 lakhs were birth defects. RBSK is a step towards universal health care for free assured services.

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features

PubMed Central

Low, Karen J; Ansari, Morad; Abou Jamra, Rami; Clarke, Angus; El Chehadeh, Salima; FitzPatrick, David R; Greenslade, Mark; Henderson, Alex; Hurst, Jane; Keller, Kory; Kuentz, Paul; Prescott, Trine; Roessler, Franziska; Selmer, Kaja K; Schneider, Michael C; Stewart, Fiona; Tatton-Brown, Katrina; Thevenon, Julien; Vigeland, Magnus D; Vogt, Julie; Willems, Marjolaine; Zonana, Jonathan; Study, D D D; Smithson, Sarah F

2017-01-01

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function. PMID:28327570

Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

PubMed

Le Guen, Tangui; Jullien, Laurent; Touzot, Fabien; Schertzer, Michael; Gaillard, Laetitia; Perderiset, Mylène; Carpentier, Wassila; Nitschke, Patrick; Picard, Capucine; Couillault, Gérard; Soulier, Jean; Fischer, Alain; Callebaut, Isabelle; Jabado, Nada; Londono-Vallejo, Arturo; de Villartay, Jean-Pierre; Revy, Patrick

2013-08-15

Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

Using optical coherence tomography to rapidly phenotype and quantify congenital heart defects associated with prenatal alcohol exposure

PubMed Central

Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu; Noonan, Amanda I.; Rollins, Andrew M.; Jenkins, Michael W.; Watanabe, Michiko

2014-01-01

Background The most commonly used method to analyze congenital heart defects involves serial sectioning and histology. However, this is often a time-consuming process where the quantification of cardiac defects can be difficult due to problems with accurate section registration. Here we demonstrate the advantages of using optical coherence tomography, a comparatively new and rising technology, to phenotype avian embryo hearts in a model of Fetal Alcohol Syndrome where a binge-like quantity of alcohol/ethanol was introduced at gastrulation. Results The rapid, consistent imaging protocols allowed for the immediate identification of cardiac anomalies, including ventricular septal defects and misaligned/missing vessels. Interventricular septum thicknesses and vessel diameters for three of the five outflow arteries were also significantly reduced. Outflow and atrio-ventricular valves were segmented using image processing software and had significantly reduced volumes compared to controls. This is the first study to our knowledge that has 3-D reconstructed the late-stage cardiac valves in precise detail in order to examine their morphology and dimensions. Conclusion We believe therefore that OCT, with its ability to rapidly image and quantify tiny embryonic structures in high resolution, will serve as an excellent and cost-effective preliminary screening tool for developmental biologists working with a variety of experimental/disease models. PMID:25546089

Drosophila Polypyrimidine Tract-Binding Protein (DmPTB) Regulates Dorso-Ventral Patterning Genes in Embryos

PubMed Central

Huntley, Jim; Wesley, Cedric S.; Singh, Ravinder

2014-01-01

The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during embryogenesis. A loss of function mutation, heph03429, results in varied defects in embryonic developmental processes, leading to embryonic lethality. However, the suite of molecular functions that are disrupted in the mutant remains unknown. We have used an unbiased high throughput sequencing approach to identify transcripts that are misregulated in this mutant. Misregulated transcripts show evidence of significantly altered patterns of splicing (exon skipping, 5′ and 3′ splice site switching), alternative 5′ ends, and mRNA level changes (up and down regulation). These findings are independently supported by reverse-transcription-polymerase chain reaction (RT-PCR) analysis and in situ hybridization. We show that a group of genes, such as Zerknüllt, z600 and screw are among the most upregulated in the mutant and have been functionally linked to dorso-ventral patterning and/or dorsal closure processes. Thus, loss of dmPTB function results in specific misregulated transcripts, including those that provide the missing link between the loss of dmPTB function and observed developmental defects in embryogenesis. This study provides the first comprehensive repertoire of genes affected in vivo in the heph mutant in Drosophila and offers insight into the role of dmPTB during embryonic development. PMID:25014769

Developmental Role and Auxin Responsiveness of Class III Homeodomain Leucine Zipper Gene Family Members in Rice1[C][W][OA

PubMed Central

Itoh, Jun-Ichi; Hibara, Ken-Ichiro; Sato, Yutaka; Nagato, Yasuo

2008-01-01

Members of the Class III homeodomain leucine zipper (Class III HD-Zip) gene family are central regulators of crucial aspects of plant development. To better understand the roles of five Class III HD-Zip genes in rice (Oryza sativa) development, we investigated their expression patterns, ectopic expression phenotypes, and auxin responsiveness. Four genes, OSHB1 to OSHB4, were expressed in a localized domain of the shoot apical meristem (SAM), the adaxial cells of leaf primordia, the leaf margins, and the xylem tissue of vascular bundles. In contrast, expression of OSHB5 was observed only in phloem tissue. Plants ectopically expressing microRNA166-resistant versions of the OSHB3 gene exhibited severe defects, including the ectopic production of leaf margins, shoots, and radialized leaves. The treatment of seedlings with auxin quickly induced ectopic OSHB3 expression in the entire region of the SAM, but not in other tissues. Furthermore, this ectopic expression of OSHB3 was correlated with leaf initiation defects. Our findings suggest that rice Class III HD-Zip genes have conserved functions with their homologs in Arabidopsis (Arabidopsis thaliana), but have also acquired specific developmental roles in grasses or monocots. In addition, some Class III HD-Zip genes may regulate the leaf initiation process in the SAM in an auxin-dependent manner. PMID:18567825

MGOUN1 encodes an Arabidopsis type IB DNA topoisomerase required in stem cell regulation and to maintain developmentally regulated gene silencing.

PubMed

Graf, Philipp; Dolzblasz, Alicja; Würschum, Tobias; Lenhard, Michael; Pfreundt, Ulrike; Laux, Thomas

2010-03-01

Maintenance of stem cells in the Arabidopsis thaliana shoot meristem is regulated by signals from the underlying cells of the organizing center, provided through the transcription factor WUSCHEL (WUS). Here, we report the isolation of several independent mutants of MGOUN1 (MGO1) as genetic suppressors of ectopic WUS activity and enhancers of stem cell defects in hypomorphic wus alleles. mgo1 mutants have previously been reported to result in a delayed progression of meristem cells into differentiating organ primordia (Laufs et al., 1998). Genetic analyses indicate that MGO1 functions together with WUS in stem cell maintenance at all stages of shoot and floral meristems. Synergistic interactions of mgo1 with several chromatin mutants suggest that MGO1 affects gene expression together with chromatin remodeling pathways. In addition, the expression states of developmentally regulated genes are randomly switched in mgo1 in a mitotically inheritable way, indicating that MGO1 stabilizes epigenetic states against stochastically occurring changes. Positional cloning revealed that MGO1 encodes a putative type IB topoisomerase, which in animals and yeast has been shown to be required for regulation of DNA coiling during transcription and replication. The specific developmental defects in mgo1 mutants link topoisomerase IB function in Arabidopsis to stable propagation of developmentally regulated gene expression.

Wash functions downstream of Rho1 GTPase in a subset of Drosophila immune cell developmental migrations

PubMed Central

Verboon, Jeffrey M.; Rahe, Travis K.; Rodriguez-Mesa, Evelyn; Parkhurst, Susan M.

2015-01-01

Drosophila immune cells, the hemocytes, undergo four stereotypical developmental migrations to populate the embryo, where they provide immune reconnoitering, as well as a number of non–immune-related functions necessary for proper embryogenesis. Here, we describe a role for Rho1 in one of these developmental migrations in which posteriorly located hemocytes migrate toward the head. This migration requires the interaction of Rho1 with its downstream effector Wash, a Wiskott–Aldrich syndrome family protein. Both Wash knockdown and a Rho1 transgene harboring a mutation that prevents Wash binding exhibit the same developmental migratory defect as Rho1 knockdown. Wash activates the Arp2/3 complex, whose activity is needed for this migration, whereas members of the WASH regulatory complex (SWIP, Strumpellin, and CCDC53) are not. Our results suggest a WASH complex–independent signaling pathway to regulate the cytoskeleton during a subset of hemocyte developmental migrations. PMID:25739458

Insect Sex Determination Manipulated by Their Endosymbionts: Incidences, Mechanisms and Implications

PubMed Central

Kageyama, Daisuke; Narita, Satoko; Watanabe, Masaya

2012-01-01

The sex-determining systems of arthropods are surprisingly diverse. Some species have male or female heterogametic sex chromosomes while other species do not have sex chromosomes. Most species are diploids but some species, including wasps, ants, thrips and mites, are haplodiploids (n in males; 2n in females). Many of the sexual aberrations, such as sexual mosaics, sex-specific lethality and conversion of sexuality, can be explained by developmental defects including double fertilization of a binucleate egg, loss of a sex chromosome or perturbation of sex-determining gene expression, which occur accidentally or are induced by certain environmental conditions. However, recent studies have revealed that such sexual aberrations can be caused by various groups of vertically-transmitted endosymbiotic microbes such as bacteria of the genera Wolbachia, Rickettsia, Arsenophonus, Spiroplasma and Cardinium, as well as microsporidian protists. In this review, we first summarize the accumulated data on endosymbiont-induced sexual aberrations, and then discuss how such endosymbionts affect the developmental system of their hosts and what kinds of ecological and evolutionary effects these endosymbionts have on their host populations. PMID:26467955

Insect Sex Determination Manipulated by Their Endosymbionts: Incidences, Mechanisms and Implications.

PubMed

Kageyama, Daisuke; Narita, Satoko; Watanabe, Masaya

2012-02-10

The sex-determining systems of arthropods are surprisingly diverse. Some species have male or female heterogametic sex chromosomes while other species do not have sex chromosomes. Most species are diploids but some species, including wasps, ants, thrips and mites, are haplodiploids (n in males; 2n in females). Many of the sexual aberrations, such as sexual mosaics, sex-specific lethality and conversion of sexuality, can be explained by developmental defects including double fertilization of a binucleate egg, loss of a sex chromosome or perturbation of sex-determining gene expression, which occur accidentally or are induced by certain environmental conditions. However, recent studies have revealed that such sexual aberrations can be caused by various groups of vertically-transmitted endosymbiotic microbes such as bacteria of the genera Wolbachia, Rickettsia, Arsenophonus, Spiroplasma and Cardinium, as well as microsporidian protists. In this review, we first summarize the accumulated data on endosymbiont-induced sexual aberrations, and then discuss how such endosymbionts affect the developmental system of their hosts and what kinds of ecological and evolutionary effects these endosymbionts have on their host populations.

Dental enamel defects in Italian children with cystic fibrosis: an observational study.

PubMed

Ferrazzano, G F; Sangianantoni, G; Cantile, T; Amato, I; Orlando, S; Ingenito, A

2012-03-01

The relationship between cystic fibrosis (CF) and caries experience has already been explored, but relatively little information is available on dental enamel defects prevalence among children affected by cystic fibrosis. The aim of this study was to investigate this issue in deciduous and permanent teeth of children with CF resident in southern Italy. This cross sectional observational study was undertaken between October 2009 and March 2010. 88 CF patients and 101 healthy age-matched participated in this study. The prevalence of dental enamel defects was calculated using a modified Developmental Defects of Enamel (DDE) index. The comparison of dental enamel defects prevalence among groups was carried out using regression binary logistic analysis. In the CF subjects there was a higher prevalence (56%) of enamel defects in comparison to the healthy group (22%). The most prevalent enamel defect was hypoplasia with loss of enamel (23% of CF patients vs 1 1/2% of control group) in permanent teeth. This study confirms that children with cystic fibrosis are at increased risk of developing hypoplastic defects on their permanent teeth.

Presentations: Adverse Outcome Pathways for Abnormal Phenotypes

EPA Science Inventory

Birth defects affect many infants and the etiology for most are unknown. Although environmental factors are known to influence pregnancy outcome, thousands of chemicals, present in the environment, are untested for developmental toxicity potential. Application of computational p...

Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F.

PubMed

Sandoval, Imelda T; Manos, Elizabeth J; Van Wagoner, Ryan M; Delacruz, Richard Glenn C; Edes, Kornelia; Winge, Dennis R; Ireland, Chris M; Jones, David A

2013-06-20

A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper-chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

mus304 encodes a novel DNA damage checkpoint protein required during Drosophila development

PubMed Central

Brodsky, Michael H.; Sekelsky, Jeff J.; Tsang, Garson; Hawley, R. Scott; Rubin, Gerald M.

2000-01-01

Checkpoints block cell cycle progression in eukaryotic cells exposed to DNA damaging agents. We show that several Drosophila homologs of checkpoint genes, mei-41, grapes, and 14-3-3ε, regulate a DNA damage checkpoint in the developing eye. We have used this assay to show that the mutagen-sensitive gene mus304 is also required for this checkpoint. mus304 encodes a novel coiled-coil domain protein, which is targeted to the cytoplasm. Similar to mei-41, mus304 is required for chromosome break repair and for genomic stability. mus304 animals also exhibit three developmental defects, abnormal bristle morphology, decreased meiotic recombination, and arrested embryonic development. We suggest that these phenotypes reflect distinct developmental consequences of a single underlying checkpoint defect. Similar mechanisms may account for the puzzling array of symptoms observed in humans with mutations in the ATM tumor suppressor gene. PMID:10733527

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.

PubMed

Kim, Myungjin; Sandford, Erin; Gatica, Damian; Qiu, Yu; Liu, Xu; Zheng, Yumei; Schulman, Brenda A; Xu, Jishu; Semple, Ian; Ro, Seung-Hyun; Kim, Boyoung; Mavioglu, R Nehir; Tolun, Aslıhan; Jipa, Andras; Takats, Szabolcs; Karpati, Manuela; Li, Jun Z; Yapici, Zuhal; Juhasz, Gabor; Lee, Jun Hee; Klionsky, Daniel J; Burmeister, Margit

2016-01-26

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.

Case Study: Organotypic human in vitro models of embryonic ...

EPA Pesticide Factsheets

Morphogenetic fusion of tissues is a common event in embryonic development and disruption of fusion is associated with birth defects of the eye, heart, neural tube, phallus, palate, and other organ systems. Embryonic tissue fusion requires precise regulation of cell-cell and cell-matrix interactions that drive proliferation, differentiation, and morphogenesis. Chemical low-dose exposures can disrupt morphogenesis across space and time by interfering with key embryonic fusion events. The Morphogenetic Fusion Task uses computer and in vitro models to elucidate consequences of developmental exposures. The Morphogenetic Fusion Task integrates multiple approaches to model responses to chemicals that leaad to birth defects, including integrative mining on ToxCast DB, ToxRefDB, and chemical structures, advanced computer agent-based models, and human cell-based cultures that model disruption of cellular and molecular behaviors including mechanisms predicted from integrative data mining and agent-based models. The purpose of the poster is to indicate progress on the CSS 17.02 Virtual Tissue Models Morphogenesis Task 1 products for the Board of Scientific Counselors meeting on Nov 16-17.

The Cytoplasmic Tail of the T Cell Receptor CD3 ε Subunit Contains a Phospholipid-Binding Motif that Regulates T Cell Functions1

PubMed Central

DeFord-Watts, Laura M.; Tassin, Tara C.; Becker, Amy M.; Medeiros, Jennifer J.; Albanesi, Joseph P.; Love, Paul E.; Wülfing, Christoph; van Oers, Nicolai S. C.

2010-01-01

The CD3 ε subunit of the TCR complex contains two defined signaling domains, a proline-rich sequence and an ITAM. We identified a third signaling sequence in CD3 ε, termed the basic-rich stretch (BRS). Herein, we show that the positively charged residues of the BRS enable this region of CD3 ε to complex a subset of acidic phospholipids, including PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P3, and PI(4,5)P2. Transgenic mice containing mutations of the BRS exhibited varying developmental defects, ranging from reduced thymic cellularity to a complete block in T cell development. Peripheral T cells from BRS-modified mice also exhibited several defects, including decreased TCR surface expression, reduced TCR-mediated signaling responses to agonist peptide-loaded APCs, and delayed CD3 ε localization to the immunological synapse. Overall, these findings demonstrate a functional role for the CD3 ε lipid-binding domain in T cell biology. PMID:19542373

Unjoined primary and secondary neural tubes: junctional neural tube defect, a new form of spinal dysraphism caused by disturbance of junctional neurulation.

PubMed

Eibach, Sebastian; Moes, Greg; Hou, Yong Jin; Zovickian, John; Pang, Dachling

2017-10-01

Primary and secondary neurulation are the two known processes that form the central neuraxis of vertebrates. Human phenotypes of neural tube defects (NTDs) mostly fall into two corresponding categories consistent with the two types of developmental sequence: primary NTD features an open skin defect, an exposed, unclosed neural plate (hence an open neural tube defect, or ONTD), and an unformed or poorly formed secondary neural tube, and secondary NTD with no skin abnormality (hence a closed NTD) and a malformed conus caudal to a well-developed primary neural tube. We encountered three cases of a previously unrecorded form of spinal dysraphism in which the primary and secondary neural tubes are individually formed but are physically separated far apart and functionally disconnected from each other. One patient was operated on, in whom both the lumbosacral spinal cord from primary neurulation and the conus from secondary neurulation are each anatomically complete and endowed with functioning segmental motor roots tested by intraoperative triggered electromyography and direct spinal cord stimulation. The remarkable feature is that the two neural tubes are unjoined except by a functionally inert, probably non-neural band. The developmental error of this peculiar malformation probably occurs during the critical transition between the end of primary and the beginning of secondary neurulation, in a stage aptly called junctional neurulation. We describe the current knowledge concerning junctional neurulation and speculate on the embryogenesis of this new class of spinal dysraphism, which we call junctional neural tube defect.

How many breaks do we need to CATCH on 22q11?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dallapiccola, B.; Pizzuti, A.; Novelli, G.

1996-07-01

The major clinical manifestations of DiGeorge syndrome (DGS; MIM 188400), which reflect developmental abnormalities of the 3d and 4th pharyngeal pouch derivatives, include thymus- and parathyroid-gland aplasia or hypoplasia and conotruncal cardiac malformations. The additional dysmorphic facial features, such as hypertelorism, cleft lip and palate, bifid uvula, and small/low-set ears, which are also common, presumably reflect the same defect. The DGS phenotype has been associated with chromosome abnormalities and, sometimes, is the effect of teratogenic agents such as retinoic acid and alcohol. 53 refs., 1 fig.

Curcumin affects development of zebrafish embryo.

PubMed

Wu, Jheng-Yu; Lin, Chin-Yi; Lin, Tien-Wei; Ken, Chuian-Fu; Wen, Yu-Der

2007-07-01

Embryotoxic and teratogenic effects of curcumin on the development of zebrafish embryo were investi-gated in this study. The LD(50) values of curcumin (24-h incubation) were estimated at 7.5 microM and 5 microM for embryos and larvae, respectively. The developmental defects caused by curcumin treatments include bent or hook-like tails, spinal column curving, edema in pericardial sac, retarded yolk sac resorption, and shorter body length. In curcumin-treated larvae, fluorescence signals of curcumin were found in edamae sac and some skin cells. Together, these results indicate that zebrafish are suitable model organisms to study the toxic effects of curcumin.

A new autosomal dominant syndrome of distinctive face showing ptosis and prominent eyes associated with cleft palate, ear anomalies, and learning disability.

PubMed

Tyshchenko, N; Neuhann, T M; Gerlach, E; Hahn, G; Heisch, K; Rump, A; Schrock, E; Tinschert, S; Hackmann, K

2011-09-01

We report on three patients from two families with apparently a novel clinical entity. The main features of which include unusual craniofacial dysmorphism with ptosis, prominent eyes, flat midface, Cupid's bow configuration of the upper lip, low-set, posteriorly rotated small ears, as well as conductive hearing loss, cleft palate, heart defect, and mild developmental delay. We suggest that this entity is an autosomal dominant disorder given the occurrence in a mother and daughter as well as in an unrelated boy. Copyright © 2011 Wiley-Liss, Inc.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

PubMed Central

Lopez-Rivera, E.; Liu, Y.P.; Verbitsky, M.; Anderson, B.R.; Capone, V.P.; Otto, E.A.; Yan, Z.; Mitrotti, A.; Martino, J.; Steers, N.J.; Fasel, D.A.; Vukojevic, K.; Deng, R.; Racedo, S.E.; Liu, Q.; Werth, M.; Westland, R.; Vivante, A.; Makar, G.S.; Bodria, M.; Sampson, M.G.; Gillies, C.E.; Vega-Warner, V.; Maiorana, M.; Petrey, D.S.; Honig, B.; Lozanovski, V.J.; Salomon, R.; Heidet, L.; Carpentier, W.; Gaillard, D.; Carrea, A.; Gesualdo, L.; Cusi, D.; Izzi, C.; Scolari, F.; van Wijk, J.A.E.; Arapovic, A.; Saraga-Babic, M.; Saraga, M.; Kunac, N.; Samii, A.; McDonald-McGinn, D.M.; Crowley, T.B.; Zackai, E.H.; Drozdz, D.; Miklaszewska, M.; Tkaczyk, M.; Sikora, P.; Szczepanska, M.; Mizerska-Wasiak, M.; Krzemien, G.; Szmigielska, A.; Zaniew, M.; Darlow, J.M.; Puri, P.; Barton, D.; Casolari, E.; Furth, S.L.; Warady, B.A.; Gucev, Z.; Hakonarson, H.; Flogelova, H.; Tasic, V.; Latos-Bielenska, A.; Materna-Kiryluk, A.; Allegri, L.; Wong, C.S.; Drummond, I.A.; D’Agati, V.; Imamoto, A.; Barasch, J.M.; Hildebrandt, F.; Kiryluk, K.; Lifton, R.P.; Morrow, B.E.; Jeanpierre, C.; Papaioannou, V.E.; Ghiggeri, G.M.; Gharavi, A.G.; Katsanis, N.; Sanna-Cherchi, S.

2017-01-01

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10−14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.) PMID:28121514

Topological defects in epithelia govern cell death and extrusion

NASA Astrophysics Data System (ADS)

Saw, Thuan Beng; Doostmohammadi, Amin; Nier, Vincent; Kocgozlu, Leyla; Thampi, Sumesh; Toyama, Yusuke; Marcq, Philippe; Lim, Chwee Teck; Yeomans, Julia M.; Ladoux, Benoit

2017-04-01

Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell-cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.

Oocyte spindle proteomics analysis leading to rescue of chromosome congression defects in cloned embryos

PubMed Central

Duan, Xunbao; Zhong, Zhisheng; Potireddy, Santhi; Moncada, Camilo; Merali, Salim; Latham, Keith E.

2015-01-01

Embryos produced by somatic cell nuclear transfer (SCNT) display low term developmental potential. This is associated with deficiencies in spindle composition prior to activation and at early mitotic divisions, including failure to assemble certain proteins on the spindle. The protein-deficient spindles are accompanied by chromosome congression defects prior to activation and during the first mitotic divisions of the embryo. The molecular basis for these deficiencies and how they might be avoided are unknown. Proteomic analyses of spindles isolated from normal metaphase II (MII) stage oocytes and SCNT constructs, along with a systematic immunofluorescent survey of known spindle-associated proteins were undertaken. This was the first proteomics study of mammalian oocyte spindles. The study revealed four proteins as being deficient in spindles of SCNT embryos in addition to those previously identified; these were clathrin heavy chain (CLTC), aurora B kinase, dynactin 4, and casein kinase 1 alpha. Due to substantial reduction in CLTC abundance after spindle removal, we undertook functional studies to explore the importance of CLTC in oocyte spindle function and in chromosome congression defects of cloned embryos. Using siRNA knockdown we demonstrated an essential role for CLTC in chromosome congression during oocyte maturation. We also demonstrated rescue of chromosome congression defects in SCNT embryos at the first mitosis using CLTC mRNA injection. These studies are the first to employ proteomics analyses coupled to functional interventions to rescue a specific molecular defect in cloned embryos. PMID:20883044

Computational Modeling and Simulation of Genital Tubercle ...

EPA Pesticide Factsheets

Hypospadias is a developmental defect of urethral tube closure that has a complex etiology. Here, we describe a multicellular agent-based model of genital tubercle development that simulates urethrogenesis from the urethral plate stage to urethral tube closure in differentiating male embryos. The model, constructed in CompuCell3D, implemented spatially dynamic signals from SHH, FGF10, and androgen signaling pathways. These signals modulated stochastic cell behaviors, such as differential adhesion, cell motility, proliferation, and apoptosis. Urethral tube closure was an emergent property of the model that was quantitatively dependent on SHH and FGF10 induced effects on mesenchymal proliferation and endodermal apoptosis, ultimately linked to androgen signaling. In the absence of androgenization, simulated genital tubercle development defaulted to the female condition. Intermediate phenotypes associated with partial androgen deficiency resulted in incomplete closure. Using this computer model, complex relationships between urethral tube closure defects and disruption of underlying signaling pathways could be probed theoretically in multiplex disturbance scenarios and modeled into probabilistic predictions for individual risk for hypospadias and potentially other developmental defects of the male genital tubercle. We identify the minimal molecular network that determines the outcome of male genital tubercle development in mice.

Sociability and synapse subtype-specific defects in mice lacking SRPX2, a language-associated gene

PubMed Central

Cong, Qifei; Palmer, Christian R.

2018-01-01

The FoxP2 transcription factor and its target genes have been implicated in developmental brain diseases with a prominent language component, such as developmental verbal dyspraxia and specific language impairment. How FoxP2 affects neural circuitry development remains poorly understood. The sushi domain protein SRPX2 is a target of FoxP2, and mutations in SRPX2 are associated with language defects in humans. We have previously shown that SRPX2 is a synaptogenic protein that increases excitatory synapse density. Here we provide the first characterization of mice lacking the SRPX2 gene, and show that these mice exhibit defects in both neural circuitry and communication and social behaviors. Specifically, we show that mice lacking SRPX2 show a specific reduction in excitatory VGlut2 synapses in the cerebral cortex, while VGlut1 and inhibitory synapses were largely unaffected. SRPX2 KO mice also exhibit an abnormal ultrasonic vocalization ontogenetic profile in neonatal pups, and reduced preference for social novelty. These data demonstrate a functional role for SRPX2 during brain development, and further implicate FoxP2 and its targets in regulating the development of vocalization and social circuits. PMID:29920554

Turmeric Extract Rescues Ethanol-Induced Developmental Defect in the Zebrafish Model for Fetal Alcohol Spectrum Disorder (FASD).

PubMed

Muralidharan, Pooja; Connors, Craig T; Mohammed, Arooj S; Sarmah, Swapnalee; Marrs, Kathleen; Marrs, James A; Chism, Grady W

2017-09-01

Prenatal ethanol exposure causes the most frequent preventable birth disorder, fetal alcohol spectrum disorder (FASD). The effect of turmeric extracts in rescuing an ethanol-induced developmental defect using zebrafish as a model was determined. Ethanol-induced oxidative stress is one of the major mechanisms underlying FASD. We hypothesize that antioxidant inducing properties of turmeric may alleviate ethanol-induced defects. Curcuminoid content of the turmeric powder extract (5 mg/mL turmeric in ethanol) was determined by UPLC and found to contain Curcumin (124.1 ± 0.2 μg/mL), Desmethoxycurcumin (43.4 ± 0.1 μg/mL), and Bisdemethoxycurcumin (36.6 ± 0.1 μg/mL). Zebrafish embryos were treated with 100 mM (0.6% v/v) ethanol during gastrulation through organogenesis (2 to 48 h postfertilization (hpf)) and supplemented with turmeric extract to obtain total curcuminoid concentrations of 0, 1.16, 1.72, or 2.32 μM. Turmeric supplementation showed significant rescue of the body length at 72 hpf compared to ethanol-treated embryos. The mechanism underlying the rescue remains to be determined. © 2017 Institute of Food Technologists®.

Impact of Co-Occurring Birth Defects on the Timing of Newborn Hearing Screening and Diagnosis

PubMed Central

Chapman, Derek A.; Stampfel, Caroline C.; Bodurtha, Joann N.; Dodson, Kelley M.; Pandya, Arti; Lynch, Kathleen B.; Kirby, Russell S.

2016-01-01

Purpose Early detection of hearing loss in all newborns and timely intervention are critical to children's cognitive, verbal, behavioral, and social development. The initiation of appropriate early intervention services before 6 months of age can prevent or reduce negative developmental consequences. The purpose of this study was to assess, using large, population-based registries, the effect of co-occurring birth defects (CBDs) on the timing and overall rate of hearing screening and diagnosis. Method The authors linked statewide data from newborn hearing screenings, a birth defects registry, and birth certificates to assess the timeliness of newborn hearing screening and diagnosis of hearing loss (HL) for infants with and without CBDs in 485 children with confirmed HL. Results Nearly one third (31.5%) of children with HL had 1 or more CBDs. The presence of CBDs prolonged the time of the initial infant hearing screening, which contributed to further delays in the subsequent diagnosis of HL. Conclusions Better coordination of HL assessment into treatment plans for children with CBDs may enable earlier diagnosis of HL and provide opportunities for intervention that will affect long-term developmental outcomes for these children. PMID:21940980

Reproductive disorders associated with pesticide exposure.

PubMed

Frazier, Linda M

2007-01-01

Exposure of men or women to certain pesticides at sufficient doses may increase the risk for sperm abnormalities, decreased fertility, a deficit of male children, spontaneous abortion, birth defects or fetal growth retardation. Pesticides from workplace or environmental exposures enter breast milk. Certain pesticides have been linked to developmental neurobehavioral problems, altered function of immune cells and possibly childhood leukemia. In well-designed epidemiologic studies, adverse reproductive or developmental effects have been associated with mixed pesticide exposure in occupational settings, particularly when personal protective equipment is not used. Every class of pesticides has at least one agent capable of affecting a reproductive or developmental endpoint in laboratory animals or people, including organophosphates, carbamates, pyrethroids, herbicides, fungicides, fumigants and especially organochlorines. Many of the most toxic pesticides have been banned or restricted in developed nations, but high exposures to these agents are still occurring in the most impoverished countries around the globe. Protective clothing, masks and gloves are more difficult to tolerate in hot, humid weather, or may be unavailable or unaffordable. Counseling patients who are concerned about reproductive and developmental effects of pesticides often involves helping them assess their exposure levels, weigh risks and benefits, and adopt practices to reduce or eliminate their absorbed dose. Patients may not realize that by the first prenatal care visit, most disruptions of organogenesis have already occurred. Planning ahead provides the best chance of lowering risk from pesticides and remediating other risk factors before conception.

Fragile X Mental Retardation Protein is Required for Programmed Cell Death and Clearance of Developmentally-Transient Peptidergic Neurons

PubMed Central

Gatto, Cheryl L.; Broadie, Kendal

2011-01-01

Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild-type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post-eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of “pruning” dysfunction may contribute to the FXS disease state. PMID:21596027

Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNS.

PubMed

Mellerick, Dervla M; Liu, Heather

2004-09-05

Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity.

Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos.

PubMed

Fisher, M C; Zeisel, S H; Mar, M H; Sadler, T W

2001-08-01

Choline is an essential nutrient in methylation, acetylcholine and phospholipid biosynthesis, and in cell signaling. The demand by an embryo or fetus for choline may place a pregnant woman and, subsequently, the developing conceptus at risk for choline deficiency. To determine whether a disruption in choline uptake and metabolism results in developmental abnormalities, early somite staged mouse embryos were exposed in vitro to either an inhibitor of choline uptake and metabolism, 2-dimethylaminoethanol (DMAE), or an inhibitor of phosphatidylcholine synthesis, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3)). Cell death following inhibitor exposure was investigated with LysoTracker Red and histology. Embryos exposed to 250-750 microM DMAE for 26 hr developed craniofacial hypoplasia and open neural tube defects in the forebrain, midbrain, and hindbrain regions. Embryos exposed to 125-275 microM ET-18-OCH(3) exhibited similar defects or expansion of the brain vesicles. ET-18-OCH(3)-affected embryos also had a distended neural tube at the posterior neuropore. Embryonic growth was reduced in embryos treated with either DMAE (375, 500, and 750 microM) or ET-18-OCH(3) (200 and 275 microM). Whole mount staining with LysoTracker Red and histological sections showed increased areas of cell death in embryos treated with 275 microM ET-18-OCH(3) for 6 hr, but there was no evidence of cell death in DMAE-exposed embryos. Inhibition of choline uptake and metabolism during neurulation results in growth retardation and developmental defects that affect the neural tube and face. Copyright 2001 Wiley-Liss, Inc.

Novel de novo pathogenic variant in the NR2F2 gene in a boy with congenital heart defect and dysmorphic features.

PubMed

Upadia, Jariya; Gonzales, Patrick R; Robin, Nathaniel H

2018-04-16

The NR2F2 gene plays an important role in angiogenesis and heart development. Moreover, this gene is involved in organogenesis in many other organs in mouse models. Variants in this gene have been reported in a number of patients with nonsyndromic atrioventricular septal defect, and in one patient with congenital heart defect and dysmorphic features. Here we report an 11-month-old Caucasian male with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect. He was later found to have a pathogenic mutation in the NR2F2 gene by whole exome sequencing. This is the second instance in which an NR2F2 mutation has been identified in a child with a congenital heart defect and other anomalies. This case suggests that some variants in NR2F2 may cause syndromic forms of congenital heart defect. © 2018 Wiley Periodicals, Inc.

Developmental neurogenetics and neuro-ophthalmology.

PubMed

Bennett, Jeffrey L

2002-12-01

The field of developmental neurogenetics has burgeoned over the past decade. Through the combined efforts of developmental biologists, geneticists, and clinicians, genetic defects resulting in neuro-ophthalmic disorders such as holoprosencephaly, microphthalmia, dominant optic atrophy, and optic nerve colobomas have been identified and characterized at the molecular level. Experimental studies in model organisms are continuing to identify novel genes critical for ocular and central nervous system development. Mutations in some of these genes have revealed a spectrum of pathology similar to that observed in septo-optic dysplasia, Möebius syndrome, and Duane retraction syndrome. This review examines our current knowledge of the molecular genetics of neuro-ophthalmic disease and focuses on several candidate genes for afferent and efferent visual system disorders.

Computational Modeling and Simulation of Developmental ...

EPA Pesticide Factsheets

SYNOPSIS: The question of how tissues and organs are shaped during development is crucial for understanding human birth defects. Data from high-throughput screening assays on human stem cells may be utilized predict developmental toxicity with reasonable accuracy. Other types of models are necessary, however, for mechanism-specific analysis because embryogenesis requires precise timing and control. Agent-based modeling and simulation (ABMS) is an approach to virtually reconstruct these dynamics, cell-by-cell and interaction-by-interaction. Using ABMS, HTS lesions from ToxCast can be integrated with patterning systems heuristically to propagate key events This presentation to FDA-CFSAN will update progress on the applications of in silico modeling tools and approaches for assessing developmental toxicity.

Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice.

PubMed

Ren, Zhen; Sahir, Nadia; Murakami, Shoko; Luellen, Beth A; Earnheart, John C; Lal, Rachnanjali; Kim, Ju Young; Song, Hongjun; Luscher, Bernhard

2015-01-01

Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2(+/-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2(+/-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2(+/-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2(+/-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

PubMed Central

Chen, Peng-Chieh; Wakimoto, Hiroko; Conner, David; Araki, Toshiyuki; Yuan, Tao; Roberts, Amy; Seidman, Christine E.; Bronson, Roderick; Neel, Benjamin G.; Seidman, Jonathan G.; Kucherlapati, Raju

2010-01-01

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%–15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS. PMID:21041952

Birth defects risk associated with maternal sport fish consumption: potential effect modification by sex of offspring.

PubMed

Mendola, Pauline; Robinson, Luther K; Buck, Germaine M; Druschel, Charlotte M; Fitzgerald, Edward F; Sever, Lowell E; Vena, John E

2005-02-01

Contaminated sport fish consumption may result in exposure to various reproductive and developmental toxicants, including pesticides and other suspected endocrine disruptors. We investigated the relation between maternal sport fish meals and risk of major birth defects among infants born to members of the New York State (NYS) Angler Cohort between 1986 and 1991 (n=2237 births). Birth defects (n=125 cases) were ascertained from both newborn medical records and the NYS Congenital Malformations Registry. For sport fish meals eaten during pregnancy, the odds ratio (OR) for all major malformations combined was slightly elevated for < or =1 meal/month (OR=1.26, 95% confidence interval (CI): 0.84, 1.89) and > or =2 meals/month (OR=1.51, CI=0.74, 3.09), with no meals during pregnancy as the reference category. Higher ORs were consistently observed among male offspring compared with females. For > or =2 meals/month, the risk for males was significantly elevated (males: OR=3.01, CI: 1.2, 7.5; females: OR=0.73, CI: 0.2, 2.4). Exposure during pregnancy and effect modification by infants sex could be important considerations for future studies of birth outcomes associated with endocrine disruptors.

Endochondral Priming: A Developmental Engineering Strategy for Bone Tissue Regeneration.

PubMed

Freeman, Fiona E; McNamara, Laoise M

2017-04-01

Tissue engineering and regenerative medicine have significant potential to treat bone pathologies by exploiting the capacity for bone progenitors to grow and produce tissue constituents under specific biochemical and physical conditions. However, conventional tissue engineering approaches, which combine stem cells with biomaterial scaffolds, are limited as the constructs often degrade, due to a lack of vascularization, and lack the mechanical integrity to fulfill load bearing functions, and as such are not yet widely used for clinical treatment of large bone defects. Recent studies have proposed that in vitro tissue engineering approaches should strive to simulate in vivo bone developmental processes and, thereby, imitate natural factors governing cell differentiation and matrix production, following the paradigm recently defined as "developmental engineering." Although developmental engineering strategies have been recently developed that mimic specific aspects of the endochondral ossification bone formation process, these findings are not widely understood. Moreover, a critical comparison of these approaches to standard biomaterial-based bone tissue engineering has not yet been undertaken. For that reason, this article presents noteworthy experimental findings from researchers focusing on developing an endochondral-based developmental engineering strategy for bone tissue regeneration. These studies have established that in vitro approaches, which mimic certain aspects of the endochondral ossification process, namely the formation of the cartilage template and the vascularization of the cartilage template, can promote mineralization and vascularization to a certain extent both in vitro and in vivo. Finally, this article outlines specific experimental challenges that must be overcome to further exploit the biology of endochondral ossification and provide a tissue engineering construct for clinical treatment of large bone/nonunion defects and obviate the need for bone tissue graft.

Identification of a Recurrent Microdeletion at 17q23.1q23.2 Flanked by Segmental Duplications Associated with Heart Defects and Limb Abnormalities

PubMed Central

Ballif, Blake C.; Theisen, Aaron; Rosenfeld, Jill A.; Traylor, Ryan N.; Gastier-Foster, Julie; Thrush, Devon Lamb; Astbury, Caroline; Bartholomew, Dennis; McBride, Kim L.; Pyatt, Robert E.; Shane, Kate; Smith, Wendy E.; Banks, Valerie; Gallentine, William B.; Brock, Pamela; Rudd, M. Katharine; Adam, Margaret P.; Keene, Julia A.; Phillips, John A.; Pfotenhauer, Jean P.; Gowans, Gordon C.; Stankiewicz, Pawel; Bejjani, Bassem A.; Shaffer, Lisa G.

2010-01-01

Segmental duplications, which comprise ∼5%–10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are ∼2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is ∼2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome. PMID:20206336

The developmental outcomes of P0-mediated ARGONAUTE destabilization in tomato.

PubMed

Hendelman, Anat; Kravchik, Michael; Stav, Ran; Zik, Moriyah; Lugassi, Nitsan; Arazi, Tzahi

2013-01-01

The plant protein ARGONAUTE1 (AGO1) functions in multiple RNA-silencing pathways, including those of microRNAs, key regulators of growth and development. Genetic analysis of ago1 mutants with informative defects has provided valuable insights into AGO1's biological functions. Tomato encodes two AGO1 homologs (SlAGO1s), but mutants have not been described to date. To analyze SlAGO1s' involvement in development, we confirmed that both undergo decay in the presence of the Polerovirus silencing suppressor P0 and produce a transgenic responder line (OP:P0HA) that, upon transactivation, expresses P0 C-terminally fused to a hemagglutinin (HA) tag (P0HA) and destabilizes SlAGO1s at the site of expression. By crossing OP:P0HA with a battery of driver lines, constitutive as well as organ- and stage-specific SlAGO1 downregulation was induced in the F1 progeny. Activated plants exhibited various developmental phenotypes that partially overlapped with those of Arabidopsis ago1 mutants. Plants that constitutively expressed P0HA had reduced SlAGO1 levels and increased accumulation of miRNA targets, indicating compromised SlAGO1-mediated silencing. Consistent with this, they exhibited pleiotropic morphological defects and their growth was arrested post-germination. Transactivation of P0HA in young leaf and floral organ primordia dramatically modified corresponding organ morphology, including the radialization of leaflets, petals and anthers, suggesting that SlAGO1s' activities are required for normal lateral organ development and polarity. Overall, our results suggest that the OP:P0HA responder line can serve as a valuable tool to suppress SlAGO1 silencing pathways in tomato. The suppression of additional SlAGOs by P0HA and its contribution to the observed phenotypes awaits investigation.

A Large-Scale Genetic Screen in Arabidopsis to Identify Genes Involved in Pollen Exine Production1[C][W][OA

PubMed Central

Dobritsa, Anna A.; Geanconteri, Aliza; Shrestha, Jay; Carlson, Ann; Kooyers, Nicholas; Coerper, Daniel; Urbanczyk-Wochniak, Ewa; Bench, Bennie J.; Sumner, Lloyd W.; Swanson, Robert; Preuss, Daphne

2011-01-01

Exine, the outer plant pollen wall, has elaborate species-specific patterns, provides a protective barrier for male gametophytes, and serves as a mediator of strong and species-specific pollen-stigma adhesion. Exine is made of sporopollenin, a material remarkable for its strength, elasticity, and chemical durability. The chemical nature of sporopollenin, as well as the developmental mechanisms that govern its assembly into diverse patterns in different species, are poorly understood. Here, we describe a simple yet effective genetic screen in Arabidopsis (Arabidopsis thaliana) that was undertaken to advance our understanding of sporopollenin synthesis and exine assembly. This screen led to the recovery of mutants with a variety of defects in exine structure, including multiple mutants with novel phenotypes. Fifty-six mutants were selected for further characterization and are reported here. In 14 cases, we have mapped defects to specific genes, including four with previously demonstrated or suggested roles in exine development (MALE STERILITY2, CYP703A2, ANTHER-SPECIFIC PROTEIN6, TETRAKETIDE α-PYRONE REDUCTASE/DIHYDROFLAVONOL-4-REDUCTASE-LIKE1), and a number of genes that have not been implicated in exine production prior to this screen (among them, fatty acid ω-hydroxylase CYP704B1, putative glycosyl transferases At1g27600 and At1g33430, 4-coumarate-coenzyme A ligase 4CL3, polygalacturonase QUARTET3, novel gene At5g58100, and nucleotide-sugar transporter At5g65000). Our study illustrates that morphological screens of pollen can be extremely fruitful in identifying previously unknown exine genes and lays the foundation for biochemical, developmental, and evolutionary studies of exine production. PMID:21849515

Reciprocal expression of integration host factor and HU in the developmental cycle and infectivity of Legionella pneumophila.

PubMed

Morash, Michael G; Brassinga, Ann Karen C; Warthan, Michelle; Gourabathini, Poornima; Garduño, Rafael A; Goodman, Steven D; Hoffman, Paul S

2009-04-01

Legionella pneumophila is an intracellular parasite of protozoa that differentiates late in infection into metabolically dormant cysts that are highly infectious. Regulation of this process is poorly understood. Here we report that the small DNA binding regulatory proteins integration host factor (IHF) and HU are reciprocally expressed over the developmental cycle, with HU expressed during exponential phase and IHF expressed postexponentially. To assess the role of these regulatory proteins in development, chromosomal deletions were constructed. Single (ihfA or ihfB) and double deletion (Deltaihf) IHF mutants failed to grow in Acanthamoeba castellanii unless complemented in trans when expressed temporally from the ihfA promoter but not under P(tac) (isopropyl-beta-d-thiogalactopyranoside). In contrast, IHF mutants were infectious for HeLa cells, though electron microscopic examination revealed defects in late-stage cyst morphogenesis (thickened cell wall, intracytoplasmic membranes, and inclusions of poly-beta-hydroxybutyrate), and were depressed for the developmental marker MagA. Green fluorescent protein promoter fusion assays indicated that IHF and the stationary-phase sigma factor RpoS were required for full postexponential expression of magA. Finally, defects in cyst morphogenesis noted for Deltaihf mutants in HeLa cells correlated with a loss of both detergent resistance and hyperinfectivity compared with results for wild-type cysts. These studies establish IHF and HU as markers of developmental stages and show that IHF function is required for both differentiation and full virulence of L. pneumophila in natural amoebic hosts.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF ARSENIC IN RODENTS: A REVIEW

EPA Science Inventory

Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal...

Computational Modeling and Simulation of Genital Tubercle Development

EPA Science Inventory

Hypospadias is a developmental defect of urethral tube closure that has a complex etiology. Here, we describe a multicellular agent-based model of genital tubercle development that simulates urethrogenesis from the urethral plate stage to urethral tube closure in differentiating ...

NEOCORTICAL HYPERTROPHY FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM IN RATS

EPA Science Inventory

Thyroid hormones (TH) are essential to the normal development of the brain. Although severe congenital hypothyroidism has long been associated with mental retardation and motor defects, it has only recently been established that even subtle decreases in maternal TH alter fetal br...

Response to "The Many Faces of Dyslexia."

ERIC Educational Resources Information Center

Galaburda, Albert M.

1986-01-01

In response to M. Rawson's paper, the author uses an analogy with coronary artery disease to show that current brain research is not entirely at odds with the position that dyslexia may be a developmental variation, rather than a defect. (Author/DB)

Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis

PubMed Central

Xuan, Shouhong; Borok, Matthew J.; Decker, Kimberly J.; Battle, Michele A.; Duncan, Stephen A.; Hale, Michael A.; Macdonald, Raymond J.; Sussel, Lori

2012-01-01

Pancreatic agenesis is a human disorder caused by defects in pancreas development. To date, only a few genes have been linked to pancreatic agenesis in humans, with mutations in pancreatic and duodenal homeobox 1 (PDX1) and pancreas-specific transcription factor 1a (PTF1A) reported in only 5 families with described cases. Recently, mutations in GATA6 have been identified in a large percentage of human cases, and a GATA4 mutant allele has been implicated in a single case. In the mouse, Gata4 and Gata6 are expressed in several endoderm-derived tissues, including the pancreas. To analyze the functions of GATA4 and/or GATA6 during mouse pancreatic development, we generated pancreas-specific deletions of Gata4 and Gata6. Surprisingly, loss of either Gata4 or Gata6 in the pancreas resulted in only mild pancreatic defects, which resolved postnatally. However, simultaneous deletion of both Gata4 and Gata6 in the pancreas caused severe pancreatic agenesis due to disruption of pancreatic progenitor cell proliferation, defects in branching morphogenesis, and a subsequent failure to induce the differentiation of progenitor cells expressing carboxypeptidase A1 (CPA1) and neurogenin 3 (NEUROG3). These studies address the conserved and nonconserved mechanisms underlying GATA4 and GATA6 function during pancreas development and provide a new mouse model to characterize the underlying developmental defects associated with pancreatic agenesis. PMID:23006325

High Throughput Sequencing Identifies Misregulated Genes in the Drosophila Polypyrimidine Tract-Binding Protein (hephaestus) Mutant Defective in Spermatogenesis.

PubMed

Sridharan, Vinod; Heimiller, Joseph; Robida, Mark D; Singh, Ravinder

2016-01-01

The Drosophila polypyrimidine tract-binding protein (dmPTB or hephaestus) plays an important role during spermatogenesis. The heph2 mutation in this gene results in a specific defect in spermatogenesis, causing aberrant spermatid individualization and male sterility. However, the array of molecular defects in the mutant remains uncharacterized. Using an unbiased high throughput sequencing approach, we have identified transcripts that are misregulated in this mutant. Aberrant transcripts show altered expression levels, exon skipping, and alternative 5' ends. We independently verified these findings by reverse-transcription and polymerase chain reaction (RT-PCR) analysis. Our analysis shows misregulation of transcripts that have been connected to spermatogenesis, including components of the actomyosin cytoskeletal apparatus. We show, for example, that the Myosin light chain 1 (Mlc1) transcript is aberrantly spliced. Furthermore, bioinformatics analysis reveals that Mlc1 contains a high affinity binding site(s) for dmPTB and that the site is conserved in many Drosophila species. We discuss that Mlc1 and other components of the actomyosin cytoskeletal apparatus offer important molecular links between the loss of dmPTB function and the observed developmental defect in spermatogenesis. This study provides the first comprehensive list of genes misregulated in vivo in the heph2 mutant in Drosophila and offers insight into the role of dmPTB during spermatogenesis.

Differential expression and molecular characterisation of Lmo7, Myo1e, Sash1, and Mcoln2 genes in Btk-defective B-cells.

PubMed

Lindvall, Jessica M; Blomberg, K Emelie M; Wennborg, Anders; Smith, C I Edvard

2005-05-01

Bruton's tyrosine kinase is crucial for B-lymphocyte development. By the use of gene expression profiling, we have identified four expressed sequence tags among 38 potential Btk target genes, which have now been characterised. Bioinformatics tools including data mining of additional unpublished gene expression profiles, sequence verification of PCR products and qualitative RT-PCR were used. Stimulations targeting the B-cell receptor and the protein kinase C were used to activate whole B-cell splenocytes. Target genes were characterised as Lim domain only 7 (Lmo7); Myosin1e (Myo1e); SAM and SH3 domain containing 1 (Sash1); and Mucolipin2 (Mcoln2). Expression was found in cell lines of different origin and developmental stages as well as in whole B-cell splenocytes and Transitional type 1 (T1) splenic B-cells from wild type and Btk-defective mice, respectively. By the use of semi-quantitative RT-PCR we found Sash1 not to be expressed in the investigated haematopoietic cell lines, while transcripts were found in whole splenic B-cells from both wild type and Btk-defective mice, whereas Lmo7, Myo1e, and Mcoln2 were expressed in both B-cell lines and primary B-lymphocytes. Except for Lmo7, the transcript level was similarly affected by stimulation in control and Btk-defective cells.

Identification and Characterization of Genes Required for Early Myxococcus xanthus Developmental Gene Expression

PubMed Central

Guo, Dongchuan; Wu, Yun; Kaplan, Heidi B.

2000-01-01

Starvation and cell density regulate the developmental expression of Myxococcus xanthus gene 4521. Three classes of mutants allow expression of this developmental gene during growth on nutrient agar, such that colonies of strains containing a Tn5 lac Ω4521 fusion are Lac+. One class of these mutants inactivates SasN, a negative regulator of 4521 expression; another class activates SasS, a sensor kinase-positive regulator of 4521 expression; and a third class blocks lipopolysaccharide (LPS) O-antigen biosynthesis. To identify additional positive regulators of 4521 expression, 11 Lac− TnV.AS transposon insertion mutants were isolated from a screen of 18,000 Lac+ LPS O-antigen mutants containing Tn5 lac Ω4521 (Tcr). Ten mutations identified genes that could encode positive regulators of 4521 developmental expression based on their ability to abolish 4521 expression during development in the absence of LPS O antigen and in an otherwise wild-type background. Eight of these mutations mapped to the sasB locus, which encodes the known 4521 regulators SasS and SasN. One mapped to sasS, whereas seven identified new genes. Three mutations mapped to a gene encoding an NtrC-like response regulator homologue, designated sasR, and four others mapped to a gene designated sasP. One mutation, designated ssp10, specifically suppressed the LPS O-antigen defect; the ssp10 mutation had no effect on 4521 expression in an otherwise wild-type background but reduced 4521 developmental expression in the absence of LPS O antigen to a level close to that of the parent strain. All of the mutations except those in sasP conferred defects during growth and development. These data indicate that a number of elements are required for 4521 developmental expression and that most of these are necessary for normal growth and fruiting body development. PMID:10913090

Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products

PubMed Central

England, Lucinda J.; Aagaard, Kjersti; Bloch, Michele; Conway, Kevin; Cosgrove, Kelly; Grana, Rachel; Gould, Thomas J.; Hatsukami, Dorothy; Jensen, Frances; Kandel, Denise; Lanphear, Bruce; Leslie, Frances; Pauly, James R.; Neiderhiser, Jenae; Rubinstein, Mark; Slotkin, Theodore A.; Spindel, Eliot; Stroud, Laura; Wakschlag, Lauren

2018-01-01

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure. PMID:27890689

The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

PubMed Central

Barry, William E; Thummel, Carl S

2016-01-01

Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal. DOI: http://dx.doi.org/10.7554/eLife.11183.001 PMID:27185732

Eye-Specific Gene Expression following Embryonic Ethanol Exposure in Zebrafish: Roles for Heat Shock Factor 1

PubMed Central

Kashyap, Bhavani; Pegorsch, Laurel; Frey, Ruth A.; Sun, Chi; Shelden, Eric A.; Stenkamp, Deborah L.

2014-01-01

The mechanisms through which ethanol exposure results in developmental defects remain unclear. We used the zebrafish model to elucidate eye-specific mechanisms that underlie ethanol-mediated microphthalmia (reduced eye size), through time-series microarray analysis of gene expression within eyes of embryos exposed to 1.5% ethanol. 62 genes were differentially expressed (DE) in ethanol-treated as compared to control eyes sampled during retinal neurogenesis (24-48 hours post-fertilization). The EDGE (extraction of differential gene expression) algorithm identified >3000 genes DE over developmental time in ethanol-exposed eyes as compared to controls. The DE lists included several genes indicating a mis-regulated cellular stress response due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino targeting heat shock factor 1 mRNA resulted in microphthalmia, suggesting convergent molecular pathways. Thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. These data suggest roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure. PMID:24355176

A Neutralizing Anti-gH/gL Monoclonal Antibody Is Protective in the Guinea Pig Model of Congenital CMV Infection

PubMed Central

Auerbach, Marcy R.; Yan, Donghong; Vij, Rajesh; Hongo, Jo-Anne; Nakamura, Gerald; Vernes, Jean-Michel; Meng, Y. Gloria; Lein, Samantha; Chan, Pamela; Ross, Jed; Carano, Richard; Deng, Rong; Lewin-Koh, Nicholas; Xu, Min; Feierbach, Becket

2014-01-01

Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection. Congenital HCMV infection occurs in 0.2–1% of all births, and causes birth defects and developmental abnormalities, including sensorineural hearing loss and developmental delay. Several key studies have established the guinea pig as a tractable model for the study of congenital HCMV infection and have shown that polyclonal antibodies can be protective [1]–[3]. In this study, we demonstrate that an anti-guinea pig CMV (GPCMV) glycoprotein H/glycoprotein L neutralizing monoclonal antibody protects against fetal infection and loss in the guinea pig. Furthermore, we have delineated the kinetics of GPCMV congenital infection, from maternal infection (salivary glands, seroconversion, placenta) to fetal infection (fetus and amniotic fluid). Our studies support the hypothesis that a neutralizing monoclonal antibody targeting an envelope GPCMV glycoprotein can protect the fetus from infection and may shed light on the therapeutic intervention of HCMV congenital infection in humans. PMID:24722349

Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products.

PubMed

England, Lucinda J; Aagaard, Kjersti; Bloch, Michele; Conway, Kevin; Cosgrove, Kelly; Grana, Rachel; Gould, Thomas J; Hatsukami, Dorothy; Jensen, Frances; Kandel, Denise; Lanphear, Bruce; Leslie, Frances; Pauly, James R; Neiderhiser, Jenae; Rubinstein, Mark; Slotkin, Theodore A; Spindel, Eliot; Stroud, Laura; Wakschlag, Lauren

2017-01-01

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure. Published by Elsevier Ltd.

Emplotting children's lives: developmental delay vs. disability.

PubMed

Landsman, Gail

2003-05-01

While it is increasingly possible to envision "perfect" babies, it is not always the case that reproduction actually proceeds according to individual will; for example, there has been no recent reduction in rates of childhood disability. Nevertheless, in most studies of new reproductive technologies, the birth of those children whom few would actively choose-"defective" or disabled infants-is presented only in hypothetical terms. This paper argues for expanding the domain of reproduction to include research on the parenting of children with disabilities. Based on a qualitative research project carried out at a hospital-based newborn follow-up program that serves as an evaluation site determining eligibility for early intervention services for infants and young children with disabilities, this paper focuses on a particular part of women's experience of acquiring new knowledge about personhood and disability, that is, on the period of time when a woman has recently had confirmed that reproduction has, in her case, gone awry. Disability in many cultures, including the United States, diminishes personhood. I suggest that American mothers' narratives, by utilizing the concept of developmental delay, can assert personhood, or rather, the potential for its future attainment; in doing so, they justify ongoing nurturance of a disabled child in spite of negative attitudes about disability. A particular case of one mother's emplotment of her child's life within a story of developmental delay, in competition with the physician's story of disability, is analyzed. The paper concludes with reflections on how stories of developmental delay told by mothers just encountering a diagnosis of disability may differ from the stories told by those who have experienced mothering a disabled child over time, and on the implications of these differences for the cultural construction of personhood in the United States.

Dual Functional Roles of Molecular Beacon as a MicroRNA Detector and Inhibitor*

PubMed Central

Li, Wai Ming; Chan, Ching-Man; Miller, Andrew L.; Lee, Chow H.

2017-01-01

MicroRNAs are essential in many cellular processes. The ability to detect microRNAs is important for understanding its function and biogenesis. This study is aimed at using a molecular beacon to detect miR-430 in developing zebrafish embryos as a proof of principle. miR-430 is crucial for the clearance of maternal mRNA during maternal zygotic transition in embryonic development. Despite its known function, the temporal and spatial expression of miR-430 remains unclear. We used various imaging techniques, including laser scanning confocal microscopy, spinning disk, and lightsheet microscopy, to study the localization of miR-430 and any developmental defects possibly caused by the molecular beacon. Our results show that miR-430 is expressed early in development and is localized in distinct cytoplasmic granules where its target mRNA can be detected. We also show that the designed molecular beacon can inhibit the function of miR-430 and cause developmental defect in the brain, notochord, heart, and kidney, depending on the delivery site within the embryo, suggesting that miR-430 plays a diverse role in embryonic morphogenesis. When compared with morpholino, molecular beacon is 2 orders of magnitude more potent in inhibiting miR-430. Thus, our results reveal that in addition to being used as a valuable tool for the detection of microRNAs in vivo, molecular beacons can also be employed to inhibit microRNAs in a specific manner. PMID:28100783

Regulation of spindle integrity and mitotic fidelity by BCCIP

PubMed Central

Huhn, S C; Liu, J; Ye, C; Lu, H; Jiang, X; Feng, X; Ganesan, S; White, E; Shen, Z

2017-01-01

Centrosomes together with the mitotic spindle ensure the faithful distribution of chromosomes between daughter cells, and spindle orientation is a major determinant of cell fate during tissue regeneration. Spindle defects are not only an impetus of chromosome instability but are also a cause of developmental disorders involving defective asymmetric cell division. In this work, we demonstrate BCCIP, especially BCCIPα, as a previously unidentified component of the mitotic spindle pole and the centrosome. We demonstrate that BCCIP localizes proximal to the mother centriole and participates in microtubule organization and then redistributes to the spindle pole to ensure faithful spindle architecture. We find that BCCIP depletion leads to morphological defects, disoriented mitotic spindles, chromosome congression defects and delayed mitotic progression. Our study identifies BCCIP as a novel factor critical for microtubule regulation and explicates a mechanism utilized by BCCIP in tumor suppression. PMID:28394342

78 FR 14553 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-06

...; deep vein thrombosis/pulmonary embolism (DVT/PE); sickle cell disease (SCD); attention-deficit/hyperactivity disorder (ADHD); and Tourette syndrome. The Children's Health Act of 2000 required the... Defects and Developmental Disabilities, Human Development and Disabilities, and Blood Disorders--NEW...

FOLATE AND HUMAN DEVELOPMENT: PREFACE

EPA Science Inventory

Neural tube defects (NTDs) are a complex developmental trait in which several genes, interacting with environmental factors, create the phenotype. In the United States, the rate of NTDs has been reported to range from 4 to 10 per 10,000 live births, and NTDs affect approximately...

20180312 - Mechanistic Modeling of Developmental Defects through Computational Embryology (SOT)

EPA Science Inventory

Significant advances in the genome sciences, in automated high-throughput screening (HTS), and in alternative methods for testing enable rapid profiling of chemical libraries for quantitative effects on diverse cellular activities. While a surfeit of HTS data and information is n...

Adverse Outcome Pathway (AOP) framework for embryonic vascular disruption and developmental defects (SOT)

EPA Science Inventory

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signal...

Global developmental delay in guanidionacetate methyltransferase deficiency: differences in formal testing and clinical observation.

PubMed

Verbruggen, Krijn T; Knijff, Wilma A; Soorani-Lunsing, Roelineke J; Sijens, Paul E; Verhoeven, Nanda M; Salomons, Gajja S; Goorhuis-Brouwer, Siena M; van Spronsen, Francjan J

2007-09-01

Guanidinoacetate N-methyltransferase (GAMT) deficiency is a defect in the biosynthesis of creatine (Cr). So far, reports have not focused on the description of developmental abilities in this disorder. Here, we present the result of formal testing of developmental abilities in a GAMT-deficient patient. Our patient, a 3-year-old boy with GAMT deficiency, presented clinically with a severe language production delay and nearly normal nonverbal development. Treatment with oral Cr supplementation led to partial restoration of the cerebral Cr concentration and a clinically remarkable acceleration of language production development. In contrast to clinical observation, formal testing showed a rather harmonic developmental delay before therapy and a general improvement, but no specific acceleration of language development after therapy. From our case, we conclude that in GAMT deficiency language delay is not always more prominent than delays in other developmental areas. The discrepancy between the clinical impression and formal testing underscores the importance of applying standardized tests in children with developmental delays. Screening for Cr deficiency by metabolite analysis of body fluids or proton magnetic resonance spectroscopy of the brain deficiency should be considered in any child with global developmental delay/mental retardation lacking clues for an alternative etiology.

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

PubMed Central

Quétier, Ivan; Marshall, Jacqueline J.T.; Spencer-Dene, Bradley; Lachmann, Sylvie; Casamassima, Adele; Franco, Claudio; Escuin, Sarah; Worrall, Joseph T.; Baskaran, Priththivika; Rajeeve, Vinothini; Howell, Michael; Copp, Andrew J.; Stamp, Gordon; Rosewell, Ian; Cutillas, Pedro; Gerhardt, Holger; Parker, Peter J.; Cameron, Angus J.M.

2016-01-01

Summary In animals, the protein kinase C (PKC) family has expanded into diversely regulated subgroups, including the Rho family-responsive PKN kinases. Here, we describe knockouts of all three mouse PKN isoforms and reveal that PKN2 loss results in lethality at embryonic day 10 (E10), with associated cardiovascular and morphogenetic defects. The cardiovascular phenotype was not recapitulated by conditional deletion of PKN2 in endothelial cells or the developing heart. In contrast, inducible systemic deletion of PKN2 after E7 provoked collapse of the embryonic mesoderm. Furthermore, mouse embryonic fibroblasts, which arise from the embryonic mesoderm, depend on PKN2 for proliferation and motility. These cellular defects are reflected in vivo as dependence on PKN2 for mesoderm proliferation and neural crest migration. We conclude that failure of the mesoderm to expand in the absence of PKN2 compromises cardiovascular integrity and development, resulting in lethality. PMID:26774483

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion.

PubMed

Quétier, Ivan; Marshall, Jacqueline J T; Spencer-Dene, Bradley; Lachmann, Sylvie; Casamassima, Adele; Franco, Claudio; Escuin, Sarah; Worrall, Joseph T; Baskaran, Priththivika; Rajeeve, Vinothini; Howell, Michael; Copp, Andrew J; Stamp, Gordon; Rosewell, Ian; Cutillas, Pedro; Gerhardt, Holger; Parker, Peter J; Cameron, Angus J M

2016-01-26

In animals, the protein kinase C (PKC) family has expanded into diversely regulated subgroups, including the Rho family-responsive PKN kinases. Here, we describe knockouts of all three mouse PKN isoforms and reveal that PKN2 loss results in lethality at embryonic day 10 (E10), with associated cardiovascular and morphogenetic defects. The cardiovascular phenotype was not recapitulated by conditional deletion of PKN2 in endothelial cells or the developing heart. In contrast, inducible systemic deletion of PKN2 after E7 provoked collapse of the embryonic mesoderm. Furthermore, mouse embryonic fibroblasts, which arise from the embryonic mesoderm, depend on PKN2 for proliferation and motility. These cellular defects are reflected in vivo as dependence on PKN2 for mesoderm proliferation and neural crest migration. We conclude that failure of the mesoderm to expand in the absence of PKN2 compromises cardiovascular integrity and development, resulting in lethality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Novel degenerative and developmental defects in a zebrafish model of mucolipidosis type IV

PubMed Central

Li, Huiqing; Pei, Wuhong; Vergarajauregui, Sivia; Zerfas, Patricia M.; Raben, Nina; Burgess, Shawn M.; Puertollano, Rosa

2017-01-01

Abstract Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family. In this study, we used genome editing to knockout the two mcoln1 genes present in Danio rerio (zebrafish). Our model successfully reproduced the retinal and neuromuscular defects observed in MLIV patients, indicating that this model is suitable for studying the disease pathogenesis. Importantly, our model revealed novel insights into the origins and progression of the MLIV pathology, including the contribution of autophagosome accumulation to muscle dystrophy and the role of mcoln1 in embryonic development, hair cell viability and cellular maintenance. The generation of a MLIV model in zebrafish is particularly relevant given the suitability of this organism for large-scale in vivo drug screening, thus providing unprecedented opportunities for therapeutic discovery. PMID:28449103

Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindsay, E.A.; Halford, S.; Wadey, R.

1993-08-01

DiGeorge syndrome (DGS) is a developmental defect characterized by cardiac defects, facial dysmorphism, and mental retardation. Several studies have described a critical region for DGS at 22q11, within which the majority of DGS patients have deletions. The authors have isolated nine cosmid and three YAC clones using previously described and newly isolated probes that have been shown to be deleted in many DGS patients. Using fluorescence in situ hybridization and digital imaging, they have mapped and ordered these clones relative to the breakpoints of two balanced translocations at 22q11 (one in a DGS patient and one in the unaffected parentmore » of a DGS child). The data indicate that the breakpoint in the unaffected individual distally limits the DGS critical region (defined as the smallest region of overlap), while proximally the region is limited by repeat-rich DNA. The critical region includes the balanced translocation breakpoint of the DGS patient that presumably disrupts the gene causing this syndrome.« less

Theoretical aspects of autism: causes--a review.

PubMed

Ratajczak, Helen V

2011-01-01

Autism, a member of the pervasive developmental disorders (PDDs), has been increasing dramatically since its description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per 10,000 children, the incidence of autism is now 1 per 110 in the United States, and 1 per 64 in the United Kingdom, with similar incidences throughout the world. Searching information from 1943 to the present in PubMed and Ovid Medline databases, this review summarizes results that correlate the timing of changes in incidence with environmental changes. Autism could result from more than one cause, with different manifestations in different individuals that share common symptoms. Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination. Therefore, autism is the result of genetic defects and/or inflammation of the brain. The inflammation could be caused by a defective placenta, immature blood-brain barrier, the immune response of the mother to infection while pregnant, a premature birth, encephalitis in the child after birth, or a toxic environment.

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

PubMed Central

He, Miao; Kratz, Lisa E.; Michel, Joshua J.; Vallejo, Abbe N.; Ferris, Laura; Kelley, Richard I.; Hoover, Jacqueline J.; Jukic, Drazen; Gibson, K. Michael; Wolfe, Lynne A.; Ramachandran, Dhanya; Zwick, Michael E.; Vockley, Jerry

2011-01-01

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β (LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. PMID:21285510

Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability

PubMed Central

Gresser, Amy L.; Gutzwiller, Lisa M.; Gauck, Mackenzie K.; Hartenstein, Volker; Cook, Tiffany A.; Gebelein, Brian

2015-01-01

Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability. PMID:26252385

The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks.

PubMed

Briand, Nolwenn; Guénantin, Anne-Claire; Jeziorowska, Dorota; Shah, Akshay; Mantecon, Matthieu; Capel, Emilie; Garcia, Marie; Oldenburg, Anja; Paulsen, Jonas; Hulot, Jean-Sebastien; Vigouroux, Corinne; Collas, Philippe

2018-04-15

The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482W-associated FPLD2. Correction of the LMNA mutation ameliorates R482W-associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex 2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multi-tissue pathogenic phenotypes.

Rapamycin treatment causes developmental delay, pigmentation defects, and gastrointestinal malformation on Xenopus embryogenesis.

PubMed

Moriyama, Yuki; Ohata, Yoshihisa; Mori, Shoko; Matsukawa, Shinya; Michiue, Tatsuo; Asashima, Makoto; Kuroda, Hiroki

2011-01-28

Rapamycin is a drug working as an inhibitor of the TOR (target of rapamycin) signaling pathway and influences various life phenomena such as cell growth, proliferation, and life span extension in eukaryote. However, the extent to which rapamycin controls early developmental events of amphibians remains to be understood. Here we report an examination of rapamycin effects during Xenopus early development, followed by a confirmation of suppression of TOR downstream kinase S6K by rapamycin treatment. First, we found that developmental speed was declined in dose-dependent manner of rapamycin. Second, black pigment spots located at dorsal and lateral skin in tadpoles were reduced by rapamycin treatment. Moreover, in tadpole stages severe gastrointestinal malformations were observed in rapamycin-treated embryos. Taken together with these results, we conclude that treatment of the drug rapamycin causes enormous influences on early developmental period. Copyright © 2010 Elsevier Inc. All rights reserved.

mRNA localization: an orchestration of assembly, traffic and synthesis.

PubMed

Xing, Lei; Bassell, Gary J

2013-01-01

Asymmetrical mRNA localization and subsequent local translation provide efficient mechanisms for protein sorting in polarized cells. Defects in mRNA localization have been linked to developmental abnormalities and neurological diseases. Thus, it is critical to understand the machineries mediating and mechanisms underlying the asymmetrical distribution of mRNA and its regulation. The goal of this review is to summarize recent advances in the understanding of mRNA transport and localization, including the assembly and sorting of transport messenger ribonucleic protein (mRNP) granules, molecular mechanisms of active mRNP transport, cytoskeletal interactions and regulation of these events by extracellular signals. © 2012 John Wiley & Sons A/S.

Novel case of paternal paracentric inversion causing partial trisomy 13 and review of the literature.

PubMed

Douglas, Chad; Smith, Stephen A; Rohena, Luis

2017-06-01

Partial trisomies have often been reported secondary to inversion mutations. These occurrences are most frequently associated with pericentric inversions. In this report, we describe the first documented case of partial trisomy 13 secondary to a parental paracentric inversion, in this case a paternal paracentric 13q inversion. Our Patient exhibits a variety of clinical findings including global developmental delay with intellectual disability, sensorineural hearing loss, bilateral congenital polar cataracts with associated foveal and optic nerve hypoplasia, right retinal detachment, atrial septal defect, absence of corpus callosum, celiac disease, microcephaly, as well as other dysmorphic features. © 2017 Wiley Periodicals, Inc.

Dental Caries and Enamel Defects in Very Low Birth Weight Adolescents

PubMed Central

Nelson, S.; Albert, J.M.; Lombardi, G.; Wishnek, S.; Asaad, G.; Kirchner, H.L.; Singer, L.T.

2011-01-01

Objectives The purpose of this study was to examine developmental enamel defects and dental caries in very low birth weight adolescents with high risk (HR-VLBW) and low risk (LR-VLBW) compared to full-term (term) adolescents. Methods The sample consisted of 224 subjects (80 HR-VLBW, 59 LR-VLBW, 85 term adolescents) recruited from an ongoing longitudinal study. Sociodemographic and medical information was available from birth. Dental examination of the adolescent at the 14-year visit included: enamel defects (opacity and hypoplasia); decayed, missing, filled teeth of incisors and molars (DMFT-IM) and of overall permanent teeth (DMFT); Simplified Oral Hygiene Index for debris/calculus on teeth, and sealant presence. A caregiver questionnaire completed simultaneously assessed dental behavior, access, insurance status and prevention factors. Hierarchical analysis utilized the zero-inflated negative binomial model and zero-inflated Poisson model. Results The zero-inflated negative binomial model controlling for sociodemographic variables indicated that the LR-VLBW group had an estimated 75% increase (p < 0.05) in number of demarcated opacities in the incisors and first molar teeth compared to the term group. Hierarchical modeling indicated that demarcated opacities were a significant predictor of DMFT-IM after control for relevant covariates. The term adolescents had significantly increased DMFT-IM and DMFT scores compared to the LR-VLBW adolescents. Conclusion LR-VLBW was a significant risk factor for increased enamel defects in the permanent incisors and first molars. Term children had increased caries compared to the LR-VLBW group. The effect of birth group and enamel defects on caries has to be investigated longitudinally from birth. PMID:20975268

Overexpression of Buffy enhances the loss of parkin and suppresses the loss of Pink1 phenotypes in Drosophila.

PubMed

M'Angale, P Githure; Staveley, Brian E

2017-03-01

Mutations in parkin (PARK2) and Pink1 (PARK6) are responsible for autosomal recessive forms of early onset Parkinson's disease (PD). Attributed to the failure of neurons to clear dysfunctional mitochondria, loss of gene expression leads to loss of nigrostriatal neurons. The Pink1/parkin pathway plays a role in the quality control mechanism aimed at eliminating defective mitochondria, and the failure of this mechanism results in a reduced lifespan and impaired locomotor ability, among other phenotypes. Inhibition of parkin or Pink1 through the induction of stable RNAi transgene in the Ddc-Gal4-expressing neurons results in such phenotypes to model PD. To further evaluate the effects of the overexpression of the Bcl-2 homologue Buffy, we analysed lifespan and climbing ability in both parkin-RNAi- and Pink1-RNAi-expressing flies. In addition, the effect of Buffy overexpression upon parkin-induced developmental eye defects was examined through GMR-Gal4-dependent expression. Curiously, Buffy overexpression produced very different effects: the parkin-induced phenotypes were enhanced, whereas the Pink1-enhanced phenotypes were suppressed. Interestingly, the overexpression of Buffy along with the inhibition of parkin in the neuron-rich eye results in the suppression of the developmental eye defects.

Cadmium affects muscle type development and axon growth in zebrafish embryonic somitogenesis.

PubMed

Hen Chow, Elly Suk; Cheng, Shuk Han

2003-05-01

We have previously reported that exposure to cadmium during zebrafish embryonic development caused morphological malformations of organs and ectopic expression of genes involved in regulating developmental process. One of the most common developmental defects observed was altered axial curvature resulting from defects in the myotomes of the somites. In this study, we investigated the mechanisms of cadmium-induced toxicity in zebrafish somitogenesis. We showed that the critical period of exposure was the gastrulation period, which actually preceded the formation of the first morphologically distinct somites. The somites thus formed lost the typical chevron V-shape and are packed disorderly. The myogenic lineage commitment of the axial mesodermal cells was not affected, as the myogenic regulatory transcription factors were expressed normally. There were, however, losses of fast and slow muscle fibers in the myotomes. The innervation of the muscle blocks by spinal motoneurons is an important process of the somitogenesis. Both primary and secondary motoneurons appear to form normally while the axon growth is affected in cadmium-treated embryos. The notochord, which is essential in the patterning of the somites and the central nervous system, showed abnormal morphological features and failed to extend to the tail region. Taken together, it appears that cadmium exposure led to abnormal somite patterning of the muscle fibers and defects in axonogenesis.

Adverse morphological development in embryonic zebrafish exposed to environmental concentrations of contaminants individually and in mixture.

PubMed

Kinch, Cassandra D; Kurrasch, Deborah M; Habibi, Hamid R

2016-06-01

Exposure to environmental contaminants has been linked to developmental and reproductive abnormalities leading to infertility, spontaneous abortion, reduced number of offspring, and metabolic disorders. In addition, there is evidence linking environmental contaminants and endocrine disruption to abnormal developmental rate, defects in heart and eye morphology, and alterations in behavior. Notably, these effects could not be explained by interaction with a single hormone receptor. Here, using a whole-organism approach, we investigated morphological changes to developing zebrafish caused by exposure to a number of environmental contaminants, including bisphenol A (BPA), di(2-ethylhexyl)phthalate (DEHP), nonylphenol, and fucosterol at concentrations measured in a local water body (Oldman River, AB), individually and in mixture. Exposure to nanomolar contaminant concentrations resulted in abnormal morphological development, including changes to body length, pericardia (heart), and the head. We also characterize the spatiotemporal expression profiles of estrogen, androgen, and thyroid hormone receptors to demonstrate that localization of these receptors might be mediating contaminant effects on development. Finally, we examined the effects of contaminants singly and in mixture. Combined, our results support the hypothesis that adverse effects of contaminants are not mediated by single hormone receptor signaling, and adversity of contaminants in mixture could not be predicted by simple additive effect of contaminants. The findings provide a framework for better understanding of developmental toxicity of environmental contaminants in zebrafish and other vertebrate species. Copyright © 2016 Elsevier B.V. All rights reserved.

C. elegans sym-1 is a downstream target of the hunchback-like-1 developmental timing transcription factor

PubMed Central

Niwa, Ryusuke; Hada, Kazumasa; Moliyama, Kouichi; Ohniwa, Ryosuke L.; Tan, Yi-Meng; Olsson-Carter, Katherine; Chi, Woo; Reinke, Valerie; Slack, Frank J.

2010-01-01

In the nematode Caenorhabditis elegans, the let-7 microRNA (miRNA) and its family members control the timing of key developmental events in part by directly regulating expression of hunchback-like-1 (hbl-1). C. elegans hbl-1 mutants display multiple developmental timing deficiencies, including cell cycle defects during larval development. While hbl-1 is predicted to encode a transcriptional regulator, downstream targets of HBL-1 have not been fully elucidated. Here we report using microarray analysis to uncover genes downstream of HBL-1. We established a transgenic strain that overexpresses hbl-1 under the control of a heat shock promoter. Heat shock-induced hbl-1 overexpression led to retarded hypodermal structures at the adult stage, opposite to the effect seen in loss of function (lf) hbl-1 mutants. The microarray screen identified numerous potential genes that are upregulated or downregulated by HBL-1, including sym-1, which encodes a leucine-rich repeat protein with a signal sequence. We found an increase in sym-1 transcription in the heat shock-induced hbl-1 overexpression strain, while loss of hbl-1 function caused a decrease in sym-1 expression levels. Furthermore, we found that sym-1(lf) modified the hypodermal abnormalities in hbl-1 mutants. Given that SYM-1 is a protein secreted from hypodermal cells to the surrounding cuticle, we propose that the adult-specific cuticular structures may be under the temporal control of HBL-1 through regulation of sym-1 transcription. PMID:19923914

Computational Modeling and Simulation of Genital Tubercle Development

EPA Pesticide Factsheets

Hypospadias is a developmental defect of urethral tube closure that has a complex etiology involving genetic and environmental factors, including anti-androgenic and estrogenic disrupting chemicals; however, little is known about the morphoregulatory consequences of androgen/estrogen balance during genital tubercle (GT) development. Computer models that predictively model sexual dimorphism of the GT may provide a useful resource to translate chemical-target bipartite networks and their developmental consequences across the human-relevant chemical universe. Here, we describe a multicellular agent-based model of genital tubercle (GT) development that simulates urethrogenesis from the sexually-indifferent urethral plate stage to urethral tube closure. The prototype model, constructed in CompuCell3D, recapitulates key aspects of GT morphogenesis controlled by SHH, FGF10, and androgen pathways through modulation of stochastic cell behaviors, including differential adhesion, motility, proliferation, and apoptosis. Proper urethral tube closure in the model was shown to depend quantitatively on SHH- and FGF10-induced effects on mesenchymal proliferation and epithelial apoptosis??both ultimately linked to androgen signaling. In the absence of androgen, GT development was feminized and with partial androgen deficiency, the model resolved with incomplete urethral tube closure, thereby providing an in silico platform for probabilistic prediction of hypospadias risk across c

Vesicoureteral reflux and the extracellular matrix connection

PubMed Central

Tokhmafshan, Fatima; Brophy, Patrick D.; Gbadegesin, Rasheed A.

2017-01-01

Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes. PMID:27139901

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study

EPA Science Inventory

Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

Comprehensive Assessment of a Chlorinated Drinking Water Concentrate in a Rat Multigenerational Reproductive Toxicity Study##

EPA Science Inventory

Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

Educating Health Professionals about Fetal Alcohol Spectrum Disorders

ERIC Educational Resources Information Center

American Journal of Health Education, 2007

2007-01-01

Prenatal exposure to alcohol is a leading preventable cause of birth defects and developmental disabilities. Individuals exposed to alcohol during fetal development can have physical, mental, behavioral, and learning disabilities, with lifelong implications. These conditions are known as fetal alcohol spectrum disorders (FASDs). Health care…

Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses1

PubMed Central

Wu, Gregory F.; Corbo, Evann; Schmidt, Michelle; Smith-Garvin, Jennifer E.; Riese, Matthew J.; Jordan, Martha S.; Laufer, Terri M.; Brown, Eric J.; Maltzman, Jonathan S.

2011-01-01

SUMMARY The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of wild-type SLP-76 protein in thymocytes. Following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T cell mediated autoimmune disease experimental autoimmune encephalomyelitis. Our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects. PMID:21469089

Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1.

PubMed

Galeone, Antonio; Han, Seung Yeop; Huang, Chengcheng; Hosomi, Akira; Suzuki, Tadashi; Jafar-Nejad, Hamed

2017-08-04

Mutations in the human N- glycanase 1 ( NGLY1 ) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N -glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during Drosophila development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an N -glycanase enzyme.

Zebrafish embryo developmental toxicology assay.

PubMed

Panzica-Kelly, Julieta M; Zhang, Cindy X; Augustine-Rauch, Karen

2012-01-01

A promising in vitro zebrafish developmental toxicology assay was generated to test compounds for their teratogenic potential. The assay's predictivity is approximately 87% in AB strain fish (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010). The procedure entails exposing dechorionated gastrulation-stage embryos to a range of compound concentrations for 5 days throughout embryonic and larva development. The larvae are evaluated for viability in order to identify an LC25 (the compound concentration in which 25% lethality is observed) and morphological anomalies using a numerical score system to identify the NOAEL (no observed adverse effect level). These values are used to calculate the teratogenic index (LC25/NOAEL ratio) of each compound. If the teratogenic index is equal to or greater than 10 then the compound is classified as a teratogen, and if the ratio is less than 10 then the compound is classified as a nonteratogen (Brannen KC et al., Birth Defects Res B Dev Reprod Toxicol 89:66-77, 2010).

Mechanical analysis of a heat-shock induced developmental defect

NASA Astrophysics Data System (ADS)

Crews, Sarah M.; McCleery, W. Tyler; Hutson, M. Shane

2014-03-01

Embryonic development in Drosophila is a complex process involving coordinated movements of mechanically interacting tissues. Perturbing this system with a transient heat shock can result in a number of developmental defects. In particular, a heat shock applied during the earliest morphogenetic movements of gastrulation can lead to apparent recovery, but then subsequent morphogenetic failure 5-6 hours later during germ band retraction. The process of germ band retraction requires an intact amnioserosa - a single layered extra-embryonic epithelial tissue - and heat shock at gastrulation can induce the later opening of holes in the amnioserosa. These holes are highly correlated with failures of germ band retraction. These holes could be caused by a combination of mechanical weakness in the amnioserosa or local increases in mechanical stress. Here, we assess the role of mechanical stress using confocal imaging to compare cell and tissue morphology in the amnioserosa of normal and heat-shocked embryos and laser hole drilling to map the stress field around the times and locations at which heat-shock induced holes open.

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Part II: morphological analysis of embryonic development following femtosecond laser manipulation

NASA Astrophysics Data System (ADS)

Kohli, V.; Elezzabi, A. Y.

2008-02-01

The zebrafish (Danio rerio) is an attractive model system that has received wide attention for its usefulness in the study of development and disease. This organism represents a closer analog to humans than the common invetebrates Drosophila melanogaster and Caenorhabditis elegans, making this species an ideal model for human health research. Non-invasive manipulation of the zebrafish has been challenging, owing to the outer proteinaceous membrane and multiple embryonic barriers. A novel tool capable of manipulating early cleavage stage embryonic cells would be important for future advancements in medial research and the aquaculture industry. Herein, we demonstrate the laser surgery of early cleavage stage (2-cell) blastomere cells using a range of average laser powers and beam dwell times. Since the novelty of this manipulation tool depends on its non-invasive application, we examined short- and long-term laser-induced developmental defects following embryonic surgery. Laser-manipulated embryos were reared to 2 and 7 days post-fertilization and compared to control embryos at the same developmental stages. Morphological analysis was performed using light microscopy and scanning electron microscopy. Developmental features that were examined included the antero- and dorsal-lateral whole body views of the larvae, the olfactory pit, dorsal, ventral and pectoral fins, notochord, pectoral fin buds, otic capsule, otic vesicle, neuromast patterning, and kinocilia of the olfactory pit rim and cristae of the lateral wall of the ear. Laser-manipulated embryos developed normally relative to the controls, with developmental patterning and morphology at 2 and 7 days indistinguishable from control larvae.

High glucose alters the expression of genes involved in proliferation and cell-fate specification of embryonic neural stem cells.

PubMed

Fu, J; Tay, S S W; Ling, E A; Dheen, S T

2006-05-01

Maternal diabetes induces neural tube defects during embryogenesis. Since the neural tube is derived from neural stem cells (NSCs), it is hypothesised that in diabetic pregnancy neural tube defects result from altered expression of developmental control genes, leading to abnormal proliferation and cell-fate choice of NSCs. Cell viability, proliferation index and apoptosis of NSCs and differentiated cells from mice exposed to physiological or high glucose concentration medium were examined by a tetrazolium salt assay, 5-bromo-2'-deoxyuridine incorporation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and immunocytochemistry. Expression of developmental genes, including sonic hedgehog (Shh), bone morphogenetic protein 4 (Bmp4), neurogenin 1/2 (Neurog1/2), achaete-scute complex-like 1 (Ascl1), oligodendrocyte transcription factor 1 (Olig1), oligodendrocyte lineage transcription factor 2 (Olig2), hairy and enhancer of split 1/5 (Hes1/5) and delta-like 1 (Dll1), was analysed by real-time RT-PCR. Proliferation index and neuronal specification in the forebrain of embryos at embryonic day 11.5 were examined histologically. High glucose decreased the proliferation of NSCs and differentiated cells. The incidence of apoptosis was increased in NSCs treated with high glucose, but not in the differentiated cells. High glucose also accelerated neuronal and glial differentiation from NSCs. The decreased proliferation index and early differentiation of neurons were evident in the telencephalon of embryos derived from diabetic mice. Exposure to high glucose altered the mRNA expression levels of Shh, Bmp4, Neurog1/2, Ascl1, Hes1, Dll1 and Olig1 in NSCs and Shh, Dll1, Neurog1/2 and Hes5 in differentiated cells. The changes in proliferation and differentiation of NSCs exposed to high glucose are associated with altered expression of genes that are involved in cell-cycle progression and cell-fate specification during neurulation. These changes may form the basis for the defective neural tube patterning observed in embryos of diabetic pregnancies.

Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation

PubMed Central

Grampa, Valentina; Odye, Gweltas; Thomas, Sophie; Elkhartoufi, Nadia; Filhol, Emilie; Niel, Olivier; Silbermann, Flora; Lebreton, Corinne; Collardeau-Frachon, Sophie; Rouvet, Isabelle; Alessandri, Jean-Luc; Devisme, Louise; Dieux-Coeslier, Anne; Cordier, Marie-Pierre; Capri, Yline; Khung-Savatovsky, Suonavy; Sigaudy, Sabine; Salomon, Rémi; Antignac, Corinne; Gubler, Marie-Claire; Benmerah, Alexandre; Terzi, Fabiola; Attié-Bitach, Tania; Jeanpierre, Cécile; Saunier, Sophie

2016-01-01

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway. PMID:26967905

Transient Early Embryonic Expression of Nkx2-5 Mutations Linked to Congenital Heart Defects in Human Causes Heart Defects in Xenopus laevis

PubMed Central

Bartlett, Heather L.; Sutherland, Lillian; Kolker, Sandra J.; Welp, Chelsea; Tajchman, Urszula; Desmarais, Vera; Weeks, Daniel L.

2007-01-01

Nkx2-5 is a homeobox containing transcription factor that is conserved and expressed in organisms that form hearts. Fruit flies lacking the gene (tinman) fail to form a dorsal vessel, mice that are homozygous null for Nkx2-5 form small, deformed hearts, and several human cardiac defects have been linked to dominant mutations in the Nkx2-5 gene. The Xenopus homologs (XNkx2-5) of two truncated forms of Nkx2-5 that have been identified in humans with congenital heart defects were used in the studies reported here. mRNAs encoding these mutations were injected into single cell Xenopus embryos, and heart development was monitored. Our results indicate that the introduction of truncated XNkx2-5 variants leads to three principle developmental defects. The atrial septum and the valve of the atrioventricular canal were both abnormal. In addition, video microscopic timing of heart contraction indicated that embryos injected with either mutant form of XNkx2-5 have conduction defects. PMID:17685485

Metabolite Profiling of Whole Murine Embryos Reveals Metabolic Perturbations Associated with Maternal Valproate-Induced Neural Tube Closure Defects

PubMed Central

Akimova, Darya; Wlodarczyk, Bogdan J.; Lin, Ying; Ross, M. Elizabeth; Finnell, Richard H.; Chen, Qiuying; Gross, Steven S.

2016-01-01

Background Valproic Acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid, a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure stage mouse embryos. Methods Pregnant SWV dams on either a 2ppm or 10ppm folic acid (FA) supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for neural tube closure status. LC/MS metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos to profiles from embryos that underwent normal neural tube closure from control dams. Results NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary folic acid supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared to the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines. Conclusions Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high folic acid diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. PMID:27860192

Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood

PubMed Central

Castori, M.

2013-01-01

Maternal diabetes mellitus is one of the strongest human teratogens. Despite recent advances in the fields of clinical embryology, experimental teratology and preventive medicine, diabetes-related perturbations of the maternofetal unit maintain a considerable impact on the Healthcare System. Classic consequences of prenatal exposure to hyperglycemia encompass (early) spontaneous abortions, perinatal death and malformations. The spectrum of related malformations comprises some recurrent blastogenic monotopic patterns, i.e. holoprosencephaly, caudal dysgenesis and oculoauriculovertebral spectrum, as well as pleiotropic syndromes, i.e. femoral hypoplasia-unusual face syndrome. Despite this, most malformed fetuses display multiple blastogenic defects of the VACTERL type, whose (apparently) casual combination preclude recognizing recurrent patterns, but accurately testifies to their developmental stage at onset. With the application of developmental biology in modern medicine, the effects of diabetes on the unborn patient are expanded to include the predisposition to develop insulin resistance in adulthood. The mechanisms underlying the transgenerational correlation between maternal diabetes and proneness to adult disorders in the offspring remain unclear, and the epigenetic plasticity may represent the missing link. In this scenario, a development-driven summary of the multifaced consequences of maternal diabetes on fertility and child health may add a practical resource to the repertoire of available information on early stages of embryogenesis. PMID:23653578

In honor of the Teratology Society's 50th anniversary: The role of Teratology Society members in the development and evolution of in vivo developmental toxicity test guidelines.

PubMed

Tyl, Rochelle W

2010-06-01

Members of the Teratology Society (established in 1960) were involved in the first governmental developmental and reproductive toxicity testing guidelines (1966) by FDA following the thalidomide epidemic, followed by other national and international governmental testing guidelines. The Segment II (developmental toxicity) study design, described in rodents and rabbits, has evolved with additional enhanced endpoints and better descriptions, mechanistic insights, range-finding studies, and toxico/pharmacokinetic ADME information (especially for pharmaceuticals). Society members were also involved in the development of the current screening assays and tests for endocrine disruptors (beginning in 1996) and are now involved with developing new testing guidelines (e.g., the extended one-generation protocol), and evaluating the current test guidelines and new initiatives under ILSI/HESI sponsorship. New initiatives include ToxCast from the U.S. EPA to screen, prioritize, and predict toxic chemicals by high throughput and high-content in vitro assays, bioinformation, and modeling to reduce (or eliminate) in vivo whole animal studies. Our Society and its journal have played vital roles in the scientific and regulatory accomplishments in birth defects research over the past 50 years and will continue to do so in the future. Happy 50th anniversary! (c) 2010 Wiley-Liss, Inc.

Cardiac Development in Zebrafish and Human Embryonic Stem Cells Is Inhibited by Exposure to Tobacco Cigarettes and E-Cigarettes

PubMed Central

Palpant, Nathan J.; Hofsteen, Peter; Pabon, Lil; Reinecke, Hans; Murry, Charles E.

2015-01-01

Background Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. Objective We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Methods Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac differentiation of human embryonic stem cells (hESCs) was used as a model for in vitro cardiac development. Results In zebrafish, exposure to both types of cigarettes results in broad, dose-dependent developmental defects coupled with severe heart malformation, pericardial edema and reduced heart function. Tobacco cigarettes are more toxic than e-cigarettes at comparable nicotine concentrations. During cardiac differentiation of hESCs, tobacco smoke exposure results in a delayed transition through mesoderm. Both types of cigarettes decrease expression of cardiac transcription factors in cardiac progenitor cells, suggesting a persistent delay in differentiation. In definitive human cardiomyocytes, both e-cigarette- and tobacco cigarette-treated samples showed reduced expression of sarcomeric genes such as MLC2v and MYL6. Furthermore, tobacco cigarette-treated samples had delayed onset of beating and showed low levels and aberrant localization of N-cadherin, reduced myofilament content with significantly reduced sarcomere length, and increased expression of the immature cardiac marker smooth muscle alpha-actin. Conclusion These data indicate a negative effect of both tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Tobacco cigarettes are more toxic than E-cigarettes and exhibit a broader spectrum of cardiac developmental defects. PMID:25978043

Label-free in vivo imaging of Drosophila melanogaster by multiphoton microscopy

NASA Astrophysics Data System (ADS)

Lin, Chiao-Ying; Hovhannisyan, Vladimir; Wu, June-Tai; Lin, Sung-Jan; Lin, Chii-Wann; Chen, Jyh-Horng; Dong, Chen-Yuan

2008-02-01

The fruit fly Drosophila melanogaster is one of the most valuable organisms in genetic and developmental biology studies. Drosophila is a small organism with a short life cycle, and is inexpensive and easy to maintain. The entire genome of Drosophila has recently been sequenced (cite the reference). These advantages make fruit fly an attractive model organism for biomedical researches. Unlike humans, Drosophila can be subjected to genetic manipulation with relative ease. Originally, Drosophila was mostly used in classical genetics studies. In the model era of molecular biology, the fruit fly has become a model organ for developmental biology researches. In the past, numerous molecularly modified mutants with well defined genetic defects affecting different aspects of the developmental processes have been identified and studied. However, traditionally, the developmental defects of the mutant flies are mostly examined in isolated fixed tissues which preclude the observation of the dynamic interaction of the different cell types and the extracellular matrix. Therefore, the ability to image different organelles of the fruit fly without extrinsic labeling is invaluable for Drosophila biology. In this work, we successfully acquire in vivo images of both developing muscles and axons of motor neurons in the three larval stages by using the minimially invasive imaging modality of multiphoton (SHG) microscopy. We found that while SHG imaging is useful in revealing the muscular architecture of the developing larva, it is the autofluorescence signal that allows label-free imaging of various organelles to be achieved. Our results demonstrate that multiphoton imaging is a powerful technique for investigation the development of Drosophila.

dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest.

PubMed

Kaplan, Rebecca E W; Chen, Yutao; Moore, Brad T; Jordan, James M; Maxwell, Colin S; Schindler, Adam J; Baugh, L Ryan

2015-12-01

Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest

PubMed Central

Moore, Brad T.; Jordan, James M.; Maxwell, Colin S.; Schindler, Adam J.; Baugh, L. Ryan

2015-01-01

Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development. PMID:26656736

Later Competence and Adaptation in Infants Who Survive Severe Heart Defects.

ERIC Educational Resources Information Center

O'Dougherty, Margaret; And Others

1983-01-01

Describes a model of risk potential for developmental outcome that was based on cardiac, medical, surgical, and family stress factors in 31 children with transposition of the great arteries. All children had undergone reparative open heart surgery utilizing cardiopulmonary bypass during infancy. (Author/RH)

78 FR 18986 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [60Day-13-0733... on proposed data collection projects, the Centers for Disease Control and Prevention (CDC) will... Center on Birth Defects and Developmental Disabilities (NCBDDD), Centers for Disease Control and...

Phenotype and management of Aicardi syndrome: new findings from a survey of 69 children

USDA-ARS?s Scientific Manuscript database

Aicardi syndrome is a rare neurodevelopmental disorder characterized by agenesis of the corpus callosum, other developmental brain abnormalities, chorioretinal lacunae, and severe seizures. Current clinical knowledge is derived from small series that focus on these major defects. The authors perform...

Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA.

PubMed Central

Garry, Vincent F; Harkins, Mary E; Erickson, Leanna L; Long-Simpson, Leslie K; Holland, Seth E; Burroughs, Barbara L

2002-01-01

We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed. PMID:12060842

Ethanol-induced impairment of polyamine homeostasis – A potential cause of neural tube defect and intrauterine growth restriction in fetal alcohol syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haghighi Poodeh, Saeid, E-mail: saeid.haghighi@oulu.fi; Medical Research Center, Oulu University Hospital, Oulu; Alhonen, Leena

Highlights: • Polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. • Alcohol administration perturbs polyamine levels in the tissues with various patterns. • Total absence of polyamines in the embryo head at 9.5 dpc is critical for development. • The deficiency is associated with reduction in endothelial cell sprouting in the head. • Retarded migration of neural crest cells may cause development of neural tube defect. - Abstract: Introduction: Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism andmore » uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting. Methods: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined. Results: No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction. Discussion: Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome.« less

A link among DNA replication, recombination, and gene expression revealed by genetic and genomic analysis of TEBICHI gene of Arabidopsis thaliana.

PubMed

Inagaki, Soichi; Nakamura, Kenzo; Morikami, Atsushi

2009-08-01

Spatio-temporal regulation of gene expression during development depends on many factors. Mutations in Arabidopsis thaliana TEBICHI (TEB) gene encoding putative helicase and DNA polymerase domains-containing protein result in defects in meristem maintenance and correct organ formation, as well as constitutive DNA damage response and a defect in cell cycle progression; but the molecular link between these phenotypes of teb mutants is unknown. Here, we show that mutations in the DNA replication checkpoint pathway gene, ATR, but not in ATM gene, enhance developmental phenotypes of teb mutants, although atr suppresses cell cycle defect of teb mutants. Developmental phenotypes of teb mutants are also enhanced by mutations in RAD51D and XRCC2 gene, which are involved in homologous recombination. teb and teb atr double mutants exhibit defects in adaxial-abaxial polarity of leaves, which is caused in part by the upregulation of ETTIN (ETT)/AUXIN RESPONSIVE FACTOR 3 (ARF3) and ARF4 genes. The Helitron transposon in the upstream of ETT/ARF3 gene is likely to be involved in the upregulation of ETT/ARF3 in teb. Microarray analysis indicated that teb and teb atr causes preferential upregulation of genes nearby the Helitron transposons. Furthermore, interestingly, duplicated genes, especially tandemly arrayed homologous genes, are highly upregulated in teb or teb atr. We conclude that TEB is required for normal progression of DNA replication and for correct expression of genes during development. Interplay between these two functions and possible mechanism leading to altered expression of specific genes will be discussed.

Molar-incisor hypomineralization (MIH) in a group of school-aged children in Benghazi, Libya.

PubMed

Fteita, D; Ali, A; Alaluusua, S

2006-06-01

Molar-incisor hypomineralization (MIH) is common in many countries and it has significant impact on treatment need. The aim of the present study was to assess developmental enamel defects with an emphasis to MIH in children from four primary schools in Benghazi, Libya. Permanent first molars of a total of 378 (188 females) 7.0-8.9-year-old children were examined for demarcated opacities, diffuse opacities and hypoplasia in their schools using a portable light, a mirror, and a probe. A subgroup of children attending two of the four schools and having all incisors and first molars erupted (N = 154) was examined for enamel defects in these teeth. Eleven children (2.9%) had MIH. The mean value of demarcated opacities in their first molars was 1.5. MIH lesions were found only in 1.1% of the children's first molars (tooth prevalence) and all lesions were mild. Six children (1.6%) had diffuse opacities and 3 (0.8%) had hypoplastic defects in their first molars. Fourteen out of 154 children (9%) who had both incisors and molars examined had some kind of developmental enamel defect: 11 children (7.1%) had demarcated opacities, 3 (1.9%) had diffuse opacities, and none had hypoplasia. MIH was rare in Benghazi, Libya. The prevalence was clearly lower than in comparable studies performed in Italy or in Nordic countries, where, according to the earlier reports, MIH is seen in every fifth or sixth child. Our result may be valuable when so far mostly unknown etiology behind MIH is investigated.

Impaired hair follicle morphogenesis and polarized keratinocyte movement upon conditional inactivation of integrin-linked kinase in the epidermis.

PubMed

Nakrieko, Kerry-Ann; Welch, Ian; Dupuis, Holly; Bryce, Dawn; Pajak, Agnieszka; St Arnaud, René; Dedhar, Shoukat; D'Souza, Sudhir J A; Dagnino, Lina

2008-04-01

Integrin-linked kinase (ILK) is key for cell survival, migration, and adhesion, but little is known about its role in epidermal development and homeostasis in vivo. We generated mice with conditional inactivation of the Ilk gene in squamous epithelia. These mice die perinatally and exhibit skin blistering and severe defects in hair follicle morphogenesis, including greatly reduced follicle numbers, failure to progress beyond very early developmental stages, and pronounced defects in follicular keratinocyte proliferation. ILK-deficient epidermis shows abnormalities in adhesion to the basement membrane and in differentiation. ILK-deficient cultured keratinocytes fail to attach and spread efficiently and exhibit multiple abnormalities in actin cytoskeletal organization. Ilk gene inactivation in cultured keratinocytes causes impaired ability to form stable lamellipodia, to directionally migrate, and to polarize. These defects are accompanied by abnormal distribution of active Cdc42 to cell protrusions, as well as reduced activation of Rac1 upon induction of cell migration in scraped keratinocyte monolayers. Significantly, alterations in cell spreading and forward movement in single cells can be rescued by expression of constitutively active Rac1 or RhoG. Our studies underscore a central and distinct role for ILK in hair follicle development and in polarized cell movements, two key aspects of epithelial morphogenesis and function.

Impaired Hair Follicle Morphogenesis and Polarized Keratinocyte Movement upon Conditional Inactivation of Integrin-linked Kinase in the Epidermis

PubMed Central

Nakrieko, Kerry-Ann; Welch, Ian; Dupuis, Holly; Bryce, Dawn; Pajak, Agnieszka; St. Arnaud, René; Dedhar, Shoukat

2008-01-01

Integrin-linked kinase (ILK) is key for cell survival, migration, and adhesion, but little is known about its role in epidermal development and homeostasis in vivo. We generated mice with conditional inactivation of the Ilk gene in squamous epithelia. These mice die perinatally and exhibit skin blistering and severe defects in hair follicle morphogenesis, including greatly reduced follicle numbers, failure to progress beyond very early developmental stages, and pronounced defects in follicular keratinocyte proliferation. ILK-deficient epidermis shows abnormalities in adhesion to the basement membrane and in differentiation. ILK-deficient cultured keratinocytes fail to attach and spread efficiently and exhibit multiple abnormalities in actin cytoskeletal organization. Ilk gene inactivation in cultured keratinocytes causes impaired ability to form stable lamellipodia, to directionally migrate, and to polarize. These defects are accompanied by abnormal distribution of active Cdc42 to cell protrusions, as well as reduced activation of Rac1 upon induction of cell migration in scraped keratinocyte monolayers. Significantly, alterations in cell spreading and forward movement in single cells can be rescued by expression of constitutively active Rac1 or RhoG. Our studies underscore a central and distinct role for ILK in hair follicle development and in polarized cell movements, two key aspects of epithelial morphogenesis and function. PMID:18234842

Genetic Control of Vulval Development in Caenorhabditis briggsae

PubMed Central

Sharanya, Devika; Thillainathan, Bavithra; Marri, Sujatha; Bojanala, Nagagireesh; Taylor, Jon; Flibotte, Stephane; Moerman, Donald G.; Waterston, Robert H.; Gupta, Bhagwati P.

2012-01-01

The nematode Caenorhabditis briggsae is an excellent model organism for the comparative analysis of gene function and developmental mechanisms. To study the evolutionary conservation and divergence of genetic pathways mediating vulva formation, we screened for mutations in C. briggsae that cause the egg-laying defective (Egl) phenotype. Here, we report the characterization of 13 genes, including three that are orthologs of Caenorhabditis elegans unc-84 (SUN domain), lin-39 (Dfd/Scr-related homeobox), and lin-11 (LIM homeobox). Based on the morphology and cell fate changes, the mutants were placed into four different categories. Class 1 animals have normal-looking vulva and vulva-uterine connections, indicating defects in other components of the egg-laying system. Class 2 animals frequently lack some or all of the vulval precursor cells (VPCs) due to defects in the migration of P-cell nuclei into the ventral hypodermal region. Class 3 animals show inappropriate fusion of VPCs to the hypodermal syncytium, leading to a reduced number of vulval progeny. Finally, class 4 animals exhibit abnormal vulval invagination and morphology. Interestingly, we did not find mutations that affect VPC induction and fates. Our work is the first study involving the characterization of genes in C. briggsae vulva formation, and it offers a basis for future investigations of these genes in C. elegans. PMID:23275885

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report.

PubMed

2014-08-01

Assisted Reproduction Treatment (ART) is here to stay. This review addresses the parental background of birth defects, before, during and after conception and focuses both on the underlying subfertility and on the question whether ART as a treatment is an additional contributing factor. Searches were performed in Medline and other databases. Summaries were discussed in a Delphi panel set-up by the European Society of Human Reproduction and Embryology (ESHRE). Several birth defects and adult diseases arise during the earliest stages of ovarian development and oocyte differentiation: this is the case of cleft palate disorders in offspring from female rat exposed to Dioxin during fetal life or the polycystic ovary diseases in female offspring (primates) exposed to elevated androgen concentration during fetal life. Human oocytes and embryos often fail to stop the propagation of aneuploid cells but maintain their ability to repair DNA damages including those introduced by the fertilizing sperm. There is a 29 % increased risk of birth defects in the newborns spontaneously conceived by subfertile couples and the risk is further increased (34 %) when conception is achieved by treating infertlity with ART (Danish IVF Registry). Periconceptional conditions are critical for ART babies: their birth weight is in general smaller (Norvegian Registry) but a more prolonged culture time doubled the number of large babies (Finnish Registry). The long-term developmental effects of ART on child and subsequent health as an adult remains a subject worthy of futher monitoring and investigation.

77 FR 37050 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

... proficient with diagnosing infants or younger children because children age 5 and younger require a different... Division of Human Development and Disability, located within NCBDDD, promotes the health of babies, children, and adults, with a focus on preventing birth defects and developmental disabilities and...

Activation and desensitization of peripheral muscle and neuronal nicotinic acetylcholine receptors by selected, naturally-occurring pyridine alkaloids

USDA-ARS?s Scientific Manuscript database

Teratogenic alkaloids can cause developmental defects due to inhibition of fetal movement that results from desensitization of fetal muscletype nicotinic acetylcholine receptors (nAChRs). We investigated the ability of two known teratogens, the piperidinyl-pyridine anabasine and its 1,2-dehydropiper...

Agonist mediated fetal muscle-type nicotinic acetylcholine receptor desensitization

USDA-ARS?s Scientific Manuscript database

The exposure of a developing embryo or fetus to teratogenic alkaloids from plants has the potential to cause developmental defects in livestock due to the inhibition of fetal movement by alkaloids. The mechanism behind the inhibition of fetal movement is the desensitization of fetal muscle-type nico...

76 FR 27325 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

... Enhanced Implementation of the ``Learn the Signs. Act Early.'' Campaign in 4 Target Sites,--New--National Center on Birth Defects and Developmental Disabilities (NCBDDD), Centers for Disease Control and Prevention (CDC). Background and Brief Description CDC's ``Learn the Signs Act Early'' campaign is a health...

Prevention of Fetal Alcohol Spectrum Disorders

ERIC Educational Resources Information Center

Floyd, R. Louise; Weber, Mary Kate; Denny, Clark; O'Connor, Mary J.

2009-01-01

Alcohol use among women of childbearing age is a leading, preventable cause of birth defects and developmental disabilities in the United States. Although most women reduce their alcohol use upon pregnancy recognition, some women report drinking during pregnancy and others may continue to drink prior to realizing they are pregnant. These findings…

Developmental toxicity of PAH mixtures in fish early life stages. Part I: adverse effects in rainbow trout.

PubMed

Le Bihanic, Florane; Morin, Bénédicte; Cousin, Xavier; Le Menach, Karyn; Budzinski, Hélène; Cachot, Jérôme

2014-12-01

A new gravel-contact assay using rainbow trout, Oncorhynchus mykiss, embryos was developed to assess the toxicity of polycyclic aromatic hydrocarbons (PAHs) and other hydrophobic compounds. Environmentally realistic exposure conditions were mimicked with a direct exposure of eyed rainbow trout embryos incubated onto chemical-spiked gravels until hatching at 10 °C. Several endpoints were recorded including survival, hatching delay, hatching success, biometry, developmental abnormalities, and DNA damage (comet and micronucleus assays). This bioassay was firstly tested with two model PAHs, fluoranthene and benzo[a]pyrene. Then, the method was applied to compare the toxicity of three PAH complex mixtures characterized by different PAH compositions: a pyrolytic extract from a PAH-contaminated sediment (Seine estuary, France) and two petrogenic extracts from Arabian Light and Erika oils, at two environmental concentrations, 3 and 10 μg g(-1) sum of PAHs. The degree and spectrum of toxicity were different according to the extract considered. Acute effects including embryo mortality and decreased hatching success were observed only for Erika oil extract. Arabian Light and pyrolytic extracts induced mainly sublethal effects including reduced larvae size and hemorrhages. Arabian Light and Erika extracts both induced repairable DNA damage as revealed by the comet assay versus the micronucleus assay. The concentration and proportion of methylphenanthrenes and methylanthracenes appeared to drive the toxicity of the three PAH fractions tested, featuring a toxic gradient as follows: pyrolytic < Arabian Light < Erika. The minimal concentration causing developmental defects was as low as 0.7 μg g(-1) sum of PAHs, indicating the high sensitivity of the assay and validating its use for toxicity assessment of particle-bound pollutants.

Regulation of chloroplast biogenesis: the immutans mutant of Arabidopsis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodermel, Steven

The immutans (im) variegation mutant of Arabidopsis is an ideal model to gain insight into factors that control chloroplast biogenesis. im defines the gene for PTOX, a plastoquinol terminal oxidase that participates in control of thylakoid redox. Here, we report that the im defect can be suppressed during the late stages of plant development by gigantea (gi2), which defines the gene for GIGANTEA (GI), a central component of the circadian clock that plays a poorly-understood role in diverse plant developmental processes. imgi2 mutants are late-flowering and display other well-known phenotypes associated with gi2, such as starch accumulation and resistance tomore » oxidative stress. We show that the restoration of chloroplast biogenesis in imgi2 is caused by a developmental-specific de-repression of cytokinin signaling that involves crosstalk with signaling pathways mediated by gibberellin (GA) and SPINDLY (SPY), a GA response inhibitor. Suppression of the plastid defect in imgi2 is likely caused by a relaxation of excitation pressures in developing plastids by factors contributed by gi2, including enhanced rates of photosynthesis and increased resistance to oxidative stress. Interestingly, the suppression phenotype of imgi can be mimicked by crossing im with the starch accumulation mutant, sex1, perhaps because sex1 utilizes pathways similar to gi. We conclude that our studies provide a direct genetic linkage between GIGANTEA and chloroplast biogenesis, and we construct a model of interactions between signaling pathways mediated by gi, GA, SPY, cytokinins, and sex1 that are required for chloroplast biogenesis.« less

Dual Functional Roles of Molecular Beacon as a MicroRNA Detector and Inhibitor.

PubMed

Li, Wai Ming; Chan, Ching-Man; Miller, Andrew L; Lee, Chow H

2017-03-03

MicroRNAs are essential in many cellular processes. The ability to detect microRNAs is important for understanding its function and biogenesis. This study is aimed at using a molecular beacon to detect miR-430 in developing zebrafish embryos as a proof of principle. miR-430 is crucial for the clearance of maternal mRNA during maternal zygotic transition in embryonic development. Despite its known function, the temporal and spatial expression of miR-430 remains unclear. We used various imaging techniques, including laser scanning confocal microscopy, spinning disk, and lightsheet microscopy, to study the localization of miR-430 and any developmental defects possibly caused by the molecular beacon. Our results show that miR-430 is expressed early in development and is localized in distinct cytoplasmic granules where its target mRNA can be detected. We also show that the designed molecular beacon can inhibit the function of miR-430 and cause developmental defect in the brain, notochord, heart, and kidney, depending on the delivery site within the embryo, suggesting that miR-430 plays a diverse role in embryonic morphogenesis. When compared with morpholino, molecular beacon is 2 orders of magnitude more potent in inhibiting miR-430. Thus, our results reveal that in addition to being used as a valuable tool for the detection of microRNAs in vivo , molecular beacons can also be employed to inhibit microRNAs in a specific manner. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Nestin is essential for zebrafish brain and eye development through control of progenitor cell apoptosis.

PubMed

Chen, Hua-Ling; Yuh, Chiou-Hwa; Wu, Kenneth K

2010-02-19

Nestin is expressed in neural progenitor cells (NPC) of developing brain. Despite its wide use as an NPC marker, the function of nestin in embryo development is unclear. As nestin is conserved in zebrafish and its predicted sequence is clustered with the mammalian nestin orthologue, we used zebrafish as a model to investigate its role in embryogenesis. Injection of nestin morpholino (MO) into fertilized eggs induced time- and dose-dependent brain and eye developmental defects. Nestin morphants exhibited characteristic morphological changes including small head, small eyes and hydrocephalus. Histological examinations show reduced hind- and mid-brain size, dilated ventricle, poorly organized retina and underdeveloped lens. Injection of control nestin MO did not induce brain or eye changes. Nestin MO injection reduced expression of ascl1b (achaete-scute complex-like 1b), a marker of NPCs, without affecting its distribution. Nestin MO did not influence Elavl3/4 (Embryonic lethal, abnormal vision, Drosophila-like 3/4) (a neuronal marker), or otx2 (a midbrain neuronal marker), but severely perturbed cranial motor nerve development and axon distribution. To determine whether the developmental defects are due to excessive NPC apoptosis and/or reduced NPC proliferation, we analyzed apoptosis by TUNEL assay and acridine orange staining and proliferation by BrdU incorporation, pcna and mcm5 expressions. Excessive apoptosis was noted in hindbrain and midbrain cells. Apoptotic signals were colocalized with ascl1b. Proliferation markers were not significantly altered by nestin MO. These results suggest that nestin is essential for zebrafish brain and eye development probably through control of progenitor cell apoptosis.

Comparison of a modified mid-coronal sectioning technique and Wilson's technique when conducting eye and brain examinations in rabbit teratology studies.

PubMed

Ziejewski, Mary K; Solomon, Howard M; Rendemonti, Joyce; Stanislaus, Dinesh

2015-02-01

There are two methods used when examining fetal rabbit eyes and brain in teratology studies. One method employs prior fixation before serial sectioning (Wilson's technique) and the other uses fresh tissue (mid-coronal sectioning). We modified the mid-coronal sectioning technique to include removal of eyes and brain for closer examination and to increase the number of structures that can be evaluated and compared it to the Wilson's technique. We found that external examination of the head, in conjunction with either sectioning method, is equally sensitive in identifying developmental defects. We evaluated 40,401 New Zealand White (NZW) and Dutch-Belted (DB) rabbit fetuses for external head alterations, of which 28,538 fetuses were further examined for eye and brain alterations using the modified mid-coronal sectioning method (16,675 fetuses) or Wilson's technique (11,863 fetuses). The fetuses were from vehicle control or drug-treated pregnant rabbits in embryo-fetal development studies conducted to meet international regulatory requirements for the development of new drugs. Both methods detected the more common alterations (microphthalmia and dilated lateral cerebral ventricles) and other less common findings (changes in size and/or shape of eye and brain structures). While both methods are equally sensitive at detecting common and rare developmental defects, the modified mid-coronal sectioning technique eliminates the use of chemicals and concomitant fixation artifacts that occur with the Wilson's technique and allows for examination of 100% intact fetuses thereby increasing potential for detecting eye and brain alterations as these findings occur infrequently in rabbits. © 2015 Wiley Periodicals, Inc.

Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization

PubMed Central

Tan, Kun; An, Lei; Miao, Kai; Ren, Likun; Hou, Zhuocheng; Tao, Li; Zhang, Zhenni; Wang, Xiaodong; Xia, Wei; Liu, Jinghao; Wang, Zhuqing; Xi, Guangyin; Gao, Shuai; Sui, Linlin; Zhu, De-Sheng; Wang, Shumin; Wu, Zhonghong; Bach, Ingolf; Chen, Dong-bao; Tian, Jianhui

2016-01-01

Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications. PMID:26951653

Array comparative genome hybridization in patients with developmental delay: two example cases.

PubMed

Hancarova, Miroslava; Drabova, Jana; Zmitkova, Zuzana; Vlckova, Marketa; Hedvicakova, Petra; Novotna, Drahuse; Vlckova, Zdenka; Vejvalkova, Sarka; Marikova, Tatana; Sedlacek, Zdenek

2012-02-15

Developmental delay is often a predictor of mental retardation (MR) or autism, two relatively frequent developmental disorders severely affecting intellectual and social functioning. The causes of these conditions remain unknown in most patients. They have a strong genetic component, but the specific genetic defects can only be identified in a fraction of patients. Recent developments in genomics supported the establishment of the causal link between copy number variants in the genomes of some patients and their affection. One of the techniques suitable for this analysis is array comparative genome hybridization, which can be used both for detailed mapping of chromosome rearrangements identified by classical cytogenetics and for the identification of novel submicroscopic gains or losses of genetic material. We illustrate the power of this approach in two patients. Patient 1 had a cytogenetically visible deletion of chromosome X and the molecular analysis was used to specify the gene content of the deletion and the prognosis of the child. Patient 2 had a seemingly normal karyotype and the analysis revealed a small recurrent deletion of chromosome 1 likely to be responsible for his phenotype. However, the genetic dissection of MR and autism is complicated by high heterogeneity of the genetic aberrations among patients and by broad variability of phenotypic effects of individual genetic defects. Copyright © 2010 Elsevier B.V. All rights reserved.

Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish.

PubMed

Signore, Iskra A; Jerez, Carolina; Figueroa, Diego; Suazo, José; Marcelain, Katherine; Cerda, Oscar; Colombo Flores, Alicia

2016-10-01

Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814-830, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Amelogenesis imperfecta and the treatment plan - interdisciplinary team approach.

PubMed

Suchancova, B; Holly, D; Janska, M; Stebel, J; Lysy, J; Thurzo, A; Sasinek, S

2014-01-01

Amelogenesis imperfecta is a set of hereditary defects representing mainly the development defects of enamel without the presence of whole-body symptoms. Developmental disorders can manifest a complete absence of enamel, which is caused by improper differentiation of ameloblasts. This article describes the diagnosis and treatment of a patient with amelogenesis imperfecta, as well as the need for interdisciplinary cooperation to achieve the best possible morphological, skeletal, functional and aesthetic rehabilitation of the patients with this diagnosis. Furthermore, the article reviews literature dealing with other anomalies occurring in association with amelogenesis imperfect (Fig. 12, Ref. 20).

The Nucleosome Remodeling and Deacetylase (NuRD) Complex in Development and Disease

PubMed Central

Basta, Jeannine; Rauchman, Michael

2014-01-01

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis and accelerated ageing. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer. PMID:24880148

The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder.

PubMed

Walden, Helen; Deans, Andrew J

2014-01-01

Mutations in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway.

Conservation of Planar Polarity Pathway Function Across the Animal Kingdom.

PubMed

Hale, Rosalind; Strutt, David

2015-01-01

Planar polarity is a well-studied phenomenon resulting in the directional coordination of cells in the plane of a tissue. In invertebrates and vertebrates, planar polarity is established and maintained by the largely independent core and Fat/Dachsous/Four-jointed (Ft-Ds-Fj) pathways. Loss of function of these pathways can result in a wide range of developmental or cellular defects, including failure of gastrulation and problems with placement and function of cilia. This review discusses the conservation of these pathways across the animal kingdom. The lack of vital core pathway components in basal metazoans suggests that the core planar polarity pathway evolved shortly after, but not necessarily alongside, the emergence of multicellularity.

Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder.

PubMed

Fuchs, Claudia; Rimondini, Roberto; Viggiano, Rocchina; Trazzi, Stefania; De Franceschi, Marianna; Bartesaghi, Renata; Ciani, Elisabetta

2015-10-01

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a rare neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability and Rett syndrome-like features. CDKL5 is highly expressed in the brain during early postnatal stages, suggesting its importance for brain maturation. Using a newly-generated Cdkl5 knockout (Cdkl5 -/Y) mouse, we recently found that loss of Cdkl5 impairs postnatal hippocampal development with a reduction in neuronal precursor survival and maturation. These defects were accompanied by increased activity of the glycogen synthase kinase 3β (GSK3β) a crucial inhibitory regulator of many neurodevelopmental processes. The goal of the current study was to establish whether inhibition of GSK3β corrects hippocampal developmental defects due to Cdkl5 loss. We found that treatment with the GSK3β inhibitor SB216763 restored neuronal precursor survival, dendritic maturation, connectivity and hippocampus-dependent learning and memory in the Cdkl5 -/Y mouse. Importantly, these effects were retained one month after treatment cessation. At present, there are no therapeutic strategies to improve the neurological defects of subjects with CDKL5 disorder. Current results point at GSK3β inhibitors as potential therapeutic tools for the improvement of abnormal brain development in CDKL5 disorder. Copyright © 2015. Published by Elsevier Inc.

Fetal Alcohol Spectrum Disorders.

PubMed

Williams, Janet F; Smith, Vincent C

2015-11-01

Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises:▪ Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use.▪ Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong.▪ Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes.▪ During pregnancy:◦no amount of alcohol intake should be considered safe;◦there is no safe trimester to drink alcohol;◦all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and◦binge drinking poses dose-related risk to the developing fetus. Copyright © 2015 by the American Academy of Pediatrics.

The Epidermis of Grhl3-Null Mice Displays Altered Lipid Processing and Cellular Hyperproliferation

PubMed Central

Ting, Stephen B; Caddy, Jacinta; Wilanowski, Tomasz; Auden, Alana; Cunningham, John M; Elias, Peter M; Holleran, Walter M

2005-01-01

The presence of an impermeable surface barrier is an essential homeostatic mechanism in almost all living organisms. We have recently described a novel gene that is critical for the developmental instruction and repair of the integument in mammals. This gene, Grainy head-like 3 (Grhl3) is a member of a large family of transcription factors that are homologs of the Drosophila developmental gene grainy head (grh). Mice lacking Grhl3 fail to form an adequate skin barrier, and die at birth due to dehydration. These animals are also unable to repair the epidermis, exhibiting failed wound healing in both fetal and adult stages of development. These defects are due, in part, to diminished expression of a Grhl3 target gene, Transglutaminase 1 (TGase 1), which encodes a key enzyme involved in cross-linking of epidermal structural proteins and lipids into the cornified envelope (CE). Remarkably, the Drosophila grh gene plays an analogous role, regulating enzymes involved in the generation of quinones, which are essential for cross-linking structural components of the fly epidermis. In an extension of our initial analyses, we focus this report on additional defects observed in the Grhl3-null epidermis, namely defective extra-cellular lipid processing, altered lamellar lipid architecture and cellular hyperproliferation. These abnormalities suggest that Grhl3 plays diverse mechanistic roles in maintaining homeostasis in the skin. PMID:19521564

The epidermis of grhl3-null mice displays altered lipid processing and cellular hyperproliferation.

PubMed

Ting, Stephen B; Caddy, Jacinta; Wilanowski, Tomasz; Auden, Alana; Cunningham, John M; Elias, Peter M; Holleran, Walter M; Jane, Stephen M

2005-04-01

The presence of an impermeable surface barrier is an essential homeostatic mechanism in almost all living organisms. We have recently described a novel gene that is critical for the developmental instruction and repair of the integument in mammals. This gene, Grainy head-like 3 (Grhl3) is a member of a large family of transcription factors that are homologs of the Drosophila developmental gene grainy head (grh). Mice lacking Grhl3 fail to form an adequate skin barrier, and die at birth due to dehydration. These animals are also unable to repair the epidermis, exhibiting failed wound healing in both fetal and adult stages of development. These defects are due, in part, to diminished expression of a Grhl3 target gene, Transglutaminase 1 (TGase 1), which encodes a key enzyme involved in cross-linking of epidermal structural proteins and lipids into the cornified envelope (CE). Remarkably, the Drosophila grh gene plays an analogous role, regulating enzymes involved in the generation of quinones, which are essential for cross-linking structural components of the fly epidermis. In an extension of our initial analyses, we focus this report on additional defects observed in the Grhl3-null epidermis, namely defective extra-cellular lipid processing, altered lamellar lipid architecture and cellular hyperproliferation. These abnormalities suggest that Grhl3 plays diverse mechanistic roles in maintaining homeostasis in the skin.

Sorting nexin 3 mutation impairs development and neuronal function in Caenorhabditis elegans.

PubMed

Vieira, Neide; Bessa, Carlos; Rodrigues, Ana J; Marques, Paulo; Chan, Fung-Yi; de Carvalho, Ana Xavier; Correia-Neves, Margarida; Sousa, Nuno

2018-06-01

The sorting nexins family of proteins (SNXs) plays pleiotropic functions in protein trafficking and intracellular signaling and has been associated with several disorders, namely Alzheimer's disease and Down's syndrome. Despite the growing association of SNXs with neurodegeneration, not much is known about their function in the nervous system. The aim of this work was to use the nematode Caenorhabditis elegans that encodes in its genome eight SNXs orthologs, to dissect the role of distinct SNXs, particularly in the nervous system. By screening the C. elegans SNXs deletion mutants for morphological, developmental and behavioral alterations, we show here that snx-3 gene mutation leads to an array of developmental defects, such as delayed hatching, decreased brood size and life span and reduced body length. Additionally, ∆snx-3 worms present increased susceptibility to osmotic, thermo and oxidative stress and distinct behavioral deficits, namely, a chemotaxis defect which is independent of the described snx-3 role in Wnt secretion. ∆snx-3 animals also display abnormal GABAergic neuronal architecture and wiring and altered AIY interneuron structure. Pan-neuronal expression of C. elegans snx-3 cDNA in the ∆snx-3 mutant is able to rescue its locomotion defects, as well as its chemotaxis toward isoamyl alcohol. Altogether, the present work provides the first in vivo evidence of the SNX-3 role in the nervous system.

Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

PubMed

Lin, Angela E; Michot, Caroline; Cormier-Daire, Valerie; L'Ecuyer, Thomas J; Matherne, G Paul; Barnes, Barrett H; Humberson, Jennifer B; Edmondson, Andrew C; Zackai, Elaine; O'Connor, Matthew J; Kaplan, Julie D; Ebeid, Makram R; Krier, Joel; Krieg, Elizabeth; Ghoshhajra, Brian; Lindsay, Mark E

2016-10-01

Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-β signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-β, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Learning defects in Drosophila growth restricted chico mutants are caused by attenuated adenylyl cyclase activity.

PubMed

Naganos, Shintaro; Ueno, Kohei; Horiuchi, Junjiro; Saitoe, Minoru

2016-04-06

Reduced insulin/insulin-like growth factor signaling (IIS) is a major cause of symmetrical intrauterine growth retardation (IUGR), an impairment in cell proliferation during prenatal development that results in global growth defects and mental retardation. In Drosophila, chico encodes the only insulin receptor substrate. Similar to other animal models of IUGR, chico mutants have defects in global growth and associative learning. However, the physiological and molecular bases of learning defects caused by chico mutations, and by symmetrical IUGR, are not clear. In this study, we found that chico mutations impair memory-associated synaptic plasticity in the mushroom bodies (MBs), neural centers for olfactory learning. Mutations in chico reduce expression of the rutabaga-type adenylyl cyclase (rut), leading to decreased cAMP synthesis in the MBs. Expressing a rut (+) transgene in the MBs restores memory-associated plasticity and olfactory associative learning in chico mutants, without affecting growth. Thus chico mutations disrupt olfactory learning, at least in part, by reducing cAMP signaling in the MBs. Our results suggest that some cognitive defects associated with reduced IIS may occur, independently of developmental defects, from acute reductions in cAMP signaling.

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

PubMed

Pillas, Demetris; Hoggart, Clive J; Evans, David M; O'Reilly, Paul F; Sipilä, Kirsi; Lähdesmäki, Raija; Millwood, Iona Y; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa; Laitinen, Jaana; Vaara, Sarianna; Glaser, Beate; Crawford, Peter; Timpson, Nicholas J; Ring, Susan M; Deng, Guohong; Zhang, Weihua; McCarthy, Mark I; Deloukas, Panos; Peltonen, Leena; Elliott, Paul; Coin, Lachlan J M; Smith, George Davey; Jarvelin, Marjo-Riitta

2010-02-26

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy

PubMed Central

Sipilä, Kirsi; Lähdesmäki, Raija; Millwood, Iona Y.; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa; Laitinen, Jaana; Vaara, Sarianna; Glaser, Beate; Crawford, Peter; Timpson, Nicholas J.; Ring, Susan M.; Deng, Guohong; Zhang, Weihua; McCarthy, Mark I.; Deloukas, Panos; Peltonen, Leena

2010-01-01

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years. PMID:20195514

Micro-RNAs and their roles in eye disorders.

PubMed

Raghunath, Azhwar; Perumal, Ekambaram

2015-01-01

Micro-RNAs (miRNAs) are members of the family of noncoding RNA molecules that regulate gene expression by translational repression and mRNA degradation. Initial identification of miRNAs revealed them only as developmental regulators; later, their radiated roles in various cellular processes have been established. They regulate several pathways, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation and proliferation. Their roles in eye disorders are being explored by biologists around the world. Eye physiology requires the perfect orchestration of all the regulatory networks; any defect in any of the networks leads to eye disorders. The dysregulation of miRNA expression has been reported in many eye disorders, which paves the way for new therapeutics. This review summarizes the biogenesis of miRNAs and their role in eye disorders. miRNA studies also have implications for the understanding of various complex metabolic pathways leading to disorders of the eye. The ultimate understanding leads to potential opportunities in evaluating miRNAs as molecular biomarkers, prognostic tools, diagnostic tools and therapeutic agents for eye disorders. © 2015 S. Karger AG, Basel.

Cerebellar Development and Disease

PubMed Central

Gleeson, Joseph G.

2008-01-01

Recent Advances The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum. PMID:18513948

Nuclear migration events throughout development

PubMed Central

Bone, Courtney R.

2016-01-01

ABSTRACT Moving the nucleus to a specific position within the cell is an important event during many cell and developmental processes. Several different molecular mechanisms exist to position nuclei in various cell types. In this Commentary, we review the recent progress made in elucidating mechanisms of nuclear migration in a variety of important developmental models. Genetic approaches to identify mutations that disrupt nuclear migration in yeast, filamentous fungi, Caenorhabditis elegans, Drosophila melanogaster and plants led to the identification of microtubule motors, as well as Sad1p, UNC-84 (SUN) domain and Klarsicht, ANC-1, Syne homology (KASH) domain proteins (LINC complex) that function to connect nuclei to the cytoskeleton. We focus on how these proteins and various mechanisms move nuclei during vertebrate development, including processes related to wound healing of fibroblasts, fertilization, developing myotubes and the developing central nervous system. We also describe how nuclear migration is involved in cells that migrate through constricted spaces. On the basis of these findings, it is becoming increasingly clear that defects in nuclear positioning are associated with human diseases, syndromes and disorders. PMID:27182060

SPEEDY babies: A putative new behavioral syndrome of unbalanced motor-speech development

PubMed Central

Haapanen, Marja-Leena; Aro, Tuomo; Isotalo, Elina

2008-01-01

Even though difficulties in motor development in children with speech and language disorders are widely known, hardly any attention is paid to the association between atypically rapidly occurring unassisted walking and delayed speech development. The four children described here presented with a developmental behavioral triad: 1) atypically speedy motor development, 2) impaired expressive speech, and 3) tongue carriage dysfunction resulting in related misarticulations. Those characteristics might be phenotypically or genetically clustered. These children didn’t have impaired cognition, neurological or mental disease, defective sense organs, craniofacial dysmorphology or susceptibility to upper respiratory infections, particularly recurrent otitis media. Attention should be paid on discordant and unbalanced achievement of developmental milestones. Present children are termed SPEEDY babies, where SPEEDY refers to rapid independent walking, SPEE and DY to dyspractic or dysfunctional speech development and lingual dysfunction resulting in linguoalveolar misarticulations. SPEEDY babies require health care that recognizes and respects their motor skills and supports their needs for motor activities and on the other hand include treatment for impaired speech. The parents may need advice and support with these children. PMID:19337462

Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry.

PubMed

Doll, Caleb A; Broadie, Kendal

2016-05-01

Neural circuit optimization occurs through sensory activity-dependent mechanisms that refine synaptic connectivity and information processing during early-use developmental critical periods. Fragile X Mental Retardation Protein (FMRP), the gene product lost in Fragile X syndrome (FXS), acts as an activity sensor during critical period development, both as an RNA-binding translation regulator and channel-binding excitability regulator. Here, we employ a Drosophila FXS disease model to assay calcium signaling dynamics with a targeted transgenic GCaMP reporter during critical period development of the mushroom body (MB) learning/memory circuit. We find FMRP regulates depolarization-induced calcium signaling in a neuron-specific manner within this circuit, suppressing activity-dependent calcium transients in excitatory cholinergic MB input projection neurons and enhancing calcium signals in inhibitory GABAergic MB output neurons. Both changes are restricted to the developmental critical period and rectified at maturity. Importantly, conditional genetic (dfmr1) rescue of null mutants during the critical period corrects calcium signaling defects in both neuron classes, indicating a temporally restricted FMRP requirement. Likewise, conditional dfmr1 knockdown (RNAi) during the critical period replicates constitutive null mutant defects in both neuron classes, confirming cell-autonomous requirements for FMRP in developmental regulation of calcium signaling dynamics. Optogenetic stimulation during the critical period enhances depolarization-induced calcium signaling in both neuron classes, but this developmental change is eliminated in dfmr1 null mutants, indicating the activity-dependent regulation requires FMRP. These results show FMRP shapes neuron class-specific calcium signaling in excitatory vs. inhibitory neurons in developing learning/memory circuitry, and that FMRP mediates activity-dependent regulation of calcium signaling specifically during the early-use critical period. Copyright © 2016 Elsevier Inc. All rights reserved.

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

PubMed Central

Wang, Chi Chiu; Man, Gene Chi Wai; Chu, Ching Yan; Borchert, Astrid; Ugun-Klusek, Aslihan; Billett, E. Ellen; Kühn, Hartmut; Ufer, Christoph

2014-01-01

Monoamine oxidases A and B (MAO-A and MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system, MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5–E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression led to elevated levels of embryonic serotonin (5-hydroxytryptamine (5-HT)), and we found that knockdown of serotonin receptor-6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescued the MAO-A knockdown phenotype and restored apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspase-3 and -9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl-2 and Bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincided with an enhanced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A-deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus induces developmental retardations. PMID:24497636

Citrinin induces apoptosis via a mitochondria-dependent pathway and inhibition of survival signals in embryonic stem cells, and causes developmental injury in blastocysts

PubMed Central

Chan, Wen-Hsiung

2007-01-01

The mycotoxin CTN (citrinin), a natural contaminant in foodstuffs and animal feeds, has cytotoxic and genotoxic effects on various mammalian cells. CTN is known to cause cell injury, including apoptosis, but the precise regulatory mechanisms of CTN action, particularly in stem cells and embryos, are currently unclear. In the present paper, I report that CTN has cytotoxic effects on mouse embryonic stem cells and blastocysts, and is associated with defects in their subsequent development, both in vitro and in vivo. Experiments in embryonic stem cells (ESC-B5) showed that CTN induces apoptosis via ROS (reactive oxygen species) generation, increased Bax/Bcl-2 ratio, loss of MMP (mitochondrial membrane potential), induction of cytochrome c release, and activation of caspase 3. In this model, CTN triggers cell death via inactivation of the HSP90 [a 90 kDa isoform of the HSP (heat-shock protein) family proteins]/multichaperone complex and subsequent degradation of Ras and Raf-1, further inhibiting anti-apoptotic processes, such as the Ras→ERK (extracellular-signal-regulated kinase) signal transduction pathway. In addition, CTN causes early developmental injury in mouse ESCs and blastocysts in vitro. Lastly, using an in vivo mouse model, I show that consumption of drinking water containing 10 μM CTN results in blastocyst apoptosis and early embryonic developmental injury. Collectively, these findings show for the first time that CTN induces ROS and mitochondria-dependent apoptotic processes, inhibits Ras→ERK survival signalling via inactivation of the HSP90/multichaperone complex, and causes developmental injury in vivo. PMID:17331071

Specific Activation of K-RasG12D Allele in the Bladder Urothelium Results in Lung Alveolar and Vascular Defects

PubMed Central

Kanasaki, Megumi; Vong, Sylvia; Rovira, Carlota; Kalluri, Raghu

2014-01-01

K-ras is essential for embryogenesis and its mutations are involved in human developmental syndromes and cancer. To determine the consequences of K-ras activation in urothelium, we used uroplakin-II (UPK II) promoter driven Cre recombinase mice and generated mice with mutated KrasG12D allele in the urothelium (UPK II-Cre;LSL-K-rasG12D). The UPK II-Cre;LSL-K-rasG12D mice died neonatally due to lung morphogenesis defects consisting of simplification with enlargement of terminal air spaces and dysmorphic pulmonary vasculature. A significant alteration in epithelial and vascular basement membranes, together with fragmentation of laminin, points to extracellular matrix degradation as the causative mechanism of alveolar and vascular defects. Our data also suggest that altered protease activity in amniotic fluid might be associated with matrix defects in lung of UPK II-Cre;LSL-K-rasG12. These defects resemble those observed in early stage human neonatal bronchopulmonary dysplasia (BPD), although the relevance of this new mouse model for BPD study needs further investigation. PMID:24760005

Localization of congenital tegmen tympani defects.

PubMed

Tóth, Miklós; Helling, Kai; Baksa, Gábor; Mann, Wolf

2007-12-01

This study sets out to demonstrate the normal developmental steps of the tegmen tympani and thus explains the typical localization of congenital tegmental defects. For this study, 79 macerated and formalin-fixed human temporal bones from 14th fetal week to adults were observed and prepared. Macroscopic and microscopic examination of the prenatal and postnatal changes of the tegmen tympani during its development. Temporal bones from 14th fetal week to adults underwent descriptive anatomic studies to understand the normal development of the tegmen tympani and to find a possible cause of its congenital defects. The medial part of the tegmen tympani develops from the otic capsule during chondral ossification, thus forming the tegmental process of the petrous part. The lateral part shows membranous ossification. The tegmental process cases a temporary bony dehiscence lateral to the geniculate ganglion between the 23rd and 25th fetal week. Congenital defects develop near the geniculate ganglion and seem to be due to an incomplete development of tegmental process of otic capsule. Because of that, congenital lesion of the tegmen tympani can be defined as an inner ear defect.

Ectopic shoot meristem generation in monocotyledonous rpk1 mutants is linked to SAM loss and altered seedling morphology.

PubMed

Fiesselmann, Birgit S; Luichtl, Miriam; Yang, Xiaomeng; Matthes, Michaela; Peis, Ottilie; Torres-Ruiz, Ramon A

2015-07-07

In dicot Arabidopsis thaliana embryos two cotyledons develop largely autonomously from the shoot apical meristem (SAM). Recessive mutations in the Arabidopsis receptor-like kinase RPK1 lead to monocotyledonous seedlings, with low (10 %) penetrance due to complex functional redundancy. In strong rpk1 alleles, about 10 % of these (i. e. 1 % of all homozygotes) did not develop a SAM. We wondered whether RPK1 might also control SAM gene expression and SAM generation in addition to its known stochastic impact on cell division and PINFORMED1 (PIN1) polarity in the epidermis. SAM-less seedlings developed a simple morphology with a straight and continuous hypocotyl-cotyledon structure lacking a recognizable epicotyl. According to rpk1's auxin-related PIN1 defect, the seedlings displayed defects in the vascular tissue. Surprisingly, SAM-less seedlings variably expressed essential SAM specific genes along the hypocotyl-cotyledon structure up into the cotyledon lamina. Few were even capable of developing an ectopic shoot meristem (eSM) on top of the cotyledon. The results highlight the developmental autonomy of the SAM vs. cotyledons and suggest that the primary rpk1 defect does not lie in the seedling's ability to express SAM genes or to develop a shoot meristem. Rather, rpk1's known defects in cell division and auxin homeostasis, by disturbed PIN1 polarity, impact on SAM and organ generation. In early embryo stages this failure generates a simplified monocotyledonous morphology. Once generated, this likely entails a loss of positional information that in turn affects the spatiotemporal development of the SAM. SAM-bearing and SAM-less monocotyledonous phenotypes show morphological similarities either to real monocots or to dicot species, which only develop one cotyledon. The specific cotyledon defect in rpk1 mutants thus sheds light upon the developmental implications of the transition from two cotyledons to one.

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.

PubMed

Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth; Pappas, John G; Rosenfeld, Jill A; McCarty, Alexandra J; Davis, Taylor; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Xia, Fan; Stong, Nicholas; Johnson, Travis K; Warr, Coral G; Yamamoto, Shinya; Adams, David R; Markello, Thomas C; Gahl, William A; Bellen, Hugo J; Wangler, Michael F; Malicdan, May Christine V

2017-01-05

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Dandy-Walker Malformation and Down Syndrome Association: Good Developmental Outcome and Successful Endoscopic Treatment of Hydrocephalus

PubMed Central

Nigri, Flavio; Cabral, Isaias Fiuza; da Silva, Raquel Tavares Boy; Pereira, Heloisa Viscaíno; Ribeiro, Carlos Roberto Telles

2014-01-01

The association of Down syndrome (DS) with Dandy Walker malformation (DWM) is extremely rare, with only 3 cases reported to date. All cases reported have shown a bad life expectancy and a bad developmental outcome. The present case reveals the possibility of a good prognosis. A 19-month-old male patient had successful endoscopic hydrocephalus treatment and a good developmental outcome. He probably had a better outcome because of good DS and DWM prognostic parameters. Our patient suffered from a DWM with vermis identification of 2 fissures and 3 lobes and a DS with a well-preserved tonus, which was not associated with other congenital systemic defects. We may conclude that the prognosis of DS-DWM association may separately depend on the degree of clinical and neurological involvement of each malformation. PMID:24932176

Dandy-walker malformation and down syndrome association: good developmental outcome and successful endoscopic treatment of hydrocephalus.

PubMed

Nigri, Flavio; Cabral, Isaias Fiuza; da Silva, Raquel Tavares Boy; Pereira, Heloisa Viscaíno; Ribeiro, Carlos Roberto Telles

2014-05-01

The association of Down syndrome (DS) with Dandy Walker malformation (DWM) is extremely rare, with only 3 cases reported to date. All cases reported have shown a bad life expectancy and a bad developmental outcome. The present case reveals the possibility of a good prognosis. A 19-month-old male patient had successful endoscopic hydrocephalus treatment and a good developmental outcome. He probably had a better outcome because of good DS and DWM prognostic parameters. Our patient suffered from a DWM with vermis identification of 2 fissures and 3 lobes and a DS with a well-preserved tonus, which was not associated with other congenital systemic defects. We may conclude that the prognosis of DS-DWM association may separately depend on the degree of clinical and neurological involvement of each malformation.

EFFECT OF VARYING MATERNAL FOLATE STATUS AND DIETARY FOLATE INTAKE ON RESPONSE TO DIVERSE DEVELOPMENTAL TOXICANTS IN THE RAT

EPA Science Inventory

Periconceptional and early pregnancy folate supplements are associated with reduced recurrence and occurrence of birth defects in humans. This study was undertaken to assess the influence of maternal folate status and dietary folate intake on outcome of exposures to diverse terat...

Child Care Provider Awareness and Prevention of Cytomegalovirus and Other Infectious Diseases

ERIC Educational Resources Information Center

Thackeray, Rosemary; Magnusson, Brianna M.

2016-01-01

Background: Child care facilities are prime locations for the transmission of infectious and communicable diseases. Children and child care providers are at high risk for cytomegalovirus (CMV) infection which causes severe birth defects and developmental delays. Objective: The goals of study were: (1) to determine the level of cytomegalovirus…

SELECTIVE VULNERABILITY OF EMBRYONIC CELL POPULATIONS TO ETHANOL-INDUCED APOPTOSIS: IMPLICATIONS FOR ALCOHOL RELATED BIRTH DEFECTS AND NEURODEVELOPMENTAL DISORDER

EPA Science Inventory

The locations of cell death and resulting malformations in embryos following teratogen exposure vary depending on the teratogen used, the genotype of the conceptus, and the developmental stage of the embryo at time of exposure. To date, ethanol-induced cell death has been charac...

Role of DNA Replication Defects in Breast Cancer

DTIC Science & Technology

2010-10-01

effect is that C3H-Mcm4Chaos3/Chaos3 mice are developmentally normal, but Mcm4Chaos3/- animals die in utero or neonatally [Shima, 2007]. To further...3e). This increase in the ratio of reticulocytes (erythrocyte precursors) to mature RBCs is characteristic of anemia . Hemizygosity for Mcm3

The non-competitive blockade of GABAA receptors by an aqueous extract of water hemlock (Cicuta douglassi) tubers

USDA-ARS?s Scientific Manuscript database

Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement from the desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChR). In this study, we tested the hypothesis that the piperidine alkaloid anabaseine a 1,2-dehydropiperidine and anabasin...

Pediatricians' Knowledge, Training, and Experience in the Care of Children with Fetal Alcohol Syndrome

ERIC Educational Resources Information Center

Gahagan, Sheila; Sharpe, Tanya Telfair; Brimacombe, Michael; Fry-Johnson, Yvonne; Levine, Robert; Mengel, Mark; O'Connor, Mary; Paley, Blair; Adubato, Susan; Brenneman, George

2007-01-01

Objectives: Prenatal exposure to alcohol interferes with fetal development and is the leading preventable cause of birth defects and developmental disabilities. The purpose of this study was to identify current knowledge, diagnosis, prevention, and intervention practices related to fetal alcohol syndrome and related conditions by members of the…

Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses.

PubMed

Wu, Gregory F; Corbo, Evann; Schmidt, Michelle; Smith-Garvin, Jennifer E; Riese, Matthew J; Jordan, Martha S; Laufer, Terri M; Brown, Eric J; Maltzman, Jonathan S

2011-07-01

The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The importance of SERINE DECARBOXYLASE1 (SDC1) and ethanolamine biosynthesis during embryogenesis of Arabidopsis thaliana.

PubMed

Yunus, Ian Sofian; Liu, Yu-Chi; Nakamura, Yuki

2016-11-01

In plants, ethanolamine is considered a precursor for the synthesis of choline, which is an essential dietary nutrient for animals. An enzyme serine decarboxylase (SDC) has been identified and characterized in Arabidopsis, which directly converts serine to ethanolamine, a precursor to phosphorylethanolamine and its subsequent metabolites in plants. However, the importance of SDC and ethanolamine production in plant growth and development remains unclear. Here, we show that SDC is required for ethanolamine biosynthesis in vivo and essential in plant embryogenesis in Arabidopsis. The knockout of SDC1 caused an embryonic lethal defect due to the developmental arrest of the embryos at the heart stage. During embryo development, the expression was observed at the later stages, at which developmental defect occurred in the knockout mutant. Overexpression of SDC1 in planta increased levels of ethanolamine, phosphatidylethanolamine, and phosphatidylcholine both in leaves and siliques. These results suggest that SDC1 plays an essential role in ethanolamine biosynthesis during the embryogenesis in Arabidopsis. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Paternal exposure to cigarette smoke condensate leads to reproductive sequelae and developmental abnormalities in the offspring of mice.

PubMed

Esakky, Prabagaran; Hansen, Deborah A; Drury, Andrea M; Felder, Paul; Cusumano, Andrew; Moley, Kelle H

2016-10-01

Paternal smoking is associated with infertility, birth defects and childhood cancers. Our earlier studies using cigarette smoke condensate (CSC) demonstrated several deleterious changes in male germ cells. Here, we hypothesize that chronic paternal exposure to CSC causes molecular and phenotypic changes in the sire and the offspring, respectively. In this mouse study, CSC caused DNA damage and cytotoxicity in testes via accumulation of benzo(a)pyrene (B[a]P) and cotinine. Decreased expression of growth arrest and DNA damage inducible alpha (Gadd45a), aryl hydrocarbon receptor (Ahr), and cyclin-dependent kinase inhibitor 1A (P21) was seen in CSC exposed testes. Apoptotic germ cell death was detected by induction of Fas, FasL, and activated caspase-3. The CSC-exposed males displayed reduction in sperm motility and fertilizing ability and sired pups with reduced body weight and crown-rump length, and smaller litter size with higher numbers of resorption. This model of CSC exposure demonstrates testicular toxicity and developmental defects in the offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome.

PubMed

Zhang, Xixi; Fan, Cunxian; Zhang, Haiwei; Zhao, Qun; Liu, Yongbo; Xu, Chengxian; Xie, Qun; Wu, Xiaoxia; Yu, Xianjun; Zhang, Jianke; Zhang, Haibing

2016-09-20

MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl(-/-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Gangliosides in the Nervous System: Biosynthesis and Degradation

NASA Astrophysics Data System (ADS)

Yu, Robert K.; Ariga, Toshio; Yanagisawa, Makoto; Zeng, Guichao

Gangliosides, abundant in the nervous system, are known to play crucial modulatory roles in cellular recognition, interaction, adhesion, and signal transduction, particularly during early developmental stages. The expression of gangliosides in the nervous system is developmentally regulated and is closely related to the differentiation state of the cell. Ganglioside biosynthesis occurs in intracellular organelles, from which gangliosides are transported to the plasma membrane. During brain development, the ganglioside composition of the nervous system undergoes remarkable changes and is strictly regulated by the activities of glycosyltransferases, which can occur at different levels of control, including glycosyltransferase gene transcription and posttranslational modification. Genes for glycosyltransferase involved in ganglioside biosynthesis have been cloned and classified into families of glycosyltransferases based on their amino acid sequence similarities. The donor and acceptor substrate specificities are determined by enzymatic analysis of the glycosyltransferase gene products. Cell-type specific regulation of these genes has also been studied. Gangliosides are degraded by lysosomal exoglycosidases. The action of these enzymes occurs frequently in cooperation with activator proteins. Several human diseases are caused by defects of degradative enzymes, resulting in massive accumulation of certain glycolipids, including gangliosides in the lysosomal compartment and other organelles in the brain and visceral organs. Some of the representative lysosomal storage diseases (LSDs) caused by the accumulation of lipids in late endosomes and lysosomes will be discussed.

Morphological and behavioral responses of zebrafish after 24 h of ketamine embryonic exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Félix, Luís M., E-mail: lfelix@utad.pt

Ketamine, one anesthetic used as an illicit drug, has been detected both in freshwater and marine ecosystems. However, knowledge of its impact on aquatic life is still limited. This study aimed to test its effects in zebrafish embryos by analyzing its time- and dose-dependent developmental toxicity and long-term behavioral changes. The 24 h-LC{sub 50} was calculated from percent survival using probit analysis. Based on the 24 h-LC{sub 50} (94.4 mg L{sup −1}), embryos (2 hour post-fertilization - hpf) were divided into four groups, including control, and exposed for 24 h to ketamine concentrations of 50, 70 or 90 mg L{supmore » −1}. Developmental parameters were evaluated on the course of the experimental period, and anatomical abnormalities and locomotor deficits were analyzed at 144 hpf. Although the portion of ketamine transferred into the embryo was higher in the lowest exposed group (about 0.056 ± 0.020 pmol per embryo), the results showed that endpoints such as increased mortality, edema, heart rate alterations, malformation and abnormal growth rates were significantly affected. At 144 hpf, the developmental abnormalities included thoracic and trunk abnormalities in the groups exposed to 70 and 90 mg L{sup −1}. Defects in cartilage (alcian blue) and bone (calcein) elements also corroborated the craniofacial anomalies observed. A significant up-regulation of the development-related gene nog3 was detected by qRT-PCR at 8 hpf. Early exposure to ketamine also resulted in long-term behavioral changes, such as an increase in thigmotaxis and disruption of avoidance behavior at 144 hpf. Altogether, this study provides new evidence on the ketamine teratogenic potential, indicating a possible pharmacological impact of ketamine in aquatic environments. - Highlights: • 24 h exposure to ketamine increases mortality. • Morphological changes were observed after exposure. • Exposure to ketamine leads to severe craniofacial anomalies. • Developmental gene expression changes in response to ketamine. • Developmental ketamine exposure produces lasting behavioral changes.« less

Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.

PubMed

Quintana, Anita M; Yu, Hung-Chun; Brebner, Alison; Pupavac, Mihaela; Geiger, Elizabeth A; Watson, Abigail; Castro, Victoria L; Cheung, Warren; Chen, Shu-Huang; Watkins, David; Pastinen, Tomi; Skovby, Flemming; Appel, Bruce; Rosenblatt, David S; Shaikh, Tamim H

2017-08-01

CblX (MIM309541) is an X-linked recessive disorder characterized by defects in cobalamin (vitamin B12) metabolism and other developmental defects. Mutations in HCFC1, a transcriptional co-regulator which interacts with multiple transcription factors, have been associated with cblX. HCFC1 regulates cobalamin metabolism via the regulation of MMACHC expression through its interaction with THAP11, a THAP domain-containing transcription factor. The HCFC1/THAP11 complex potentially regulates genes involved in diverse cellular functions including cell cycle, proliferation, and transcription. Thus, it is likely that mutation of THAP11 also results in biochemical and other phenotypes similar to those observed in patients with cblX. We report a patient who presented with clinical and biochemical phenotypic features that overlap cblX, but who does not have any mutations in either MMACHC or HCFC1. We sequenced THAP11 by Sanger sequencing and discovered a potentially pathogenic, homozygous variant, c.240C > G (p.Phe80Leu). Functional analysis in the developing zebrafish embryo demonstrated that both THAP11 and HCFC1 regulate the proliferation and differentiation of neural precursors, suggesting important roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role for HCFC1 in vertebrate craniofacial development. High throughput RNA-sequencing analysis reveals several overlapping gene targets of HCFC1 and THAP11. Thus, both HCFC1 and THAP11 play important roles in the regulation of cobalamin metabolism as well as other pathways involved in early vertebrate development. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Panhypopituitarism presenting as life-threatening heart failure caused by an inherited microdeletion in 1q25 including LHX4.

PubMed

Filges, Isabel; Bischof-Renner, Andrea; Röthlisberger, Benno; Potthoff, Christian; Glanzmann, René; Günthard, Joëlle; Schneider, Jacques; Huber, Andreas R; Zumsteg, Urs; Miny, Peter; Szinnai, Gabor

2012-02-01

Clinical presentation of hypopituitarism in the neonate may be variable, ranging from absent to severe nonspecific symptoms and may be life-threatening in patients with adrenocorticotropic hormone deficiency. The LIM homeobox gene 4 (LHX4) transcription factor regulates early embryonic development of the anterior pituitary gland. Autosomal dominant mutations in LHX4 cause congenital hypopituitarism with variable combined pituitary hormone deficiency (CPHD). We report on a neonate with unexplained heart failure and minor physical anomalies, suggesting a midline defect. She was diagnosed with complete CPHD. Cardiac function was rescued by replacement with hydrocortisone and thyroxine; hypoglycaemia stopped under growth hormone therapy. Magnetic resonance imaging revealed a dysgenetic pituitary gland suggesting an early developmental defect. Array comparative genomic hybridization showed a maternally inherited 1.5-megabase microdeletion in 1q25.2q25.3, including the LHX4 gene. Haploinsufficiency of LHX4 likely explains the predominant pituitary phenotype in the proposita and we suggest variable intrafamilial penetrance of the inherited microdeletion. To the best of our knowledge, we are the first to report on heart failure as a rare nonspecific symptom of treatable CPHD in the newborn. Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development.

Harsh childhood environmental characteristics predict exploitation and retaliation in humans

PubMed Central

McCullough, Michael E.; Pedersen, Eric J.; Schroder, Jaclyn M.; Tabak, Benjamin A.; Carver, Charles S.

2013-01-01

Across and within societies, people vary in their propensities towards exploitative and retaliatory defection in potentially cooperative interaction. We hypothesized that this variation reflects adaptive responses to variation in cues during childhood that life will be harsh, unstable and short—cues that probabilistically indicate that it is in one's fitness interests to exploit co-operators and to retaliate quickly against defectors. Here, we show that childhood exposure to family neglect, conflict and violence, and to neighbourhood crime, were positively associated for men (but not women) with exploitation of an interaction partner and retaliatory defection after that partner began to defect. The associations between childhood environment and both forms of defection for men appeared to be mediated by participants' endorsement of a ‘code of honour’. These results suggest that individual differences in mutual benefit cooperation are not merely due to genetic noise, random developmental variation or the operation of domain-general cultural learning mechanisms, but rather, might reflect the adaptive calibration of social strategies to local social–ecological conditions. PMID:23118435

Parent stress across molecular subtypes of children with Angelman syndrome.

PubMed

Miodrag, N; Peters, S

2015-09-01

Parenting stress has been consistently reported among parents of children with developmental disabilities. However, to date, no studies have investigated the impact of a molecular subtype of Angelman syndrome (AS) on parent stress, despite distinct phenotypic differences among subtypes. Data for 124 families of children with three subtypes of AS: class I and II deletions (n = 99), imprinting centre defects (IC defects; n = 11) and paternal uniparental disomy (UPD; n = 14) were drawn from the AS Rare Diseases Clinical Research Network (RDCRN) database and collected from five research sites across the Unites States. The AS study at the RDCRN gathered health information to understand how the syndrome develops and how to treat it. Parents completed questionnaires on their perceived psychological stress, the severity of children's aberrant behaviour and children's sleep patterns. Children's adaptive functioning and developmental levels were clinically evaluated. Child-related stress reached clinical levels for 40% of parents of children with deletions, 100% for IC defects and 64.3% for UPD. Sleep difficulties were similar and elevated across subtypes. There were no differences between molecular subtypes for overall child and parent-related stress. However, results showed greater isolation and lack of perceived parenting skills for parents of children with UPD compared with deletions. Better overall cognition for children with deletions was significantly related to more child-related stress while their poorer adaptive functioning was associated with more child-related stress. For all three groups, the severity of children's inappropriate behaviour was positively related to different aspects of stress. How parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can lead to tailored interventions that fit the particular needs of families of children with different AS subtypes. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Applying Evolutionary Genetics to Developmental Toxicology and Risk Assessment

PubMed Central

Leung, Maxwell C. K.; Procter, Andrew C.; Goldstone, Jared V.; Foox, Jonathan; DeSalle, Robert; Mattingly, Carolyn J.; Siddall, Mark E.; Timme-Laragy, Alicia R.

2018-01-01

Evolutionary thinking continues to challenge our views on health and disease. Yet, there is a communication gap between evolutionary biologists and toxicologists in recognizing the connections among developmental pathways, high-throughput screening, and birth defects in humans. To increase our capability in identifying potential developmental toxicants in humans, we propose to apply evolutionary genetics to improve the experimental design and data interpretation with various in vitro and whole-organism models. We review five molecular systems of stress response and update 18 consensual cell-cell signaling pathways that are the hallmark for early development, organogenesis, and differentiation; and revisit the principles of teratology in light of recent advances in high-throughput screening, big data techniques, and systems toxicology. Multiscale systems modeling plays an integral role in the evolutionary approach to cross-species extrapolation. Phylogenetic analysis and comparative bioinformatics are both valuable tools in identifying and validating the molecular initiating events that account for adverse developmental outcomes in humans. The discordance of susceptibility between test species and humans (ontogeny) reflects their differences in evolutionary history (phylogeny). This synthesis not only can lead to novel applications in developmental toxicity and risk assessment, but also can pave the way for applying an evo-devo perspective to the study of developmental origins of health and disease. PMID:28267574

Environmental exposures to metals in Native communities and implications for child development: basis for the Navajo birth cohort study.

PubMed

Lewis, Johnnye; Gonzales, Melissa; Burnette, Courtney; Benally, Malcolm; Seanez, Paula; Shuey, Christopher; Nez, Helen; Nez, Christopher; Nez, Seraphina

2015-01-01

Two disparate statistics often cited for the Western United States raise concern about risks for developmental disabilities in Native American children. First, 13 of the states with the highest percentage of Native American population are located in the Western United States (U.S. Census Bureau, 2012 ). Second, more than 161,000 abandoned hard-rock mines are located in 12 Western states (General Accounting Office, 2014 ). Moreover, numerous studies have linked low-level metals exposure with birth defects and developmental delays. Concern has emerged among tribal populations that metals exposure from abandoned mines might threaten development of future generations.

Rebuilding a broken heart: lessons from developmental and regenerative biology.

PubMed

Kuyumcu-Martinez, Muge N; Bressan, Michael C

2016-11-01

In May 2016, the annual Weinstein Cardiovascular Development and Regeneration Conference was held in Durham, North Carolina, USA. The meeting assembled leading investigators, junior scientists and trainees from around the world to discuss developmental and regenerative biological approaches to understanding the etiology of congenital heart defects and the repair of diseased cardiac tissue. In this Meeting Review, we present several of the major themes that were discussed throughout the meeting and highlight the depth and range of research currently being performed to uncover the causes of human cardiac diseases and develop potential therapies. © 2016. Published by The Company of Biologists Ltd.

Deletion of OTX2 in neural ectoderm delays anterior pituitary development

PubMed Central

Mortensen, Amanda H.; Schade, Vanessa; Lamonerie, Thomas; Camper, Sally A.

2015-01-01

OTX2 is a homeodomain transcription factor that is necessary for normal head development in mouse and man. Heterozygosity for loss-of-function alleles causes an incompletely penetrant, haploinsufficiency disorder. Affected individuals exhibit a spectrum of features that range from developmental defects in eye and/or pituitary development to acephaly. To investigate the mechanism underlying the pituitary defects, we used different cre lines to inactivate Otx2 in early head development and in the prospective anterior and posterior lobes. Mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification. The morphological defects mimic those observed in humans and mice with OTX2 heterozygous mutations. Mice homozygous for Otx2 deficiency in the pituitary neural ectoderm exhibited altered patterning of gene expression and ablation of FGF signaling. The posterior pituitary lobe and stalk, which normally arise from neural ectoderm, were extremely hypoplastic. Otx2 expression was intact in Rathke's pouch, the precursor to the anterior lobe, but the anterior lobe was hypoplastic. The lack of FGF signaling from the neural ectoderm was sufficient to impair anterior lobe growth, but not the differentiation of hormone-producing cells. This study demonstrates that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitary growth. Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland. PMID:25315894

3D characterization of EMT cell density in developing cardiac cushions using optical coherence tomography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Yu, Siyao; Gu, Shi; Zhao, Xiaowei; Liu, Yehe; Jenkins, Michael W.; Watanabe, Michiko; Rollins, Andrew M.

2017-02-01

Congenital heart defects (CHDs) are the most common birth defect, affecting between 4 and 75 per 1,000 live births depending on the inclusion criteria. Many of these defects can be traced to defects of cardiac cushions, critical structures during development that serve as precursors to many structures in the mature heart, including the atrial and ventricular septa, and all four sets of cardiac valves. Epithelial-mesenchymal transition (EMT) is the process through which cardiac cushions become populated with cells. Altered cushion size or altered cushion cell density has been linked to many forms of CHDs, however, quantitation of cell density in the complex 3D cushion structure poses a significant challenge to conventional histology. Optical coherence tomography (OCT) is a technique capable of 3D imaging of the developing heart, but typically lacks the resolution to differentiate individual cells. Our goal is to develop an algorithm to quantitatively characterize the density of cells in the developing cushion using 3D OCT imaging. First, in a heart volume, the atrioventricular (AV) cushions were manually segmented. Next, all voxel values in the region of interest were pooled together to generate a histogram. Finally, two populations of voxels were classified using either K-means classification, or a Gaussian mixture model (GMM). The voxel population with higher values represents cells in the cushion. To test the algorithm, we imaged and evaluated avian embryonic hearts at looping stages. As expected, our result suggested that the cell density increases with developmental stages. We validated the technique against scoring by expert readers.

Developmental imaging: the avian embryo hatches to the challenge.

PubMed

Kulesa, Paul M; McKinney, Mary C; McLennan, Rebecca

2013-06-01

The avian embryo provides a multifaceted model to study developmental mechanisms because of its accessibility to microsurgery, fluorescence cell labeling, in vivo imaging, and molecular manipulation. Early two-dimensional planar growth of the avian embryo mimics human development and provides unique access to complex cell migration patterns using light microscopy. Later developmental events continue to permit access to both light and other imaging modalities, making the avian embryo an excellent model for developmental imaging. For example, significant insights into cell and tissue behaviors within the primitive streak, craniofacial region, and cardiovascular and peripheral nervous systems have come from avian embryo studies. In this review, we provide an update to recent advances in embryo and tissue slice culture and imaging, fluorescence cell labeling, and gene profiling. We focus on how technical advances in the chick and quail provide a clearer understanding of how embryonic cell dynamics are beautifully choreographed in space and time to sculpt cells into functioning structures. We summarize how these technical advances help us to better understand basic developmental mechanisms that may lead to clinical research into human birth defects and tissue repair. Copyright © 2013 Wiley Periodicals, Inc.

Rapamycin treatment causes developmental delay, pigmentation defects, and gastrointestinal malformation on Xenopus embryogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moriyama, Yuki; Ohata, Yoshihisa; Mori, Shoko

Research highlights: {yields} Does famous anti-aging drug rapamycin work from the beginning of life? The answer is yes. {yields} This study shows that developmental speed of frog embryo was dose-dependently decreased by rapamycin treatment. {yields} In additions, morphogenetic effects such as less pigmentations and gut malformation are occurred by rapamycin. -- Abstract: Rapamycin is a drug working as an inhibitor of the TOR (target of rapamycin) signaling pathway and influences various life phenomena such as cell growth, proliferation, and life span extension in eukaryote. However, the extent to which rapamycin controls early developmental events of amphibians remains to be understood.more » Here we report an examination of rapamycin effects during Xenopus early development, followed by a confirmation of suppression of TOR downstream kinase S6K by rapamycin treatment. First, we found that developmental speed was declined in dose-dependent manner of rapamycin. Second, black pigment spots located at dorsal and lateral skin in tadpoles were reduced by rapamycin treatment. Moreover, in tadpole stages severe gastrointestinal malformations were observed in rapamycin-treated embryos. Taken together with these results, we conclude that treatment of the drug rapamycin causes enormous influences on early developmental period.« less

Xenopus as a Model Organism for Birth Defects – Congenital Heart Disease and Heterotaxy

PubMed Central

Duncan, Anna R.; Khokha, Mustafa K.

2016-01-01

Congenital heart disease is the leading cause of birth defects, affecting 9 out of 1000 newborns each year. A particularly severe form of congenital heart disease is heterotaxy, a disorder of left-right development. Despite aggressive surgical management, patients with heterotaxy have poor survival rates and severe morbidity due to their complex congenital heart disease. Recent genetic analysis of affected patients has found novel candidate genes for heterotaxy although their underlying mechanisms remain unknown. In this review, we discuss the importance and challenges of birth defects research including high locus heterogeneity and few second alleles that make defining disease causality difficult. A powerful strategy moving forward is to analyze these candidate genes in a high-throughput human disease model. Xenopus is ideal for these studies. We present multiple examples demonstrating the power of Xenopus in discovery new biology from the analysis of candidate heterotaxy genes such as GALNT11, NEK2 and BCOR. These genes have diverse roles in embryos and have led to a greater understanding of complex signaling pathways and basic developmental biology. It is our hope that the mechanistic analysis of these candidate genes in Xenopus enabled by next generation sequencing of patients will provide clinicians with a greater understanding of patient pathophysiology allowing more precise and personalized medicine, to help them more effectively in the future. PMID:26910255

Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development.

PubMed

Sakai, Daisuke; Trainor, Paul A

2016-09-01

One-third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue-specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies. © 2016 Japanese Society of Developmental Biologists.

Holoprosencephaly: signalling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans

PubMed Central

Graf, Daniel; Marcucio, Ralph

2014-01-01

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain characterized by inadequate or absent midline division of the forebrain into cerebral hemispheres, with concomitant midline facial defects in the majority of cases. Understanding the pathogenesis of HPE requires knowledge of the relationship between the developing brain and the facial structures during embryogenesis. A number of signalling pathways control and coordinate the development of the brain and face, including Sonic hedgehog (SHH), Bone Morphogenetic Protein (BMP), Fibroblast Growth Factor (FGF), and Nodal signalling. Mutations in these pathways have been identified in animal models of HPE and human patients. Due to incomplete penetrance and variable expressivity of HPE, patients carrying defined mutations may not manifest the disease at all, or have a spectrum of defects. It is currently unknown what drives manifestation of HPE in genetically at risk individuals, but it has been speculated that other gene mutations and environmental factors may combine as cumulative insults. HPE can be diagnosed in utero by a high-resolution prenatal ultrasound or a fetal magnetic resonance imaging, sometimes in combination with molecular testing from chorionic villi or amniotic fluid sampling. Currently, there are no effective preventive methods for HPE. Better understanding of the mechanisms of gene-environment interactions in HPE would provide avenues for such interventions. PMID:25339593

Analysis of leukotrienes in cerebrospinal fluid of a reference population and patients with inborn errors of metabolism: further evidence for a pathognomonic profile in LTC(4)-synthesis deficiency.

PubMed

Mayatepek, E; Zelezny, R; Hoffmann, G F

2000-02-25

Cysteinyl leukotrienes (LTC(4), LTD(4), LTE(4)) are potent lipid mediators derived from arachidonate in the 5-lipoxygenase pathway. Recently, the first inborn error of leukotriene synthesis, LTC(4)-synthesis deficiency, has been identified in association with a fatal developmental syndrome. The absence of leukotrienes in cerebrospinal fluid was one of the most striking biochemical findings in this disorder. We analysed leukotrienes in cerebrospinal fluid of patients with a broad spectrum of other well-defined inborn errors of metabolism, including glutathione synthetase deficiency (n=2), Zellweger syndrome (n=3), mitochondrial disorders (n=8), fatty acid oxidation defects (n=7), organic acidurias (n=7), neurotransmitter defects (n=5) and patients with non-specific neurological symptoms, as a reference population (n=120). The concentrations of leukotrienes were not related to age. Representative percentiles were calculated as reference intervals of each leukotriene. In all patients with an inborn error of metabolism concentration of cysteinyl leukotrienes and LTB(4) did not differ from the reference group. Our results indicate that absence of cysteinyl leukotrienes (<5 pg/ml) in association with normal or increased LTB(4) (50.0-67.3 pg/ml) is pathognomonic for LTC(4)-synthesis deficiency. The unique profile of leukotrienes in cerebrospinal fluid in this new disorder is primarily related to the defect and represents a new diagnostic approach.

Fanconi anemia: a disorder defective in the DNA damage response.

PubMed

Kitao, Hiroyuki; Takata, Minoru

2011-04-01

Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin-phosphorylation network called the "FA pathway" and cooperate with other proteins involved in DNA repair and cell cycle control to repair ICL lesions and to maintain genome stability. In this review, we summarize recent exciting discoveries that have expanded our view of the molecular mechanisms operating in DNA repair and DNA damage signaling.

Septate Junction Proteins Play Essential Roles in Morphogenesis Throughout Embryonic Development in Drosophila

PubMed Central

Hall, Sonia; Ward, Robert E.

2016-01-01

The septate junction (SJ) is the occluding junction found in the ectodermal epithelia of invertebrate organisms, and is essential to maintain chemically distinct compartments in epithelial organs, to provide the blood–brain barrier in the nervous system, and to provide an important line of defense against invading pathogens. More than 20 genes have been identified to function in the establishment or maintenance of SJs in Drosophila melanogaster. Numerous studies have demonstrated the cell biological function of these proteins in establishing the occluding junction, whereas very few studies have examined further developmental roles for them. Here we examined embryos with mutations in nine different core SJ genes and found that all nine result in defects in embryonic development as early as germ band retraction, with the most penetrant defect observed in head involution. SJ genes are also required for cell shape changes and cell rearrangements that drive the elongation of the salivary gland during midembryogenesis. Interestingly, these developmental events occur at a time prior to the formation of the occluding junction, when SJ proteins localize along the lateral membrane and have not yet coalesced into the region of the SJ. Together, these observations reveal an underappreciated role for a large group of SJ genes in essential developmental events during embryogenesis, and suggest that the function of these proteins in facilitating cell shape changes and rearrangements is independent of their role in the occluding junction. PMID:27261004

Manifestations, Treatment Implications and Speech-Language Consideration in Gorlin Syndrome: A Case Study.

ERIC Educational Resources Information Center

Andrews, Alice E.; Stonestreet, Ruth H.

This paper presents a case study of Gorlin Syndrome, also known as Basal Cell Nevus Syndrome, a rare genetic disorder characterized by widespread developmental defects. Criteria for diagnosis are listed, noting the presence of frequent basal cell carcinomas at a relatively young age and multiple cysts of the jaw. Speech and/or language impairments…

EGF AND TGF ALPHA EXPRESSION INFLUENCE THE DEVELOPMENTAL TOXICITY OF TCDD: DOSE RESPONSE AND AHR PHENOTYPE IN EGF, TGF ALPHA AND EGF+TGF ALPHA KNOCKOUT MICE

EPA Science Inventory

Abstract
The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate (CP) and hydronephrosis (HN) in mice. The etiology of these defects involves hyperproliferation of epithelial cells of the secondary palatal shelf and ureter, respectively. ...

Of Heart & Kidneys: Hands-On Activities for Demonstrating Organ Function & Repair

ERIC Educational Resources Information Center

Kao, Robert M.

2014-01-01

A major challenge in teaching organ development and disease is deconstructing a complex choreography of molecular and cellular changes over time into a linear stepwise process for students. As an entry toward learning developmental concepts, I propose two inexpensive hands-on activities to help facilitate learning of (1) how to identify defects in…

Microcephaly: computational and organotypic modeling of a ...

EPA Pesticide Factsheets

lecture discusses computational and organotypic models of microcephaly in an AOP Framework and ToxCast assays. Lecture slide presentation at UNC Chapel Hill for Advanced Toxicology course lecture on Computational Approaches to Developmental and Reproductive Toxicology with presentation on computational and organotypic modeling of a complex human birth defect microcephaly with is associated with the recent Zika virus outbreak.

Defective Number Sense or Impaired Access? Differential Impairments in Different Subgroups of Children with Mathematics Difficulties

ERIC Educational Resources Information Center

Wong, Terry T.-Y.; Ho, Connie S.-H.; Tang, Joey

2017-01-01

Developmental dyscalculia (DD) is a specific learning disability in mathematics that affects around 6% of the population. Currently, the core deficit of DD remains unknown. While the number sense deficit hypothesis suggests that the core deficit of DD lies in the inability to represent nonsymbolic numerosity, the access deficit hypothesis suggests…

Developmentally regulated HEART STOPPER, a mitochondrially targeted L18 ribosomal protein gene, is required for cell division, differentiation, and seed development in Arabidopsis

PubMed Central

Zhang, Hongyu; Luo, Ming; Day, Robert C.; Talbot, Mark J.; Ivanova, Aneta; Ashton, Anthony R.; Chaudhury, Abed M.; Macknight, Richard C.; Hrmova, Maria; Koltunow, Anna M.

2015-01-01

Evidence is presented for the role of a mitochondrial ribosomal (mitoribosomal) L18 protein in cell division, differentiation, and seed development after the characterization of a recessive mutant, heart stopper (hes). The hes mutant produced uncellularized endosperm and embryos arrested at the late globular stage. The mutant embryos differentiated partially on rescue medium with some forming callus. HES (At1g08845) encodes a mitochondrially targeted member of a highly diverged L18 ribosomal protein family. The substitution of a conserved amino residue in the hes mutant potentially perturbs mitoribosomal function via altered binding of 5S rRNA and/or influences the stability of the 50S ribosomal subunit, affecting mRNA binding and translation. Consistent with this, marker genes for mitochondrial dysfunction were up-regulated in the mutant. The slow growth of the endosperm and embryo indicates a defect in cell cycle progression, which is evidenced by the down-regulation of cell cycle genes. The down-regulation of other genes such as EMBRYO DEFECTIVE genes links the mitochondria to the regulation of many aspects of seed development. HES expression is developmentally regulated, being preferentially expressed in tissues with active cell division and differentiation, including developing embryos and the root tips. The divergence of the L18 family, the tissue type restricted expression of HES, and the failure of other L18 members to complement the hes phenotype suggest that the L18 proteins are involved in modulating development. This is likely via heterogeneous mitoribosomes containing different L18 members, which may result in differential mitochondrial functions in response to different physiological situations during development. PMID:26105995

X-Linked Retinitis Pigmentosa 2 Is a Novel Maternal-Effect Gene Required for Left-Right Asymmetry in Zebrafish.

PubMed

Desvignes, Thomas; Nguyen, Thaovi; Chesnel, Franck; Bouleau, Aurélien; Fauvel, Christian; Bobe, Julien

2015-08-01

Retinitis pigmentosa 2 (RP2) gene is responsible for up to 20% of X-linked retinitis pigmentosa, a severe heterogeneous genetic disorder resulting in progressive retinal degeneration in humans. In vertebrates, several bodies of evidence have clearly established the role of Rp2 protein in cilia genesis and/or function. Unexpectedly, some observations in zebrafish have suggested the oocyte-predominant expression of the rp2 gene, a typical feature of maternal-effect genes. In the present study, we investigate the maternal inheritance of rp2 gene products in zebrafish eggs in order to address whether rp2 could be a novel maternal-effect gene required for normal development. Although both rp2 mRNA and corresponding protein are expressed during oogenesis, rp2 mRNA is maternally inherited, in contrast to Rp2 protein. A knockdown of the protein transcribed from both rp2 maternal and zygotic mRNA results in delayed epiboly and severe developmental defects, including eye malformations, that were not observed when only the protein from zygotic origin was knocked down. Moreover, the knockdown of maternal and zygotic Rp2 revealed a high incidence of left-right asymmetry establishment defects compared to only zygotic knockdown. Here we show that rp2 is a novel maternal-effect gene exclusively expressed in oocytes within the zebrafish ovary and demonstrate that maternal rp2 mRNA is essential for successful embryonic development and thus contributes to egg developmental competence. Our observations also reveal that Rp2 protein translated from maternal mRNA is important to allow normal heart loop formation, thus providing evidence of a direct maternal contribution to left-right asymmetry establishment. © 2015 by the Society for the Study of Reproduction, Inc.

Bruton's tyrosine kinase and SLP-65 regulate pre-B cell differentiation and the induction of Ig light chain gene rearrangement.

PubMed

Kersseboom, Rogier; Ta, Van B T; Zijlstra, A J Esther; Middendorp, Sabine; Jumaa, Hassan; van Loo, Pieter Fokko; Hendriks, Rudolf W

2006-04-15

Bruton's tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We show that Btk- and SLP-65-deficient pre-B cells have a specific defect in Ig lambda L chain germline transcription. In Btk/SLP-65 double-deficient pre-B cells, both kappa and lambda germline transcripts are severely reduced. Although these observations point to an important role for Btk and SLP-65 in the initiation of L chain gene rearrangement, the possibility remained that these signaling molecules are only required for termination of pre-B cell proliferation or for pre-B cell survival, whereby differentiation and L chain rearrangement is subsequently initiated in a Btk/SLP-65-independent fashion. Because transgenic expression of the antiapoptotic protein Bcl-2 did not rescue the developmental arrest of Btk/SLP-65 double-deficient pre-B cells, we conclude that defective L chain opening in Btk/SLP-65-deficient small resting pre-B cells is not due to their reduced survival. Next, we analyzed transgenic mice expressing the constitutively active Btk mutant E41K. The expression of E41K-Btk in Ig H chain-negative pro-B cells induced 1) surface marker changes that signify cellular differentiation, including down-regulation of surrogate L chain and up-regulation of CD2, CD25, and MHC class II; and 2) premature rearrangement and expression of kappa and lambda light chains. These findings demonstrate that Btk and SLP-65 transmit signals that induce cellular maturation and Ig L chain rearrangement independently of their role in termination of pre-B cell expansion.

Transient Exposure to Ethanol during Zebrafish Embryogenesis Results in Defects in Neuronal Differentiation: An Alternative Model System to Study FASD

PubMed Central

Joya, Xavier; Garcia-Algar, Oscar; Vall, Oriol; Pujades, Cristina

2014-01-01

Background The exposure of the human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the impairment of the development of the central nervous system (CNS). In spite of the importance for human health, the molecular basis of prenatal ethanol exposure remains poorly understood, mainly to the difficulty of sample collection. Zebrafish is now emerging as a powerful organism for the modeling and the study of human diseases. In this work, we have assessed the sensitivity of specific subsets of neurons to ethanol exposure during embryogenesis and we have visualized the sensitive embryonic developmental periods for specific neuronal groups by the use of different transgenic zebrafish lines. Methodology/Principal Findings In order to evaluate the teratogenic effects of acute ethanol exposure, we exposed zebrafish embryos to ethanol in a given time window and analyzed the effects in neurogenesis, neuronal differentiation and brain patterning. Zebrafish larvae exposed to ethanol displayed small eyes and/or a reduction of the body length, phenotypical features similar to the observed in children with prenatal exposure to ethanol. When neuronal populations were analyzed, we observed a clear reduction in the number of differentiated neurons in the spinal cord upon ethanol exposure. There was a decrease in the population of sensory neurons mainly due to a decrease in cell proliferation and subsequent apoptosis during neuronal differentiation, with no effect in motoneuron specification. Conclusion Our investigation highlights that transient exposure to ethanol during early embryonic development affects neuronal differentiation although does not result in defects in early neurogenesis. These results establish the use of zebrafish embryos as an alternative research model to elucidate the molecular mechanism(s) of ethanol-induced developmental toxicity at very early stages of embryonic development. PMID:25383948

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.

PubMed

Wesdorp, Mieke; de Koning Gans, Pia A M; Schraders, Margit; Oostrik, Jaap; Huynen, Martijn A; Venselaar, Hanka; Beynon, Andy J; van Gaalen, Judith; Piai, Vitória; Voermans, Nicol; van Rossum, Michelle M; Hartel, Bas P; Lelieveld, Stefan H; Wiel, Laurens; Verbist, Berit; Rotteveel, Liselotte J; van Dooren, Marieke F; Lichtner, Peter; Kunst, Henricus P M; Feenstra, Ilse; Admiraal, Ronald J C; Yntema, Helger G; Hoefsloot, Lies H; Pennings, Ronald J E; Kremer, Hannie

2018-05-12

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

The role of diet and nutrition in the etiology and prevention of oral diseases.

PubMed

Moynihan, Paula J

2005-09-01

Diet plays an important role in preventing oral diseases including dental caries, dental erosion, developmental defects, oral mucosal diseases and, to a lesser extent, periodontal disease. This paper is intended to provide an overview of the evidence for an association between diet, nutrition and oral diseases and to clarify areas of uncertainty. Undernutrition increases the severity of oral mucosal and periodontal diseases and is a contributing factor to life-threatening noma. Undernutrition is associated with developmental defects of the enamel which increase susceptibility to dental caries. Dental erosion is perceived to be increasing. Evidence suggests that soft drinks, a major source of acids in the diet in developed countries, are a significant causative factor. Convincing evidence from experimental, animal, human observational and human intervention studies shows that sugars are the main dietary factor associated with dental caries. Despite the indisputable role of fluoride in the prevention of caries, it has not eliminated dental caries and many communities are not exposed to optimal quantities of fluoride. Controlling the intake of sugars therefore remains important for caries prevention. Research has consistently shown that when the intake of free sugars is < 15 kg/person/year, the level of dental caries is low. Despite experimental and animal studies suggesting that some starch-containing foods and fruits are cariogenic, this is not supported by epidemiological data, which show that high intakes of starchy staple foods, fruits and vegetables are associated with low levels of dental caries. Following global recommendations that encourage a diet high in starchy staple foods, fruit and vegetables and low in free sugars and fat will protect both oral and general health.

The role of diet and nutrition in the etiology and prevention of oral diseases.

PubMed Central

Moynihan, Paula J.

2005-01-01

Diet plays an important role in preventing oral diseases including dental caries, dental erosion, developmental defects, oral mucosal diseases and, to a lesser extent, periodontal disease. This paper is intended to provide an overview of the evidence for an association between diet, nutrition and oral diseases and to clarify areas of uncertainty. Undernutrition increases the severity of oral mucosal and periodontal diseases and is a contributing factor to life-threatening noma. Undernutrition is associated with developmental defects of the enamel which increase susceptibility to dental caries. Dental erosion is perceived to be increasing. Evidence suggests that soft drinks, a major source of acids in the diet in developed countries, are a significant causative factor. Convincing evidence from experimental, animal, human observational and human intervention studies shows that sugars are the main dietary factor associated with dental caries. Despite the indisputable role of fluoride in the prevention of caries, it has not eliminated dental caries and many communities are not exposed to optimal quantities of fluoride. Controlling the intake of sugars therefore remains important for caries prevention. Research has consistently shown that when the intake of free sugars is < 15 kg/person/year, the level of dental caries is low. Despite experimental and animal studies suggesting that some starch-containing foods and fruits are cariogenic, this is not supported by epidemiological data, which show that high intakes of starchy staple foods, fruits and vegetables are associated with low levels of dental caries. Following global recommendations that encourage a diet high in starchy staple foods, fruit and vegetables and low in free sugars and fat will protect both oral and general health. PMID:16211161

Sema4d is required for the development of the hindbrain boundary and skeletal muscle in zebrafish

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Jie; Zeng, Zhen; Wei, Juncheng

2013-04-05

Highlights: ► Sema4d was expressed at all developmental stages of zebrafish. ► Knockdown of sema4d in embryos resulted in defects in the hindbrain and the trunk structure. ► Knockdown of sema4d in embryos upregulated the expression of three hindbrain rhombomere markers. ► Knockdown of sema4d in embryos increased the expression of myogenic regulatory factors. ► Knockdown of sema4d in embryos resulted in an obvious increase of cell apoptosis. -- Abstract: Semaphorin4d (SEMA4D), also known as CD100, an oligodendrocyte secreted R-Ras GTPase-activating protein (GAP), affecting axonal growth is involved in a range of processes including cell adhesion, motility, angiogenesis, immune responsesmore » and tumour progression. However, its actual physiological mechanisms and its role in development remain unclear. This study has focused on the role of sema4d in the development and expression patterns in zebrafish embryos and the effect of its suppression on development using sema4d-specific antisense morpholino-oligonucleotides. In this study the knockdown of sema4d, expressed at all developmental stages, lead to defects in the hindbrain and trunk structure of zebrafish embryos. In addition, these phenotypes appeared to be associated with the abnormal expression of three hindbrain rhombomere boundary markers, wnt1, epha4a and foxb1.2, and two myogenic regulatory factors, myod and myog. Further, a notable increase of cell apoptosis appeared in the sema4d knockdown embryos, while no obvious reduction in cell proliferation was observed. Collectively, these data suggest that sema4d plays an important role in the development of the hindbrain and skeletal muscle.« less

Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma

PubMed Central

Reis, Linda M.; Semina, Elena V.

2016-01-01

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and, finally, provide an avenue for the development and testing of therapeutic interventions. PMID:26046913

Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma.

PubMed

Reis, Linda M; Semina, Elena V

2015-06-01

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia, and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors, confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and finally, provide an avenue for the development and testing of therapeutic interventions. © 2015 Wiley Periodicals, Inc.

Single-Cell Resolution of Temporal Gene Expression during Heart Development.

PubMed

DeLaughter, Daniel M; Bick, Alexander G; Wakimoto, Hiroko; McKean, David; Gorham, Joshua M; Kathiriya, Irfan S; Hinson, John T; Homsy, Jason; Gray, Jesse; Pu, William; Bruneau, Benoit G; Seidman, J G; Seidman, Christine E

2016-11-21

Activation of complex molecular programs in specific cell lineages governs mammalian heart development, from a primordial linear tube to a four-chamber organ. To characterize lineage-specific, spatiotemporal developmental programs, we performed single-cell RNA sequencing of >1,200 murine cells isolated at seven time points spanning embryonic day 9.5 (primordial heart tube) to postnatal day 21 (mature heart). Using unbiased transcriptional data, we classified cardiomyocytes, endothelial cells, and fibroblast-enriched cells, thus identifying markers for temporal and chamber-specific developmental programs. By harnessing these datasets, we defined developmental ages of human and mouse pluripotent stem-cell-derived cardiomyocytes and characterized lineage-specific maturation defects in hearts of mice with heterozygous mutations in Nkx2.5 that cause human heart malformations. This spatiotemporal transcriptome analysis of heart development reveals lineage-specific gene programs underlying normal cardiac development and congenital heart disease. Copyright © 2016 Elsevier Inc. All rights reserved.

The Developmental Regulator SEEDSTICK Controls Structural and Mechanical Properties of the Arabidopsis Seed Coat

PubMed Central

Beauzamy, Léna; Caporali, Elisabetta; Koroney, Abdoul-Salam

2016-01-01

Although many transcription factors involved in cell wall morphogenesis have been identified and studied, it is still unknown how genetic and molecular regulation of cell wall biosynthesis is integrated into developmental programs. We demonstrate by molecular genetic studies that SEEDSTICK (STK), a transcription factor controlling ovule and seed integument identity, directly regulates PMEI6 and other genes involved in the biogenesis of the cellulose-pectin matrix of the cell wall. Based on atomic force microscopy, immunocytochemistry, and chemical analyses, we propose that structural modifications of the cell wall matrix in the stk mutant contribute to defects in mucilage release and seed germination under water-stress conditions. Our studies reveal a molecular network controlled by STK that regulates cell wall properties of the seed coat, demonstrating that developmental regulators controlling organ identity also coordinate specific aspects of cell wall characteristics. PMID:27624758

Update on Foregut Molecular Embryology and Role of Regenerative Medicine Therapies

PubMed Central

Perin, Silvia; McCann, Conor J.; Borrelli, Osvaldo; De Coppi, Paolo; Thapar, Nikhil

2017-01-01

Esophageal atresia (OA) represents one of the commonest and most severe developmental disorders of the foregut, the most proximal segment of the gastrointestinal (GI) tract (esophagus and stomach) in embryological terms. Of intrigue is the common origin from this foregut of two very diverse functional entities, the digestive and respiratory systems. OA appears to result from incomplete separation of the ventral and dorsal parts of the foregut during development, resulting in disruption of esophageal anatomy and frequent association with tracheo-oesophageal fistula. Not surprisingly, and likely inherent to OA, are associated abnormalities in components of the enteric neuromusculature and ultimately loss of esophageal functional integrity. An appreciation of such developmental processes and associated defects has not only enhanced our understanding of the etiopathogenesis underlying such devastating defects but also highlighted the potential of novel corrective therapies. There has been considerable progress in the identification and propagation of neural crest stem cells from the GI tract itself or derived from pluripotent cells. Such cells have been successfully transplanted into models of enteric neuropathy confirming their ability to functionally integrate and replenish missing or defective enteric nerves. Combinatorial approaches in tissue engineering hold significant promise for the generation of organ-specific scaffolds such as the esophagus with current initiatives directed toward their cellularization to facilitate optimal function. This chapter outlines the most current understanding of the molecular embryology underlying foregut development and OA, and also explores the promise of regenerative medicine. PMID:28503544

[Neurological and psychomotor development of foetuses and children with congenital heart disease--causes and prevalence of disorders and long-term prognosis].

PubMed

Herberg, U; Hövels-Gürich, H

2012-06-01

Children with severe congenital heart defects (CHD) requiring open heart surgery in the first year of life are at high risk for developing neurological and psychomotor abnormalities. Depending on the type and severity of the CHD, between 15 and over 50% of these children have deficits, which are usually confined to distinct domains of development, although formal intelligence tends to be normal. Children with mild CHD, who comprise the majority of congenital heart defects, have a far better developmental prognosis than those with complex CHD. This review concentrates on the impact of severe CHD on the developing brain of the foetus and infant. It also provides a summary of recent clinical and neuroimaging studies, and an overview of the long-term neurological prognosis. Advanced neuroimaging modalities indicate that, related to altered cerebral blood flow and oxygenation, foetuses with severe CHD show delayed third trimester brain maturation and increased vulnerability for hypoxic injury. Morphological and neurological abnormalities are present before surgery, commonly affecting the white matter. In the long-term, impaired neurological and developmental outcomes are related to the combination of prenatal, perinatal and additional perioperative risk factors. Therefore, new therapeutic approaches aim to optimise the intra- and perinatal management of foetuses and newborns with congenital heart defects. Identification and avoidance of risk factors, early neurodevelopmental assessment and therapy may optimise the long-term outcome in this high-risk population. © Georg Thieme Verlag KG Stuttgart · New York.

Update on Foregut Molecular Embryology and Role of Regenerative Medicine Therapies.

PubMed

Perin, Silvia; McCann, Conor J; Borrelli, Osvaldo; De Coppi, Paolo; Thapar, Nikhil

2017-01-01

Esophageal atresia (OA) represents one of the commonest and most severe developmental disorders of the foregut, the most proximal segment of the gastrointestinal (GI) tract (esophagus and stomach) in embryological terms. Of intrigue is the common origin from this foregut of two very diverse functional entities, the digestive and respiratory systems. OA appears to result from incomplete separation of the ventral and dorsal parts of the foregut during development, resulting in disruption of esophageal anatomy and frequent association with tracheo-oesophageal fistula. Not surprisingly, and likely inherent to OA, are associated abnormalities in components of the enteric neuromusculature and ultimately loss of esophageal functional integrity. An appreciation of such developmental processes and associated defects has not only enhanced our understanding of the etiopathogenesis underlying such devastating defects but also highlighted the potential of novel corrective therapies. There has been considerable progress in the identification and propagation of neural crest stem cells from the GI tract itself or derived from pluripotent cells. Such cells have been successfully transplanted into models of enteric neuropathy confirming their ability to functionally integrate and replenish missing or defective enteric nerves. Combinatorial approaches in tissue engineering hold significant promise for the generation of organ-specific scaffolds such as the esophagus with current initiatives directed toward their cellularization to facilitate optimal function. This chapter outlines the most current understanding of the molecular embryology underlying foregut development and OA, and also explores the promise of regenerative medicine.

A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies.

PubMed

Pedace, Lucia; Castori, Marco; Binni, Francesco; Pingi, Alberto; Grammatico, Barbara; Scommegna, Salvatore; Majore, Silvia; Grammatico, Paola

2009-01-01

Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.

Microcephalic Osteodysplastic Primordial Dwarfism type I with biallelic mutations in the RNU4ATAC gene

PubMed Central

Nagy, Rebecca; Wang, Heng; Albrecht, Beate; Wieczorek, Dagmar; Gillessen-Kaesbach, Gabriele; Haan, Eric; Meinecke, Peter; de la Chapelle, Albert; Westman, Judith A.

2011-01-01

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene. PMID:21815888

Morphological and behavioral responses of zebrafish after 24h of ketamine embryonic exposure.

PubMed

Félix, Luís M; Serafim, Cindy; Martins, Maria J; Valentim, Ana M; Antunes, Luís M; Matos, Manuela; Coimbra, Ana M

2017-04-15

Ketamine, one anesthetic used as an illicit drug, has been detected both in freshwater and marine ecosystems. However, knowledge of its impact on aquatic life is still limited. This study aimed to test its effects in zebrafish embryos by analyzing its time- and dose-dependent developmental toxicity and long-term behavioral changes. The 24h-LC 50 was calculated from percent survival using probit analysis. Based on the 24h-LC 50 (94.4mgL -1 ), embryos (2hour post-fertilization - hpf) were divided into four groups, including control, and exposed for 24h to ketamine concentrations of 50, 70 or 90mgL -1 . Developmental parameters were evaluated on the course of the experimental period, and anatomical abnormalities and locomotor deficits were analyzed at 144hpf. Although the portion of ketamine transferred into the embryo was higher in the lowest exposed group (about 0.056±0.020pmol per embryo), the results showed that endpoints such as increased mortality, edema, heart rate alterations, malformation and abnormal growth rates were significantly affected. At 144hpf, the developmental abnormalities included thoracic and trunk abnormalities in the groups exposed to 70 and 90mgL -1 . Defects in cartilage (alcian blue) and bone (calcein) elements also corroborated the craniofacial anomalies observed. A significant up-regulation of the development-related gene nog3 was detected by qRT-PCR at 8 hpf. Early exposure to ketamine also resulted in long-term behavioral changes, such as an increase in thigmotaxis and disruption of avoidance behavior at 144 hpf. Altogether, this study provides new evidence on the ketamine teratogenic potential, indicating a possible pharmacological impact of ketamine in aquatic environments. Copyright © 2017 Elsevier Inc. All rights reserved.

The prevalence of chromosomal deletions relating to developmental delay and/or intellectual disability in human euploid blastocysts.

PubMed

He, Wenyin; Sun, Xiaofang; Liu, Lian; Li, Man; Jin, Hua; Wang, Wei-Hua

2014-01-01

Chromosomal anomalies in human embryos produced by in vitro fertilization are very common, which include numerical (aneuploidy) and structural (deletion, duplication or others) anomalies. Our previous study indicated that chromosomal deletion(s) is the most common structural anomaly accounting for approximately 8% of euploid blastocysts. It is still unknown if these deletions in human euploid blastocysts have clinical significance. In this study, we analyzed 15 previously diagnosed euploid blastocysts that had chromosomal deletion(s) using Agilent oligonucleotide DNA microarray platform and localized the gene location in each deletion. Then, we used OMIM gene map and phenotype database to investigate if these deletions are related with some important genes that cause genetic diseases, especially developmental delay or intellectual disability. As results, we found that the detectable chromosomal deletion size with Agilent microarray is above 2.38 Mb, while the deletions observed in human blastocysts are between 11.6 to 103 Mb. With OMIM gene map and phenotype database information, we found that deletions can result in loss of 81-464 genes. Out of these genes, 34-149 genes are related with known genetic problems. Furthermore, we found that 5 out of 15 samples lost genes in the deleted region, which were related to developmental delay and/or intellectual disability. In conclusion, our data indicates that all human euploid blastocysts with chromosomal deletion(s) are abnormal and transfer of these embryos may cause birth defects and/or developmental and intellectual disabilities. Therefore, the embryos with chromosomal deletion revealed by DNA microarray should not be transferred to the patients, or further gene map and/or phenotype seeking is necessary before making a final decision.

Prevalence of enamel defects and association with dental caries in preschool children.

PubMed

Massignan, C; Ximenes, M; da Silva Pereira, C; Dias, L; Bolan, M; Cardoso, M

2016-12-01

This was to evaluate the prevalence of the developmental defects of enamel (DDE) in primary teeth and its association with dental caries. A cross-sectional study with a randomised representative sample was carried out with 1101 children aged 2-5 years enrolled in public preschools (50% prevalence of DDE in primary teeth, a standard error of 3%, and a confidence level of 95%). Three calibrated dentists (K > 0.62) performed clinical examination. Data collected were: sex, age, DDE (Modified DDE Index) and dental caries (WHO). Descriptive analysis, Chi-square test and multinomial logistic regression were applied for data analysis. Among children, 565 (51.3%) were boys; mean age was 3.7 (±0.9 years). The prevalence of enamel defect was 39.1%; the prevalence of diffuse opacities, demarcated opacities and enamel hypoplasia was 25.3, 19.1 and 6.1%, respectively. The prevalence of dental caries was 31.0%, with mean def-t 1.14 (±2.44). Primary teeth with enamel hypoplasia had three times the odds of having dental caries than those with absence of enamel defects (OR = 3.10; 95% CI: 1.91, 5.01). The presence of enamel defects was moderate and associated with dental caries.

Physics and the canalization of morphogenesis: a grand challenge in organismal biology

PubMed Central

von Dassow, Michelangelo; Davidson, Lance A.

2011-01-01

Morphogenesis takes place in a background of organism-to-organism and environmental variation. Therefore, a fundamental question in the study of morphogenesis is how the mechanical processes of tissue movement and deformation are affected by that variability, and in turn, how the mechanics of the system modulates phenotypic variation. We highlight a few key factors, including environmental temperature, embryo size, and environmental chemistry that might perturb the mechanics of morphogenesis in natural populations. Then we discuss several ways in which mechanics – including feedback from mechanical cues – might influence intra-specific variation in morphogenesis. To understand morphogenesis it will be necessary to consider whole-organism, environment, and evolutionary scales because these larger scales present the challenges that developmental mechanisms have evolved to cope with. Studying the variation organisms express and the variation organisms experience will aid in deciphering the causes of birth defects. PMID:21750364

Multimodality optical imaging of embryonic heart microstructure

PubMed Central

Yelin, Ronit; Yelin, Dvir; Oh, Wang-Yuhl; Yun, Seok H.; Boudoux, Caroline; Vakoc, Benjamin J.; Bouma, Brett E.; Tearney, Guillermo J.

2009-01-01

Study of developmental heart defects requires the visualization of the microstructure and function of the embryonic myocardium, ideally with minimal alterations to the specimen. We demonstrate multiple endogenous contrast optical techniques for imaging the Xenopus laevis tadpole heart. Each technique provides distinct and complementary imaging capabilities, including: 1. 3-D coherence microscopy with subcellular (1 to 2 µm) resolution in fixed embryos, 2. real-time reflectance confocal microscopy with large penetration depth in vivo, and 3. ultra-high speed (up to 900 frames per second) that enables real-time 4-D high resolution imaging in vivo. These imaging modalities can provide a comprehensive picture of the morphologic and dynamic phenotype of the embryonic heart. The potential of endogenous-contrast optical microscopy is demonstrated for investigation of the teratogenic effects of ethanol. Microstructural abnormalities associated with high levels of ethanol exposure are observed, including compromised heart looping and loss of ventricular trabecular mass. PMID:18163837

Multimodality optical imaging of embryonic heart microstructure.

PubMed

Yelin, Ronit; Yelin, Dvir; Oh, Wang-Yuhl; Yun, Seok H; Boudoux, Caroline; Vakoc, Benjamin J; Bouma, Brett E; Tearney, Guillermo J

2007-01-01

Study of developmental heart defects requires the visualization of the microstructure and function of the embryonic myocardium, ideally with minimal alterations to the specimen. We demonstrate multiple endogenous contrast optical techniques for imaging the Xenopus laevis tadpole heart. Each technique provides distinct and complementary imaging capabilities, including: 1. 3-D coherence microscopy with subcellular (1 to 2 microm) resolution in fixed embryos, 2. real-time reflectance confocal microscopy with large penetration depth in vivo, and 3. ultra-high speed (up to 900 frames per second) that enables real-time 4-D high resolution imaging in vivo. These imaging modalities can provide a comprehensive picture of the morphologic and dynamic phenotype of the embryonic heart. The potential of endogenous-contrast optical microscopy is demonstrated for investigation of the teratogenic effects of ethanol. Microstructural abnormalities associated with high levels of ethanol exposure are observed, including compromised heart looping and loss of ventricular trabecular mass.

Inhibiting the Mitochondrial Calcium Uniporter during Development Impairs Memory in Adult Drosophila.

PubMed

Drago, Ilaria; Davis, Ronald L

2016-09-06

The uptake of cytoplasmic calcium into mitochondria is critical for a variety of physiological processes, including calcium buffering, metabolism, and cell survival. Here, we demonstrate that inhibiting the mitochondrial calcium uniporter in the Drosophila mushroom body neurons (MBn)-a brain region critical for olfactory memory formation-causes memory impairment without altering the capacity to learn. Inhibiting uniporter activity only during pupation impaired adult memory, whereas the same inhibition during adulthood was without effect. The behavioral impairment was associated with structural defects in MBn, including a decrease in synaptic vesicles and an increased length in the axons of the αβ MBn. Our results reveal an in vivo developmental role for the mitochondrial uniporter complex in establishing the necessary structural and functional neuronal substrates for normal memory formation in the adult organism. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Minimal Phenotype of Mice Homozygous for a Null Mutation in the Forkhead/Winged Helix Gene, Mf2

PubMed Central

Kume, Tsutomu; Deng, Keyu; Hogan, Brigid L. M.

2000-01-01

Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix transcription factor expressed in numerous tissues of the mouse embryo, including paraxial mesoderm, somites, branchial arches, vibrissae, developing central nervous system, and developing kidney. We have generated mice homozygous for a null mutation in the Mf2 gene (Mf2lacZ) to examine its role during embryonic development. The lacZ allele also allows monitoring of Mf2 gene expression. Homozygous null mutants are viable and fertile and have no major developmental defects. Some mutants show renal abnormalities, including kidney hypoplasia and hydroureter, but the penetrance of this phenotype is only 40% or lower, depending on the genetic background. These data suggest that Mf2 can play a unique role in kidney development, but there is functional redundancy in this organ and other tissues with other forkhead/winged helix genes. PMID:10648626

Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2.

PubMed

Kume, T; Deng, K; Hogan, B L

2000-02-01

Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix transcription factor expressed in numerous tissues of the mouse embryo, including paraxial mesoderm, somites, branchial arches, vibrissae, developing central nervous system, and developing kidney. We have generated mice homozygous for a null mutation in the Mf2 gene (Mf2(lacZ)) to examine its role during embryonic development. The lacZ allele also allows monitoring of Mf2 gene expression. Homozygous null mutants are viable and fertile and have no major developmental defects. Some mutants show renal abnormalities, including kidney hypoplasia and hydroureter, but the penetrance of this phenotype is only 40% or lower, depending on the genetic background. These data suggest that Mf2 can play a unique role in kidney development, but there is functional redundancy in this organ and other tissues with other forkhead/winged helix genes.

Unilateral terminal aphalangia in father and daughter--exogenous or genetic cause?

PubMed

Neumann, L; Pelz, J; Kunze, J

1998-07-24

Published cases of familial unilateral terminal transverse defects are scarce. We report on a morphologically similar defect of the hand in a father and his daughter. The hand anomaly is similar in both, but on the opposite side. Thalidomide was taken in the sensitive period of the pregnancy by the father's mother. To our knowledge this is the second description of unilateral terminal aphalangia in successive generations. In order to evaluate the possible genetic basis we analyze epidemiological studies in respect to the recurrence risk of cases with isolated limb reduction defects. We compare reports of familial occurrence concerning the degree of relationship as well as the pattern of malformation. The latter seems to be an important aspect from an evolutionary and a developmental viewpoint. For our observation an autosomal dominant transmission is the most likely although multifactorial determination cannot be excluded.

Definition of mutually optimum NDI and proof test criteria for 2219 aluminum pressure vessels. Volume 1: Methods

NASA Technical Reports Server (NTRS)

Schwartzberg, F. R.; King, R. G.; Todd, P. H., Jr.

1979-01-01

The requirements for proof testing and nondestructive inspection of aluminum pressure vessels were discussed. The following conclusions are (1) lack-of-fusion weld defects are sufficiently tight in the as-welded condition to be considered undetectable; (2) proof-level loads are required to fully open lack-of-fusion weld defects; (3) significant crack opening occurs at subproof levels so that an inspection enhancement loading treatment designed to avoid catastrophic failure is feasible; (4) currently used proof levels for 2219 pressure vessels are adequate for postproof inspection; (5) quantification of defect size and location using collimated ultrasonic pitch-catch techniques appears sufficiently feasible for tankage to warrant developmental work; (6) for short-time single-cycle pressure-vessel applications, postproof inspection is desirable; and (7) for long-term multiple-cycle pressure-vessel applications, postproof inspection is essential for life assurance.

Inversin relays Frizzled-8 signals to promote proximal pronephros development

PubMed Central

Lienkamp, Soeren; Ganner, Athina; Boehlke, Christopher; Schmidt, Thorsten; Arnold, Sebastian J.; Schäfer, Tobias; Romaker, Daniel; Schuler, Julia; Hoff, Sylvia; Powelske, Christian; Eifler, Annekathrin; Krönig, Corinna; Bullerkotte, Axel; Nitschke, Roland; Kuehn, E. Wolfgang; Kim, Emily; Burkhardt, Hans; Brox, Thomas; Ronneberger, Olaf; Gloy, Joachim; Walz, Gerd

2010-01-01

Mutations of inversin cause type II nephronophthisis, an infantile autosomal recessive disease characterized by cystic kidney disease and developmental defects. Inversin regulates Wnt signaling and is required for convergent extension movements during early embryogenesis. We now show that Inversin is essential for Xenopus pronephros formation, involving two distinct and opposing forms of cell movements. Knockdown of Inversin abrogated both proximal pronephros extension and distal tubule differentiation, phenotypes similar to that of Xenopus deficient in Frizzled-8. Exogenous Inversin rescued the pronephric defects caused by lack of Frizzled-8, indicating that Inversin acts downstream of Frizzled-8 in pronephros morphogenesis. Depletion of Inversin prevents the recruitment of Dishevelled in response to Frizzled-8 and impeded the accumulation of Dishevelled at the apical membrane of tubular epithelial cells in vivo. Thus, defective tubule morphogenesis seems to contribute to the renal pathology observed in patients with nephronophthisis type II. PMID:21059920

The Blind Child and His Parents: Congenital Visual Defect and the Repercussion of Family Attitudes on the Early Development of the Child.

ERIC Educational Resources Information Center

Lairy, G. C.; Harrison-Covello, A.

Discussed are the effects of parental attitudes on the early development of the congenitally blind child. The disproportion between family reactions and the limitations of the handicap are attributed to symbolic aspects of blindness and previously existing pathological elements in the parents. Compared are developmental milestones (such as the…

Glucose Transporter Type 1 Deficiency Syndrome with Carbohydrate-Responsive Symptoms but without Epilepsy

ERIC Educational Resources Information Center

Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan

2011-01-01

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female…

Incidentally detected asplenia in a healthy 64-year-old female live kidney donor.

PubMed

Wolff, Leoniek D; Nijboer, Mijntje N; Vd Wetering, Jacqueline; Dor, Frank J M F

2017-04-01

Heterotaxia syndromes are rare birth defects which can result in developmental malformations. A 64-year-old woman presented to the hospital for preoperative screening for kidney donation; during which she was found to have no gallbladder and no spleen, without any signs of surgical removal. This could be a new description of a heterotaxia syndrome.

DEHP (DI-N-ETHYLHEXYL PHTHALATE), WHEN ADMINISTERED DURING SEXUAL DIFFERENTIATION, INDUCES DOSE DEPENDENT DECREASES IN FETAL TESTIS INSL3 GENE EXPRESSION AND STERIOD HORMONE SYNTHESIS

EPA Science Inventory

Cryptorchidism is a fairly common human malformation, being displayed in 1-3 males per 100 at birth. Since only a small percentage of these lesions can be linked to known genetic defects, developmental exposure to man-made chemicals has been implicated in the increase in thisrepr...

Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.

PubMed

Gan, T; Jude, C D; Zaffuto, K; Ernst, P

2010-10-01

The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.

Editorial brain malformation surveillance in the Zika era

PubMed Central

Trevathan, Edwin

2016-01-01

The current surveillance systems for congenital microcephaly are necessary to monitor the impact of Zika virus (ZIKV) on the developing human brain, as well as the ZIKV prevention efforts. However, these congenital microcephaly surveillance systems are insufficient. Abnormalities of neuronal differentiation, development and migration may occur among infants with normal head circumference who have intrauterine exposure to ZIKV. Therefore, surveillance for congenital microcephaly does not ascertain many of the infants seriously impacted by congenital ZIKV infection. Furthermore, many infants with normal head circumference and with malformations of the brain cortex do not have clinical manifestations of their congenital malformations until several months to many years after birth, when they present with clinical manifestations such as seizures/epilepsy, developmental delays with or without developmental regression, and/or motor impairment. In response to the ZIKV threat, public health surveillance systems must be enhanced to ascertain a wide variety of congenital brain malformations, as well as their clinical manifestations that lead to diagnostic brain imaging. Birth Defects Research (Part A) 106:869–874, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27891785

Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging.

PubMed

Kim, Myungjin; Park, Hae Li; Park, Hwan-Woo; Ro, Seung-Hyun; Nam, Samuel G; Reed, John M; Guan, Jun-Lin; Lee, Jun Hee

2013-08-01

Autophagy-related 1 (Atg1)/Unc-51-like protein kinases (ULKs) are evolutionarily conserved proteins that play critical physiological roles in controlling autophagy, cell growth and neurodevelopment. RB1-inducible coiled-coil 1 (RB1CC1), also known as PTK2/FAK family-interacting protein of 200 kDa (FIP200) is a recently discovered binding partner of ULK1. Here we isolated the Drosophila RB1CC1/FIP200 homolog (Fip200/CG1347) and showed that it mediates Atg1-induced autophagy as a genetically downstream component in diverse physiological contexts. Fip200 loss-of-function mutants experienced severe mobility loss associated with neuronal autophagy defects and neurodegeneration. The Fip200 mutants were also devoid of both developmental and starvation-induced autophagy in salivary gland and fat body, while having no defects in axonal transport and projection in developing neurons. Interestingly, moderate downregulation of Fip200 accelerated both developmental growth and aging, accompanied by target of rapamycin (Tor) signaling upregulation. These results suggest that Fip200 is a critical downstream component of Atg1 and specifically mediates Atg1's autophagy-, aging- and growth-regulating functions.

Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging

PubMed Central

Kim, Myungjin; Park, Hae Li; Park, Hwan-Woo; Ro, Seung-Hyun; Nam, Samuel G.; Reed, John M.; Guan, Jun-Lin; Lee, Jun Hee

2013-01-01

Autophagy-related 1 (Atg1)/Unc-51-like protein kinases (ULKs) are evolutionarily conserved proteins that play critical physiological roles in controlling autophagy, cell growth and neurodevelopment. RB1-inducible coiled-coil 1 (RB1CC1), also known as PTK2/FAK family-interacting protein of 200 kDa (FIP200) is a recently discovered binding partner of ULK1. Here we isolated the Drosophila RB1CC1/FIP200 homolog (Fip200/CG1347) and showed that it mediates Atg1-induced autophagy as a genetically downstream component in diverse physiological contexts. Fip200 loss-of-function mutants experienced severe mobility loss associated with neuronal autophagy defects and neurodegeneration. The Fip200 mutants were also devoid of both developmental and starvation-induced autophagy in salivary gland and fat body, while having no defects in axonal transport and projection in developing neurons. Interestingly, moderate downregulation of Fip200 accelerated both developmental growth and aging, accompanied by target of rapamycin (Tor) signaling upregulation. These results suggest that Fip200 is a critical downstream component of Atg1 and specifically mediates Atg1’s autophagy-, aging- and growth-regulating functions. PMID:23819996

A novel Xp22.13 microdeletion in Nance-Horan syndrome.

PubMed

Accogli, Andrea; Traverso, Monica; Madia, Francesca; Bellini, Tommaso; Vari, Maria Stella; Pinto, Francesca; Capra, Valeria

2017-07-03

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder characterized by congenital cataract, dental anomalies and facial dysmorphisms. Notably, up to 30% of NHS patients have intellectual disability and a few patients have been reported to have congenital cardiac defects. Nance-Horan syndrome is caused by mutations in the NHS gene that is highly expressed in the midbrain, retina, lens, tooth, and is conserved across vertebrate species. Although most pathogenic mutations are nonsense mutations, a few genomic rearrangements involving NHS locus have been reported, suggesting a possible pathogenic role of the flanking genes. Here, we report a microdeletion of 170,6 Kb at Xp22.13 (17.733.948-17.904.576) (GRCh37/hg19), detected by array-based comparative genomic hybridization in an Italian boy with NHS syndrome. The microdeletion harbors the NHS, SCLML1, and RAI2 genes and results in a phenotype consistent with NSH syndrome and developmental delay. We compare our case with the previous Xp22.13 microdeletions and discuss the possible pathogenetic role of the flanking genes. Birth Defects Research 109:866-868, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester.

PubMed

Clark, Robert L

2017-08-15

The World Health Organization currently recommends quinine+clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing = 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine+pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine+pyrimethamine and artemether+lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios ≤2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above. Birth Defects Research 109:1075-1126, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

CHARGE association in a child with de novo inv dup (14)(q22{yields}q24.3)

DOE Office of Scientific and Technical Information (OSTI.GOV)

North, K.; Wu, B.L.; Whiteman, D.

1994-09-01

The CHARGE association is an increasingly recognized complex of multiple malformations, that include Coloboma, Heart defect, choanal Atresia, Retardation of mental and somatic development, hypoplastic Genitalia, and Ear abnormalities or deafness. It has been postulated that many of the defects result from abnormalities in the development, migration or interaction of cells of the cephalic neural crest. The majority of cases are sporadic. We report a case of an inverted duplication (14)(q22{yields}q24.3) associated with CHARGE association. The patient was a 4 {1/2}-year-old female and was the product of a normal pregnancy. Family history was unremarkable. The clinical manifestations included the combinationmore » of congenital anomalies (coloboma, ventricular septal defect, severe developmental delay and growth retardation, genital hypoplasia and sensorineural deafness) in association with soft tissue choanal atresia, dysphagia, and minor dysmorphic features (low set ears, upslanting palpebral fissures). High resolution cytogenetic studies revealed that the child has 46,XX,inv dup(14)(q22{yields}q24.3) and parents have normal chromosomes. FISH with a chromosome 14 paint probe confirmed that the duplicated region is entirely derived from chromosome 14. FISH with D22S75 probe for region 22q11.2 detected no deletion for this locus. Several duplications or deletions involving different chromosomes have been reported for patients with conditions resembling CHARGE association. This indicates that CHARGE is possible genetically heterogenous, parallelling the phenotypic heterogeneity of the disorder. Two published cases with unbalanced rearrengements involving 14q22 have some comparable features with our case, which suggests that the locus for a gene causing some of the features of CHARGE association may reside at 14q22 or 14q24.3.« less

Diagnosis of a terminal deletion of 4p with duplication of Xp22.31 in a patient with findings of Opitz G/BBB syndrome and Wolf-Hirschhorn syndrome.

PubMed

So, Joyce; Müller, Ines; Kunath, Melanie; Herrmann, Susanne; Ullmann, Reinhard; Schweiger, Susann

2008-01-01

Opitz G/BBB syndrome (OS) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay and cardiac defects. The X-linked form is caused by mutations in the MID1 gene, while no gene has yet been identified for the autosomal dominant form. Here, we report on a 15-year-old boy who was referred for MID1 mutation analysis with findings typical of OS, including apparent hypertelorism, hypospadias, a history of feeding difficulties, dysphagia secondary to esophageal arteria lusoria, growth retardation and developmental delay. No MID1 mutation was found, but subsequent sub-megabase resolution array CGH unexpectedly documented a 2.34 Mb terminal 4p deletion, suggesting a diagnosis of WHS, and a duplication in Xp22.31. Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving terminal chromosome 4p deletions, in particular 4p16.3. WHS is characterized by typical facial appearance ("Greek helmet facies"), mental retardation, congenital hypotonia, and growth retardation. While the severity of developmental delay in this patient supports the diagnosis of WHS rather than OS, this case illustrates the striking similarities of clinical findings in seemingly unrelated syndromes, suggesting common or interacting pathways at the molecular and pathogenetic level. This is the first report of arteria lusoria (esophageal vascular ring) in a patient with WHS. (c) 2007 Wiley-Liss, Inc.

A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.

PubMed

Xiao, Ying; Thoresen, Daniel T; Miao, Lingling; Williams, Jonathan S; Wang, Chaochen; Atit, Radhika P; Wong, Sunny Y; Brownell, Isaac

2016-07-01

The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.

Developmental toxicity of 2,4-dichlorophenoxyacetic acid in zebrafish embryos.

PubMed

Li, Kang; Wu, Jia-Qi; Jiang, Ling-Ling; Shen, Li-Zhen; Li, Jian-Ying; He, Zhi-Heng; Wei, Ping; Lv, Zhuo; He, Ming-Fang

2017-03-01

2,4-Dichlorophenoxyacetic acid (2,4-D) is widely used in agriculture as herbicide/pesticide, plant growth regulator and fruit preservative agent. It progressively accumulates in the environment including surface water, air and soil. It could be detected in human food and urine, which poses great risk to the living organisms. In the present study, we investigated the developmental toxicity of 2,4-D on zebrafish (Danio rerio) embryo. 2,4-D exposure significantly decreased both the survival rate (LC 50  = 46.71 mg/L) and hatching rate (IC 50  = 46.26 mg/L) of zebrafish embryos. The most common developmental defect in 2,4-D treated embryos was pericardial edema. 2,4-D (25 mg/L) upregulated marker genes of cardiac development (vmhc, amhc, hand2, vegf, and gata1) and downregulated marker genes of oxidative stress (cat and gpx1a). Whole mount in situ hybridization confirmed the vmhc and amhc upregulation by 2,4-D treatment. LC/MS/MS showed that the bioaccumulation of 2,4-D in zebrafish embryos were increased in a time-dependent manner after 25 mg/L of 2,4-D treatment. Taken together, our study investigated the toxic effects of 2,4-D on zebrafish embryonic development and its potential molecular mechanisms, gave evidence for the full understanding of 2,4-D toxicity on living organisms and shed light on its environmental impact. Copyright © 2016 Elsevier Ltd. All rights reserved.

The guanosine nucleotide (p)ppGpp initiates development and A-factor production in myxococcus xanthus.

PubMed

Harris, B Z; Kaiser, D; Singer, M

1998-04-01

Guanosine 3'-di-5'-(tri)di-phosphate nucleotides [(p)ppGpp], synthesized in response to amino acid limitation, induce early gene expression leading to multicellular fruiting body formation in Myxococcus xanthus. A mutant (DK527) that fails to accumulate (p)ppGpp in response to starvation was found to be blocked in development prior to aggregation. By use of a series of developmentally regulated Tn5lac transcriptional fusion reporters, the time of developmental arrest in DK527 was narrowed to within the few hours of development, the period of starvation recognition. The mutant is also defective in the production of A-factor, an early extracellular cell-density signal. The relA gene from Escherichia coli, which encodes a ribosome-dependent (p)ppGpp synthetase, rescues this mutant. We also demonstrate that inactivation of the M. xanthus relA homolog blocks development and the accumulation of (p)ppGpp. Moreover, the wild-type allele of Myxococcus relA rescues DK527. These observations support a model in which accumulation of (p)ppGpp, in response to starvation, initiates the program of fruiting body development, including the production of A-factor.

Meeting the challenge: using policy to improve children's health.

PubMed

Brush, Charles Adam; Kelly, Maggie M; Green, Denise; Gaffney, Marcus; Kattwinkel, John; French, Molly

2005-11-01

We reflect on the proceedings of a symposium at a conference of the Centers for Disease Control and Prevention National Center on Birth Defects and Developmental Disabilities. We present examples of bridging the gap between science and policy to achieve improvements in children's health through case studies in early hearing detection and intervention, folic acid fortification to prevent birth defects, sleep positioning recommendations to reduce infant mortality, and workplace lactation support programs. We discuss case studies that present different policy strategies (public health law and voluntary practices) for improving public health. These case studies demonstrate both the power of policy as a tool for improving children's health and the challenges of communicating public health research to policy decisionmakers.

Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development.

PubMed

Christensen, Karen E; Hou, Wenyang; Bahous, Renata H; Deng, Liyuan; Malysheva, Olga V; Arning, Erland; Bottiglieri, Teodoro; Caudill, Marie A; Jerome-Majewska, Loydie A; Rozen, Rima

2016-11-01

Moderately high folic acid intake in pregnant women has led to concerns about deleterious effects on the mother and fetus. Common polymorphisms in folate genes, such as methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) R653Q, may modulate the effects of elevated folic acid intake. We investigated the effects of moderate folic acid supplementation on reproductive outcomes and assessed the potential interaction of the supplemented diet with MTHFD1-synthetase (Mthfd1S) deficiency in mice, which is a model for the R653Q variant. Female Mthfd1S +/+ and Mthfd1S +/- mice were fed a folic acid-supplemented diet (FASD) (5-fold higher than recommended) or control diets before mating and during pregnancy. Embryos and placentas were assessed for developmental defects at embryonic day 10.5 (E10.5). Maternal folate and choline metabolites and gene expression in folate-related pathways were examined. The combination of FASD and maternal MTHFD1-synthetase deficiency led to a greater incidence of defects in E10.5 embryos (diet × maternal genotype, P = 0.0016; diet × embryonic genotype, P = 0.054). The methylenetetrahydrofolate reductase (MTHFR) protein and methylation potential [ratio of S-adenosylmethionine (major methyl donor):S-adenosylhomocysteine) were reduced in maternal liver. Although 5-methyltetrahydrofolate (methylTHF) was higher in maternal circulation, the methylation potential was lower in embryos. The presence of developmental delays and defects in Mthfd1S +/- embryos was associated with placental defects (P = 0.003). The labyrinth layer failed to form properly in the majority of abnormal placentas, which compromised the integration of the maternal and fetal circulation and presumably the transfer of methylTHF and other nutrients. Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater incidence of defects in embryos. Although maternal circulating methylTHF was higher, it may not have reached the embryos because of abnormal placental development; abnormal placentas were observed predominantly in abnormally developed embryos. These findings have implications for women with high folate intakes, particularly if they are polymorphic for MTHFD1 R653Q. © 2016 American Society for Nutrition.

Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome

PubMed Central

Saqran, Lubna; Herrick, Scott P.; Frosch, Matthew P.; Hyman, Bradley T.

2017-01-01

Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivo. SIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo. This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients. PMID:28899917

Defects in middle ear cavitation cause conductive hearing loss in the Tcof1 mutant mouse.

PubMed

Richter, Carol A; Amin, Susan; Linden, Jennifer; Dixon, Jill; Dixon, Michael J; Tucker, Abigail S

2010-04-15

Conductive hearing loss (CHL) is one of the most common forms of human deafness. Despite this observation, a surprising gap in our understanding of the mechanisms underlying CHL remains, particularly with respect to the molecular mechanisms underlying middle ear development and disease. Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development that results from mutations in the gene TCOF1. CHL is a common feature of TCS but the causes of the hearing defect have not been studied. In this study, we have utilized Tcof1 mutant mice to dissect the developmental mechanisms underlying CHL. Our results demonstrate that effective cavitation of the middle ear is intimately linked to growth of the auditory bulla, the neural crest cell-derived structure that encapsulates all middle ear components, and that defects in these processes have a profoundly detrimental effect on hearing. This research provides important insights into a poorly characterized cause of human deafness, and provides the first mouse model for the study of middle ear cavity defects, while also being of direct relevance to a human genetic disorder.

Prevalence of enamel defects in primary and permanent teeth in a group of schoolchildren from Granada (Spain).

PubMed

Robles, Maria-Jesús; Ruiz, Matilde; Bravo-Perez, Manuel; González, Encarnación; Peñalver, Maria-Angustias

2013-03-01

The purpose of this study was to determine and compare the prevalence and presentations of developmental defects of the enamel (DDE) in the primary and permanent dentitions of a group of healthy schoolchildren residing in Granada (Spain). A total of 1,414 healthy schoolchildren were examined using modified DDE criteria for recording enamel defects. The prevalence of DDE of any type was 40.2% in primary dentition and 52% in permanent dentition (p<0.033). Of the 31,820 primary and permanent teeth examined in the study, 699 (4.1%) primary and 1,232 (8.3%) permanent teeth had some form of DDE. Diffuse opacity was the most common type of DDE observed in primary teeth, and demarcated opacity in the permanent teeth. Enamel hypoplasia was the least prevalent defect in both dentition types. The study population showed a high prevalence of DDE in primary as well as in permanent dentition, reflecting the current increasing trend of this condition, which should be considered as a significant public health problem.

Prosthetic Rehabilitation of Defects of the Head and Neck

PubMed Central

Salinas, Thomas J.

2010-01-01

Patients afflicted with head and neck cancer, traumatic injuries to the head and neck, or those with congenital or developmental defects benefit from multidisciplinary team management. The head and neck region participates in complex physiologic processes that can often be impeded by these circumstances. Evaluation of the patient by the maxillofacial prosthodontist can assist the other members of the team in providing treatment planning options for the patients. Intraoral defects arising from these circumstances can be treated with prosthodontics that serve to assist with speech, swallowing, and to some degree mastication. If chemotherapeutic or radiation modalities are also used to treat the head and neck, assessment of the patient by the maxillofacial prosthodontist may prove to identify factors that may predispose to undesirable sequelae. Preventive treatment by elective tooth extraction, prosthodontic assessment, and patient education prove to assist in predictable management of these oftentimes complex presenting conditions. Facial defects arising from similar circumstances can be an alternative or adjunct to plastic surgical reconstruction and offer the added advantage of tumor surveillance in susceptible patients. PMID:22550451

Mouse Models for Investigating the Developmental Bases of Human Birth Defects

PubMed Central

MOON, ANNE M.

2006-01-01

Clinicians and basic scientists share an interest in discovering how genetic or environmental factors interact to perturb normal development and cause birth defects and human disease. Given the complexity of such interactions, it is not surprising that 4% of human infants are born with a congenital malformation, and cardiovascular defects occur in nearly 1%. Our research is based on the fundamental hypothesis that an understanding of normal and abnormal development will permit us to generate effective strategies for both prevention and treatment of human birth defects. Animal models are invaluable in these efforts because they allow one to interrogate the genetic, molecular and cellular events that distinguish normal from abnormal development. Several features of the mouse make it a particularly powerful experimental model: it is a mammalian system with similar embryology, anatomy and physiology to humans; genes, proteins and regulatory programs are largely conserved between human and mouse; and finally, gene targeting in murine embryonic stem cells has made the mouse genome amenable to sophisticated genetic manipulation currently unavailable in any other model organism. PMID:16641221

Analysis of the Ush2a gene in medaka fish (Oryzias latipes).

PubMed

Aller, Elena; Sánchez-Sánchez, Ana V; Chicote, Javier U; García-García, Gema; Udaondo, Patricia; Cavallé, Laura; Piquer-Gil, Marina; García-España, Antonio; Díaz-Llopis, Manuel; Millán, José M; Mullor, José L

2013-01-01

Patients suffering from Usher syndrome (USH) exhibit sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. USH is the most common genetic disorder affecting hearing and vision and is included in a group of hereditary pathologies associated with defects in ciliary function known as ciliopathies. This syndrome is clinically classified into three types: USH1, USH2 and USH3. USH2 accounts for well over one-half of all Usher cases and mutations in the USH2A gene are responsible for the majority of USH2 cases, but also for atypical Usher syndrome and recessive non-syndromic RP. Because medaka fish (Oryzias latypes) is an attractive model organism for genetic-based studies in biomedical research, we investigated the expression and function of the USH2A ortholog in this teleost species. Ol-Ush2a encodes a protein of 5.445 aa codons, containing the same motif arrangement as the human USH2A. Ol-Ush2a is expressed during early stages of medaka fish development and persists into adulthood. Temporal Ol-Ush2a expression analysis using whole mount in situ hybridization (WMISH) on embryos at different embryonic stages showed restricted expression to otoliths and retina, suggesting that Ol-Ush2a might play a conserved role in the development and/or maintenance of retinal photoreceptors and cochlear hair cells. Knockdown of Ol-Ush2a in medaka fish caused embryonic developmental defects (small eyes and heads, otolith malformations and shortened bodies with curved tails) resulting in late embryo lethality. These embryonic defects, observed in our study and in other ciliary disorders, are associated with defective cell movement specifically implicated in left-right (LR) axis determination and planar cell polarity (PCP).

Adult Restoration of Shank3 Expression Rescues Selective Autistic-Like Phenotypes

PubMed Central

Mei, Yuan; Monteiro, Patricia; Zhou, Yang; Kim, Jin-Ah; Gao, Xian; Fu, Zhanyan; Feng, Guoping

2016-01-01

Because ASD is a neurodevelopmental disorder and patients typically display symptoms before the age of three1, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigated the developmental requirement of Shank3, one of the most prominent monogenic ASD genes that is estimated to contribute to ~1% of all ASD cases2–6. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density (PSD) macromolecular signaling complex7–9. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviors including anxiety, social interaction deficits, and repetitive behavior10–13. We generated a novel Shank3 conditional knock-in mouse model and used it to demonstrate that re-expression of the Shank3 gene in adult led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provided behavioral evidence that certain behavioral abnormalities including social interaction deficit and repetitive grooming behavior could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results elucidate the profound impact of post-developmental activation of Shank3 expression on neural function and demonstrate certain degree of continued plasticity in the adult diseased brain. PMID:26886798

C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling.

PubMed

Reiner, David J; Ailion, Michael; Thomas, James H; Meyer, Barbara J

2008-08-05

Different environmental stimuli, including exposure to dauer pheromone, food deprivation, and high temperature, can induce C. elegans larvae to enter the dauer stage, a developmentally arrested diapause state. Although molecular and cellular pathways responsible for detecting dauer pheromone and temperature have been defined in part, other sensory inputs are poorly understood, as are the mechanisms by which these diverse sensory inputs are integrated to achieve a consistent developmental outcome. In this paper, we analyze a wild C. elegans strain isolated from a desert oasis. Unlike wild-type laboratory strains, the desert strain fails to respond to dauer pheromone at 25 degrees C, but it does respond at higher temperatures, suggesting a unique adaptation to the hot desert environment. We map this defect in dauer response to a mutation in the scd-2 gene, which, we show, encodes the nematode anaplastic lymphoma kinase (ALK) homolog, a proto-oncogene receptor tyrosine kinase. scd-2 acts in a genetic pathway shown here to include the HEN-1 ligand, the RTK adaptor SOC-1, and the MAP kinase SMA-5. The SCD-2 pathway modulates TGF-beta signaling, which mediates the response to dauer pheromone, but SCD-2 might mediate a nonpheromone sensory input, such as food. Our studies identify a new sensory pathway controlling dauer formation and shed light on ALK signaling, integration of signaling pathways, and adaptation to extreme environmental conditions.

Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder.

PubMed

Pindolia, Kirit; Jordan, Megan; Guo, Caiying; Matthews, Nell; Mock, Donald M; Strovel, Erin; Blitzer, Miriam; Wolf, Barry

2011-02-01

Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase deficiency usually exhibit neurological symptoms including lethargy, hypotonia, seizures, developmental delay, sensorineural hearing loss and optic atrophy; and cutaneous symptoms including skin rash, conjunctivitis and alopecia. Although the clinical features of the disorder markedly improve or are prevented with biotin supplementation, some symptoms, once they occur, such as developmental delay, hearing loss and optic atrophy, are usually irreversible. To prevent development of symptoms, the disorder is screened for in the newborn period in essentially all states and in many countries. In order to better understand many aspects of the pathophysiology of the disorder, we have developed a transgenic biotinidase-deficient mouse. The mouse has a null mutation that results in no detectable serum biotinidase activity or cross-reacting material to antibody prepared against biotinidase. When fed a biotin-deficient diet these mice develop neurological and cutaneous symptoms, carboxylase deficiency, mild hyperammonemia, and exhibit increased urinary excretion of 3-hydroxyisovaleric acid and biotin and biotin metabolites. The clinical features are reversed with biotin supplementation. This biotinidase-deficient animal can be used to study systematically many aspects of the disorder and the role of biotinidase, biotin and biocytin in normal and in enzyme-deficient states. Copyright © 2010 Elsevier Inc. All rights reserved.

Effects of gamma radiation on the early developmental stages of Zebrafish (Danio rerio).

PubMed

Praveen Kumar, M K; Shyama, S K; Kashif, Shamim; Dubey, S K; Avelyno, D'costa; Sonaye, B H; Kadam Samit, B; Chaubey, R C

2017-08-01

The zebrafish is gaining importance as a popular vertebrate model organism and is widely employed in ecotoxicological studies, especially for the biomonitoring of pollution in water bodies. There is limited data on the genetic mechanisms governing the adverse health effects in regards to an early developmental exposure to gamma radiation. In the present study zebrafish (Danio rerio) embryos were exposed to 1, 2.5, 5, 7.5 and 10Gy of gamma radiation at 3h post fertilization (hpf). Different developmental toxicity endpoints were investigated. Further, expression of genes associated with the development and DNA damage i.e. (sox2 sox19a and p53) were evaluated using Quantitative PCR (qPCR). The significant changes in the expression of sox2 sox19a and p53 genes were observed. This data was supported the developmental defects observed in the zebrafish embryo exposed to gamma radiation such as i.e. increased DNA damage, decreased hatching rate, increase in median hatching time, decreased body length, increased mortality rate, increased morphological deformities. Further, study shows that the potential ecotoxicological threat of gamma radiation on the early developmental stages of zebrafish. Further, it revealed that the above parameters can be used as predictive biomarkers of gamma radiation exposure. Copyright © 2017. Published by Elsevier Inc.

Glyphosate and adverse pregnancy outcomes, a systematic review of observational studies.

PubMed

de Araujo, Jessica S A; Delgado, Isabella F; Paumgartten, Francisco J R

2016-06-06

A study in frog and chicken embryos, and reports of a high incidence of birth defects in regions of intensive GM-soy planting have raised concerns on the teratogenic potential of glyphosate-based herbicides. These public concerns prompted us to conduct a systematic review of the epidemiological studies testing hypotheses of associations between glyphosate exposure and adverse pregnancy outcomes including birth defects. A systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Bireme-BVS and SCOPUS databases using different combinations of exposure and outcome terms. A case-control study on the association between pesticides and congenital malformations in areas of extensive GM soy crops in South America, and reports on the occurrence of birth defects in these regions were reviewed as well. The search found ten studies testing associations between glyphosate and birth defects, abortions, pre-term deliveries, small for gestational date births, childhood diseases or altered sex ratios. Two additional studies examined changes of time-to-pregnancy in glyphosate-exposed populations. Except for an excess of Attention Deficit Hyperactivity Disorder - ADHD (OR = 3.6, 1.3-9.6) among children born to glyphosate appliers, no significant associations between this herbicide and adverse pregnancy outcomes were described. Evidence that in South American regions of intensive GM-soy planting incidence of birth defects is high remains elusive. Current epidemiological evidence, albeit limited to a few studies using non-quantitative and indirect estimates and dichotomous analysis of exposures, does not lend support to public concerns that glyphosate-based pesticides might pose developmental risks to the unborn child. Nonetheless, owing to methodological limitations of existing analytical observational studies, and particularly to a lack of a direct measurement (urine and/or blood levels), or an indirect estimation of exposure that has proven valid, these negative findings cannot be taken as definitive evidence that GLY, at current levels of occupational and environmental exposures, brings no risk for human development and reproduction.

Teratology on the crossroads: historical aspects and modern approaches.

PubMed

Ujházy, Eduard; Mach, Mojmír; Navarová, Jana; Dubovický, Michal

2012-01-01

Teratology is the science of congenital developmental disorders (CDDs), overt or latent defects of the organism resulting from the effect of internal and external factors on developmental processes. In this article the significance and position of present-day teratology is discussed in the context of development of this branch of science and related disciplines. The authors present an updated overview of the most important milestones and stages of the development of teratology. Based on the analysis of the historical development of theses and theories that represent a decisive contribution to this field, we present a survey of the fundamental principles of experimental and clinical teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realize that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in the development of congenital developmental disorders. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 50% of all congenital defects. One-half of the unidentified cases are referred to as "multifactorial", a term that is rather ambiguous. It either means that some of the basic principles of teratogenesis still escape our attention, or the interpretation of some of the well known principles might be misleading. A third possibility is rather pessimistic. The development of the individual is so sophisticated and dependent on a delicate network of a multitude of factors mutually affecting each other that it is extremely prone to give rise to a plethora of spontaneous errors which are unpredictable and impossible to prevent. Nevertheless, the long and complicated history of scientific endeavour has yielded considerable present-day knowledge on causes and mechanisms of CDDs, a history whose beginnings date back to antiquity.

The Arabidopsis Rho of Plants GTPase AtROP6 Functions in Developmental and Pathogen Response Pathways1[C][W][OA

PubMed Central

Poraty-Gavra, Limor; Zimmermann, Philip; Haigis, Sabine; Bednarek, Paweł; Hazak, Ora; Stelmakh, Oksana Rogovoy; Sadot, Einat; Schulze-Lefert, Paul; Gruissem, Wilhelm; Yalovsky, Shaul

2013-01-01

How plants coordinate developmental processes and environmental stress responses is a pressing question. Here, we show that Arabidopsis (Arabidopsis thaliana) Rho of Plants6 (AtROP6) integrates developmental and pathogen response signaling. AtROP6 expression is induced by auxin and detected in the root meristem, lateral root initials, and leaf hydathodes. Plants expressing a dominant negative AtROP6 (rop6DN) under the regulation of its endogenous promoter are small and have multiple inflorescence stems, twisted leaves, deformed leaf epidermis pavement cells, and differentially organized cytoskeleton. Microarray analyses of rop6DN plants revealed that major changes in gene expression are associated with constitutive salicylic acid (SA)-mediated defense responses. In agreement, their free and total SA levels resembled those of wild-type plants inoculated with a virulent powdery mildew pathogen. The constitutive SA-associated response in rop6DN was suppressed in mutant backgrounds defective in SA signaling (nonexpresser of PR genes1 [npr1]) or biosynthesis (salicylic acid induction deficient2 [sid2]). However, the rop6DN npr1 and rop6DN sid2 double mutants retained the aberrant developmental phenotypes, indicating that the constitutive SA response can be uncoupled from ROP function(s) in development. rop6DN plants exhibited enhanced preinvasive defense responses to a host-adapted virulent powdery mildew fungus but were impaired in preinvasive defenses upon inoculation with a nonadapted powdery mildew. The host-adapted powdery mildew had a reduced reproductive fitness on rop6DN plants, which was retained in mutant backgrounds defective in SA biosynthesis or signaling. Our findings indicate that both the morphological aberrations and altered sensitivity to powdery mildews of rop6DN plants result from perturbations that are independent from the SA-associated response. These perturbations uncouple SA-dependent defense signaling from disease resistance execution. PMID:23319551

Whole-Genome Sequencing of Sordaria macrospora Mutants Identifies Developmental Genes.

PubMed

Nowrousian, Minou; Teichert, Ines; Masloff, Sandra; Kück, Ulrich

2012-02-01

The study of mutants to elucidate gene functions has a long and successful history; however, to discover causative mutations in mutants that were generated by random mutagenesis often takes years of laboratory work and requires previously generated genetic and/or physical markers, or resources like DNA libraries for complementation. Here, we present an alternative method to identify defective genes in developmental mutants of the filamentous fungus Sordaria macrospora through Illumina/Solexa whole-genome sequencing. We sequenced pooled DNA from progeny of crosses of three mutants and the wild type and were able to pinpoint the causative mutations in the mutant strains through bioinformatics analysis. One mutant is a spore color mutant, and the mutated gene encodes a melanin biosynthesis enzyme. The causative mutation is a G to A change in the first base of an intron, leading to a splice defect. The second mutant carries an allelic mutation in the pro41 gene encoding a protein essential for sexual development. In the mutant, we detected a complex pattern of deletion/rearrangements at the pro41 locus. In the third mutant, a point mutation in the stop codon of a transcription factor-encoding gene leads to the production of immature fruiting bodies. For all mutants, transformation with a wild type-copy of the affected gene restored the wild-type phenotype. Our data demonstrate that whole-genome sequencing of mutant strains is a rapid method to identify developmental genes in an organism that can be genetically crossed and where a reference genome sequence is available, even without prior mapping information.

Whole-Genome Sequencing of Sordaria macrospora Mutants Identifies Developmental Genes

PubMed Central

Nowrousian, Minou; Teichert, Ines; Masloff, Sandra; Kück, Ulrich

2012-01-01

The study of mutants to elucidate gene functions has a long and successful history; however, to discover causative mutations in mutants that were generated by random mutagenesis often takes years of laboratory work and requires previously generated genetic and/or physical markers, or resources like DNA libraries for complementation. Here, we present an alternative method to identify defective genes in developmental mutants of the filamentous fungus Sordaria macrospora through Illumina/Solexa whole-genome sequencing. We sequenced pooled DNA from progeny of crosses of three mutants and the wild type and were able to pinpoint the causative mutations in the mutant strains through bioinformatics analysis. One mutant is a spore color mutant, and the mutated gene encodes a melanin biosynthesis enzyme. The causative mutation is a G to A change in the first base of an intron, leading to a splice defect. The second mutant carries an allelic mutation in the pro41 gene encoding a protein essential for sexual development. In the mutant, we detected a complex pattern of deletion/rearrangements at the pro41 locus. In the third mutant, a point mutation in the stop codon of a transcription factor-encoding gene leads to the production of immature fruiting bodies. For all mutants, transformation with a wild type-copy of the affected gene restored the wild-type phenotype. Our data demonstrate that whole-genome sequencing of mutant strains is a rapid method to identify developmental genes in an organism that can be genetically crossed and where a reference genome sequence is available, even without prior mapping information. PMID:22384404

Comparing three novel endpoints for developmental osteotoxicity in the embryonic stem cell test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nieden, Nicole I. zur, E-mail: nicole.zurnieden@ucr.ed; Department of Cell Biology and Neuroscience and Stem Cell Center, University of California Riverside, Riverside, CA 92521; Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, 04103 Leipzig

Birth defects belong to the most serious side effects of pharmaceutical compounds or environmental chemicals. In vivo, teratogens most often affect the normal development of bones, causing growth retardation, limb defects or craniofacial malformations. The embryonic stem cell test (EST) is one of the most promising models that allow the in vitro prediction of embryotoxicity, with one of its endpoints being bone tissue development. The present study was designed to describe three novel inexpensive endpoints to assess developmental osteotoxicity using the model compounds penicillin G (non-teratogenic), 5-fluorouracil (strong teratogen) and all-trans retinoic acid (bone teratogen). These three endpoints were: quantificationmore » of matrix incorporated calcium by (1) morphometric analysis and (2) measurement of calcium levels as well as (3) activity of alkaline phosphatase, an enzyme involved in matrix calcification. To evaluate our data, we have compared the concentration curves and resulting ID{sub 50}s of the new endpoints with mRNA expression for osteocalcin. Osteocalcin is an exclusive marker found only in mineralized tissues, is regulated upon compound treatment and reliably predicts the potential of a chemical entity acting as a bone teratogen. By comparing the new endpoints to quantitative expression of osteocalcin, which we previously identified as suitable to detect developmental osteotoxicity, we were ultimately able to illustrate IMAGE analysis and Ca{sup 2+} deposition assays as two reliable novel endpoints for the EST. This is of particular importance for routine industrial assessment of novel compounds as these two new endpoints may substitute previously used molecular read-out methods, which are often costly and time-consuming.« less

Genetic studies in a patient with X-linked retinoschisis coexisting with developmental delay and sensorineural hearing loss.

PubMed

Sudha, Dhandayuthapani; Patric, Irene Rosita Pia; Ganapathy, Aparna; Agarwal, Smitha; Krishna, Shuba; Neriyanuri, Srividya; Sripriya, Sarangapani; Sen, Parveen; Chidambaram, Subbulakshmi; Arunachalam, Jayamuruga Pandian

2017-01-01

In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. RS1 gene screening for XLRS was performed by Sanger sequencing. Whole genome SNP 6.0 array analysis was carried out to investigate gross chromosomal aberrations that could result in systemic phenotype. In addition, targeted next generation sequencing (NGS) was employed to determine any possible involvement of X-linked syndromic and non-syndromic mental retardation genes. This NGS panel consisted of 550 genes implicated in several other rare inherited diseases. RS1 gene screening revealed a pathogenic hemizygous splice site mutation (c.78+1G>T), inherited from the mother. SNP 6.0 array analysis did not indicate any significant chromosomal aberrations that could be disease-associated. Targeted resequencing did not identify any mutations in the X-linked mental retardation genes. However, variations in three other genes (NSD1, LARGE, and POLG) were detected, which were all inherited from the patient's unaffected father. Taken together, RS1 mutation was found to segregate with retinoschisis phenotype while none of the other identified variations were co-segregating with the systemic defects. Hereby, we infer that the multisystemic defects harbored by the patient are a rare coexistence of XLRS, developmental delay, sensorineural hearing loss, and reduced axial tone reported for the first time in the literature.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

True Lies: The Double Life of the Nucleotide Excision Repair Factors in Transcription and DNA Repair

PubMed Central

Le May, Nicolas; Egly, Jean-Marc; Coin, Frédéric

2010-01-01

Nucleotide excision repair (NER) is a major DNA repair pathway in eukaryotic cells. NER removes structurally diverse lesions such as pyrimidine dimers, arising upon UV irradiation or bulky chemical adducts, arising upon exposure to carcinogens and some chemotherapeutic drugs. NER defects lead to three genetic disorders that result in predisposition to cancers, accelerated aging, neurological and developmental defects. During NER, more than 30 polypeptides cooperate to recognize, incise, and excise a damaged oligonucleotide from the genomic DNA. Recent papers reveal an additional and unexpected role for the NER factors. In the absence of a genotoxic attack, the promoters of RNA polymerases I- and II-dependent genes recruit XPA, XPC, XPG, and XPF to initiate gene expression. A model that includes the growth arrest and DNA damage 45α protein (Gadd45α) and the NER factors, in order to maintain the promoter of active genes under a hypomethylated state, has been proposed but remains controversial. This paper focuses on the double life of the NER factors in DNA repair and transcription and describes the possible roles of these factors in the RNA synthesis process. PMID:20725631

A genetic screen for temperature-sensitive cell-division mutants of Caenorhabditis elegans.

PubMed Central

O'Connell, K F; Leys, C M; White, J G

1998-01-01

A novel screen to isolate conditional cell-division mutants in Caenorhabditis elegans has been developed. The screen is based on the phenotypes associated with existing cell-division mutations: some disrupt postembryonic divisions and affect formation of the gonad and ventral nerve cord-resulting in sterile, uncoordinated animals-while others affect embryonic divisions and result in lethality. We obtained 19 conditional mutants that displayed these phenotypes when shifted to the restrictive temperature at the appropriate developmental stage. Eighteen of these mutations have been mapped; 17 proved to be single alleles of newly identified genes, while 1 proved to be an allele of a previously identified gene. Genetic tests on the embryonic lethal phenotypes indicated that for 13 genes, embryogenesis required maternal expression, while for 6, zygotic expression could suffice. In all cases, maternal expression of wild-type activity was found to be largely sufficient for embryogenesis. Cytological analysis revealed that 10 mutants possessed embryonic cell-division defects, including failure to properly segregate DNA, failure to assemble a mitotic spindle, late cytokinesis defects, prolonged cell cycles, and improperly oriented mitotic spindles. We conclude that this approach can be used to identify mutations that affect various aspects of the cell-division cycle. PMID:9649522

Bardet-Biedl Syndrome

PubMed Central

Suspitsin, Evgeny N.; Imyanitov, Evgeny N.

2016-01-01

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder. It is characterized by heterogeneous clinical manifestations including primary features of the disease (rod-cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning difficulties) and secondary BBS characteristics (developmental delay, speech deficit, brachydactyly or syndactyly, dental defects, ataxia or poor coordination, olfactory deficit, diabetes mellitus, congenital heart disease, etc.); most of these symptoms may not be present at birth but appear and progressively worsen during the first and second decades of life. At least 20 BBS genes have already been identified, and all of them are involved in primary cilia functioning. Genetic diagnosis of BBS is complicated due to lack of gene-specific disease symptoms; however, it is gradually becoming more accessible with the invention of multigene sequencing technologies. Clinical management of BBS is largely limited to a symptomatic treatment. Mouse experiments demonstrate that the most debilitating complication of BBS, blindness, can be rescued by topical gene therapy. There is a published case report describing the delay of BBS symptoms by nutritional compensation of the disease-related biochemical deficiencies. Progress in DNA testing technologies is likely to rapidly resolve all limitations in BBS diagnosis; however, much slower improvement is expected with regard to BBS treatment. PMID:27385962

Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass.

PubMed

Hirozane, Toru; Tohmonda, Takahide; Yoda, Masaki; Shimoda, Masayuki; Kanai, Yae; Matsumoto, Morio; Morioka, Hideo; Nakamura, Masaya; Horiuchi, Keisuke

2016-09-28

Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-κB signaling and an increase in the expression of NF-κB-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

Brassinosteroids Are Master Regulators of Gibberellin Biosynthesis in Arabidopsis

PubMed Central

Unterholzner, Simon J.; Rozhon, Wilfried; Papacek, Michael; Ciomas, Jennifer; Lange, Theo; Kugler, Karl G.; Mayer, Klaus F.; Sieberer, Tobias; Poppenberger, Brigitte

2015-01-01

Plant growth and development are highly regulated processes that are coordinated by hormones including the brassinosteroids (BRs), a group of steroids with structural similarity to steroid hormones of mammals. Although it is well understood how BRs are produced and how their signals are transduced, BR targets, which directly confer the hormone’s growth-promoting effects, have remained largely elusive. Here, we show that BRs regulate the biosynthesis of gibberellins (GAs), another class of growth-promoting hormones, in Arabidopsis thaliana. We reveal that Arabidopsis mutants deficient in BR signaling are severely impaired in the production of bioactive GA, which is correlated with defective GA biosynthetic gene expression. Expression of the key GA biosynthesis gene GA20ox1 in the BR signaling mutant bri1-301 rescues many of its developmental defects. We provide evidence that supports a model in which the BR-regulated transcription factor BES1 binds to a regulatory element in promoters of GA biosynthesis genes in a BR-induced manner to control their expression. In summary, our study underscores a role of BRs as master regulators of GA biosynthesis and shows that this function is of major relevance for the growth and development of vascular plants. PMID:26243314

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect.

PubMed

Aleksiūnienė, Beata; Preiksaitiene, Egle; Morkūnienė, Aušra; Ambrozaitytė, Laima; Utkus, Algirdas

2018-01-01

Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features. © 2018 S. Karger AG, Basel.

Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.

PubMed

Tham, Emma; Lindstrand, Anna; Santani, Avni; Malmgren, Helena; Nesbitt, Addie; Dubbs, Holly A; Zackai, Elaine H; Parker, Michael J; Millan, Francisca; Rosenbaum, Kenneth; Wilson, Golder N; Nordgren, Ann

2015-03-05

Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genome-wide transcriptomic analysis of BR-deficient Micro-Tom reveals correlations between drought stress tolerance and brassinosteroid signaling in tomato.

PubMed

Lee, Jinsu; Shim, Donghwan; Moon, Suyun; Kim, Hyemin; Bae, Wonsil; Kim, Kyunghwan; Kim, Yang-Hoon; Rhee, Sung-Keun; Hong, Chang Pyo; Hong, Suk-Young; Lee, Ye-Jin; Sung, Jwakyung; Ryu, Hojin

2018-06-01

Brassinosteroids (BRs) are plant steroid hormones that play crucial roles in a range of growth and developmental processes. Although BR signal transduction and biosynthetic pathways have been well characterized in model plants, their biological roles in an important crop, tomato (Solanum lycopersicum), remain unknown. Here, cultivated tomato (WT) and a BR synthesis mutant, Micro-Tom (MT), were compared using physiological and transcriptomic approaches. The cultivated tomato showed higher tolerance to drought and osmotic stresses than the MT tomato. However, BR-defective phenotypes of MT, including plant growth and stomatal closure defects, were completely recovered by application of exogenous BR or complementation with a SlDWARF gene. Using genome-wide transcriptome analysis, 619 significantly differentially expressed genes (DEGs) were identified between WT and MT plants. Several DEGs were linked to known signaling networks, including those related to biotic/abiotic stress responses, lignification, cell wall development, and hormone responses. Consistent with the higher susceptibility of MT to drought stress, several gene sets involved in responses to drought and osmotic stress were differentially regulated between the WT and MT tomato plants. Our data suggest that BR signaling pathways are involved in mediating the response to abiotic stress via fine-tuning of abiotic stress-related gene networks in tomato plants. Copyright © 2018. Published by Elsevier Masson SAS.

Child oral health-related quality of life (COHQoL), enamel defects of the first permanent molars and caries experience among children in Western Australia.

PubMed

Arrow, P

2013-09-01

Published reports suggest that children with enamel defects, especially where enamel is missing or breaking down, experience considerable discomfort and are generally more fearful of dental treatment. However, children's oral health-related quality of life in relation to enamel defects has not been reported. The aim of this study was to examine the association between oral health-related quality of life among children (COHQoL) with enamel defects of the first permanent molars and deciduous caries experience. Children attending pre-primary schools in metropolitan Perth, Western Australia, were recruited and classified for enamel defects using the modified Developmental Defects of Enamel index. Caries experience of deciduous molars and canines was also recorded. Parents completed a child oral health-related quality of life questionnaire. Data were analysed using Kruskal-Wallis, Spearman's rank correlation, chi-square, multiple linear regression and ordered logistic regression to test the factors for their influence on the COHQoL. From the 550 children assessed (mean age 7.2 years) 522 COHQoL questionnaires were returned. Mean COHQoL score was 8.9 (sd 8.8). Bivariate tests showed no association of COHQoL with enamel defect status of the first permanent molars. COHQoL was associated with dmft (mean dmft 1.96, sd 2.62). Higher caries experience children had poorer reported oral health-related quality of life. The presence of enamel defects in the first permanent molars did not affect the children's oral health-related quality of life.

Engineering human cell spheroids to model embryonic tissue fusion in vitro

PubMed Central

Wolf, Cynthia J.; Wood, Carmen; Ren, Hongzu; Grindstaff, Rachel; Padgett, William; Swank, Adam; MacMillan, Denise; Fisher, Anna; Winnik, Witold; Abbott, Barbara D.

2017-01-01

Epithelial-mesenchymal interactions drive embryonic fusion events during development, and perturbations of these interactions can result in birth defects. Cleft palate and neural tube defects can result from genetic defects or environmental exposures during development, yet very little is known about the effect of chemical exposures on fusion events during human development because of a lack of relevant and robust human in vitro assays of developmental fusion behavior. Given the etiology and prevalence of cleft palate and the relatively simple architecture and composition of the embryonic palate, we sought to develop a three-dimensional culture system that mimics the embryonic palate and could be used to study fusion behavior in vitro using human cells. We engineered size-controlled human Wharton’s Jelly stromal cell (HWJSC) spheroids and established that 7 days of culture in osteogenesis differentiation medium was sufficient to promote an osteogenic phenotype consistent with embryonic palatal mesenchyme. HWJSC spheroids supported the attachment of human epidermal keratinocyte progenitor cells (HPEKp) on the outer spheroid surface likely through deposition of collagens I and IV, fibronectin, and laminin by mesenchymal spheroids. HWJSC spheroids coated in HPEKp cells exhibited fusion behavior in culture, as indicated by the removal of epithelial cells from the seams between spheroids, that was dependent on epidermal growth factor signaling and fibroblast growth factor signaling in agreement with palate fusion literature. The method described here may broadly apply to the generation of three-dimensional epithelial-mesenchymal co-cultures to study developmental fusion events in a format that is amenable to predictive toxicology applications. PMID:28898253

Developmental sub-chronic exposure to chlorpyrifos reduces anxiety-related behavior in zebrafish larvae

PubMed Central

Richendrfer, Holly; Pelkowski, Sean D.; Colwill, Ruth M.; Créton, Robbert

2013-01-01

Neurobehavioral disorders such as anxiety, autism, and attention deficit hyperactivity disorders are typically influenced by genetic and environmental factors. Although several genetic risk factors have been identified in recent years, little is known about the environmental factors that either cause neurobehavioral disorders or contribute to their progression in genetically predisposed individuals. One environmental factor that has raised concerns is chlorpyrifos, an organophosphate pesticide that is widely used in agriculture and is found ubiquitously in the environment. In the present study, we examined the effects of sub-chronic chlorpyrifos exposure on anxiety-related behavior during development using zebrafish larvae. We found that sub-chronic exposure to 0.01 or 0.1 μM chlorpyrifos during development induces specific behavioral defects in 7-day-old zebrafish larvae. The larvae displayed decreases in swim speed and thigmotaxis, yet no changes in avoidance behavior were seen. Exposure to 0.001 μM chlorpyrifos did not affect swimming, thigmotaxis, or avoidance behavior and exposure to 1 μM chlorpyrifos induced behavioral defects, but also induced defects in larval morphology. Since thigmotaxis, a preference for the edge, is an anxiety-related behavior in zebrafish larvae, we propose that sub-chronic chlorpyrifos exposure interferes with the development of anxiety-related behaviors. The results of this study provide a good starting point for examination of the molecular, cellular, developmental, and neural mechanisms that are affected by environmentally relevant concentrations of organophosphate pesticides. A more detailed understanding of these mechanisms is important for the development of predictive models and refined health policies to prevent toxicant-induced neurobehavioral disorders. PMID:22579535

Auxin Import and Local Auxin Biosynthesis Are Required for Mitotic Divisions, Cell Expansion and Cell Specification during Female Gametophyte Development in Arabidopsis thaliana

PubMed Central

Panoli, Aneesh; Martin, Maria Victoria; Alandete-Saez, Monica; Simon, Marissa; Neff, Christina; Swarup, Ranjan; Bellido, Andrés; Yuan, Li; Pagnussat, Gabriela C.; Sundaresan, Venkatesan

2015-01-01

The female gametophyte of flowering plants, called the embryo sac, develops from a haploid cell named the functional megaspore, which is specified after meiosis by the diploid sporophyte. In Arabidopsis, the functional megaspore undergoes three syncitial mitotic divisions followed by cellularization to form seven cells of four cell types including two female gametes. The plant hormone auxin is important for sporophytic developmental processes, and auxin levels are known to be regulated by biosynthesis and transport. Here, we investigated the role of auxin biosynthetic genes and auxin influx carriers in embryo sac development. We find that genes from the YUCCA/TAA pathway (YUC1, YUC2, YUC8, TAA1, TAR2) are expressed asymmetrically in the developing ovule and embryo sac from the two-nuclear syncitial stage until cellularization. Mutants for YUC1 and YUC2 exhibited defects in cell specification, whereas mutations in YUC8, as well as mutations in TAA1 and TAR2, caused defects in nuclear proliferation, vacuole formation and anisotropic growth of the embryo sac. Additionally, expression of the auxin influx carriers AUX1 and LAX1 were observed at the micropylar pole of the embryo sac and in the adjacent cells of the ovule, and the aux1 lax1 lax2 triple mutant shows multiple gametophyte defects. These results indicate that both localized auxin biosynthesis and auxin import, are required for mitotic divisions, cell expansion and patterning during embryo sac development. PMID:25970627

Auxin Import and Local Auxin Biosynthesis Are Required for Mitotic Divisions, Cell Expansion and Cell Specification during Female Gametophyte Development in Arabidopsis thaliana.

PubMed

Panoli, Aneesh; Martin, Maria Victoria; Alandete-Saez, Monica; Simon, Marissa; Neff, Christina; Swarup, Ranjan; Bellido, Andrés; Yuan, Li; Pagnussat, Gabriela C; Sundaresan, Venkatesan

2015-01-01

The female gametophyte of flowering plants, called the embryo sac, develops from a haploid cell named the functional megaspore, which is specified after meiosis by the diploid sporophyte. In Arabidopsis, the functional megaspore undergoes three syncitial mitotic divisions followed by cellularization to form seven cells of four cell types including two female gametes. The plant hormone auxin is important for sporophytic developmental processes, and auxin levels are known to be regulated by biosynthesis and transport. Here, we investigated the role of auxin biosynthetic genes and auxin influx carriers in embryo sac development. We find that genes from the YUCCA/TAA pathway (YUC1, YUC2, YUC8, TAA1, TAR2) are expressed asymmetrically in the developing ovule and embryo sac from the two-nuclear syncitial stage until cellularization. Mutants for YUC1 and YUC2 exhibited defects in cell specification, whereas mutations in YUC8, as well as mutations in TAA1 and TAR2, caused defects in nuclear proliferation, vacuole formation and anisotropic growth of the embryo sac. Additionally, expression of the auxin influx carriers AUX1 and LAX1 were observed at the micropylar pole of the embryo sac and in the adjacent cells of the ovule, and the aux1 lax1 lax2 triple mutant shows multiple gametophyte defects. These results indicate that both localized auxin biosynthesis and auxin import, are required for mitotic divisions, cell expansion and patterning during embryo sac development.

Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development.

PubMed

Enkhmandakh, Badam; Makeyev, Aleksandr V; Erdenechimeg, Lkhamsuren; Ruddle, Frank H; Chimge, Nyam-Osor; Tussie-Luna, Maria Isabel; Roy, Ananda L; Bayarsaihan, Dashzeveg

2009-01-06

GTF2I and GTF2IRD1 encoding the multifunctional transcription factors TFII-I and BEN are clustered at the 7q11.23 region hemizygously deleted in Williams-Beuren syndrome (WBS), a complex multisystemic neurodevelopmental disorder. Although the biochemical properties of TFII-I family transcription factors have been studied in depth, little is known about the specialized contributions of these factors in pathways required for proper embryonic development. Here, we show that homozygous loss of either Gtf2ird1 or Gtf2i function results in multiple phenotypic manifestations, including embryonic lethality; brain hemorrhage; and vasculogenic, craniofacial, and neural tube defects in mice. Further analyses suggest that embryonic lethality may be attributable to defects in yolk sac vasculogenesis and angiogenesis. Microarray data indicate that the Gtf2ird1 homozygous phenotype is mainly caused by an impairment of the genes involved in the TGFbetaRII/Alk1/Smad5 signal transduction pathway. The effect of Gtf2i inactivation on this pathway is less prominent, but downregulation of the endothelial growth factor receptor-2 gene, resulting in the deterioration of vascular signaling, most likely exacerbates the severity of the Gtf2i mutant phenotype. A subset of Gtf2ird1 and Gtf2i heterozygotes displayed microcephaly, retarded growth, and skeletal and craniofacial defects, therefore showing that haploinsufficiency of TFII-I proteins causes various developmental anomalies that are often associated with WBS.

Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

PubMed Central

Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J.; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H.; Lieberman, Paul M.; Tzfati, Yehuda

2013-01-01

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal–Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres. PMID:23959892

Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.

PubMed

Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H; Lieberman, Paul M; Tzfati, Yehuda

2013-09-03

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.

Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene.

PubMed

Nagy, R; Wang, H; Albrecht, B; Wieczorek, D; Gillessen-Kaesbach, G; Haan, E; Meinecke, P; de la Chapelle, A; Westman, J A

2012-08-01

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene. © 2011 John Wiley & Sons A/S.

Defects in hepatic Notch signaling result in disruption of the communicating intrahepatic bile duct network in mice.

PubMed

Sparks, Erin E; Perrien, Daniel S; Huppert, Kari A; Peterson, Todd E; Huppert, Stacey S

2011-05-01

Abnormal Notch signaling in humans results in Alagille syndrome, a pleiotropic disease characterized by a paucity of intrahepatic bile ducts (IHBDs). It is not clear how IHBD paucity develops as a consequence of atypical Notch signaling, whether by a developmental lack of bile duct formation, a post-natal lack of branching and elongation or an inability to maintain formed ducts. Previous studies have focused on the role of Notch in IHBD development, and demonstrated a dosage requirement of Notch signaling for proper IHBD formation. In this study, we use resin casting and X-ray microtomography (microCT) analysis to address the role of Notch signaling in the maintenance of formed IHBDs upon chronic loss or gain of Notch function. Our data show that constitutive expression of the Notch1 intracellular domain in bi-potential hepatoblast progenitor cells (BHPCs) results in increased IHBD branches at post-natal day 60 (P60), which are maintained at P90 and P120. By contrast, loss of Notch signaling via BHPC-specific deletion of RBP-J (RBP KO), the DNA-binding partner for all Notch receptors, results in progressive loss of intact IHBD branches with age. Interestingly, in RBP KO mice, we observed a reduction in bile ducts per portal vein at P60; no further reduction had occurred at P120. Thus, bile duct structures are not lost with age; instead, we propose a model in which BHPC-specific loss of Notch signaling results in an initial developmental defect resulting in fewer bile ducts being formed, and in an acquired post-natal defect in the maintenance of intact IHBD architecture as a result of irresolvable cholestasis. Our studies reveal a previously unappreciated role for Notch signaling in the post-natal maintenance of an intact communicating IHBD structure, and suggest that liver defects observed in Alagille syndrome patients might be more complex than bile duct paucity.

Defects in hepatic Notch signaling result in disruption of the communicating intrahepatic bile duct network in mice

PubMed Central

Sparks, Erin E.; Perrien, Daniel S.; Huppert, Kari A.; Peterson, Todd E.; Huppert, Stacey S.

2011-01-01

SUMMARY Abnormal Notch signaling in humans results in Alagille syndrome, a pleiotropic disease characterized by a paucity of intrahepatic bile ducts (IHBDs). It is not clear how IHBD paucity develops as a consequence of atypical Notch signaling, whether by a developmental lack of bile duct formation, a post-natal lack of branching and elongation or an inability to maintain formed ducts. Previous studies have focused on the role of Notch in IHBD development, and demonstrated a dosage requirement of Notch signaling for proper IHBD formation. In this study, we use resin casting and X-ray microtomography (microCT) analysis to address the role of Notch signaling in the maintenance of formed IHBDs upon chronic loss or gain of Notch function. Our data show that constitutive expression of the Notch1 intracellular domain in bi-potential hepatoblast progenitor cells (BHPCs) results in increased IHBD branches at post-natal day 60 (P60), which are maintained at P90 and P120. By contrast, loss of Notch signaling via BHPC-specific deletion of RBP-J (RBP KO), the DNA-binding partner for all Notch receptors, results in progressive loss of intact IHBD branches with age. Interestingly, in RBP KO mice, we observed a reduction in bile ducts per portal vein at P60; no further reduction had occurred at P120. Thus, bile duct structures are not lost with age; instead, we propose a model in which BHPC-specific loss of Notch signaling results in an initial developmental defect resulting in fewer bile ducts being formed, and in an acquired post-natal defect in the maintenance of intact IHBD architecture as a result of irresolvable cholestasis. Our studies reveal a previously unappreciated role for Notch signaling in the post-natal maintenance of an intact communicating IHBD structure, and suggest that liver defects observed in Alagille syndrome patients might be more complex than bile duct paucity. PMID:21282722

Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.

PubMed

Faundes, Víctor; Newman, William G; Bernardini, Laura; Canham, Natalie; Clayton-Smith, Jill; Dallapiccola, Bruno; Davies, Sally J; Demos, Michelle K; Goldman, Amy; Gill, Harinder; Horton, Rachel; Kerr, Bronwyn; Kumar, Dhavendra; Lehman, Anna; McKee, Shane; Morton, Jenny; Parker, Michael J; Rankin, Julia; Robertson, Lisa; Temple, I Karen; Banka, Siddharth

2018-01-04

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A de novo interstitial 6q deletion in a boy with a split hand malformation.

PubMed

Duran-Gonzalez, Jorge; Gutierrez-Angulo, Melva; Garcia-Cruz, Diana; Ayala, Maria de la Luz; Padilla, Miguel; Davalos, Ingrid P

2007-01-01

We report on a de novo interstitial deletion of (6)(q15q22.2) in a 5-year-old boy with developmental delay, microcephaly, facial dysmorphism, cryptorchidism, congenital heart defect, and split-hand malformation. Previous reports and this patient suggest that 6q21 may contain a gene or genes related either directly or indirectly to limb development.

DEVELOPMENTAL TOXICITY OF METHANOL: PATHOGENESIS IN CD-1 AND C57BL/6J MICE EXPOSED IN WHOLE EMBRYO CULTURE

EPA Science Inventory

BACKGROUND: Methanol causes axial skeleton and craniofacial defects in both CD-1 and C57BL/6J mice during gastrulation, but C57BL/6J embryos are more severely affected. We evaluated methanol-induced pathogenesis in CD-1 and C57BL/6J embryos exposed during gastrulation in whole em...

What Happened to My Child? Unknown Causes of Developmental Disability and Research in Genetics

ERIC Educational Resources Information Center

Pevsner, Jonathan; Silverman, Wayne

2007-01-01

At one time or the other, virtually every parent has gone to the doctor concerned about his or her child. Thanks to the advances of modern medicine, the doctor can diagnose the problem most of the time and treat it successfully. Many potential problems, some life-threatening like diphtheria and neural tube defects, can even be prevented altogether…

Cell death in neural precursor cells and neurons before neurite formation prevents the emergence of abnormal neural structures in the Drosophila optic lobe.

PubMed

Hara, Yusuke; Sudo, Tatsuya; Togane, Yu; Akagawa, Hiromi; Tsujimura, Hidenobu

2018-04-01

Programmed cell death is a conserved strategy for neural development both in vertebrates and invertebrates and is recognized at various developmental stages in the brain from neurogenesis to adulthood. To understand the development of the central nervous system, it is essential to reveal not only molecular mechanisms but also the role of neural cell death (Pinto-Teixeira et al., 2016). To understand the role of cell death in neural development, we investigated the effect of inhibition of cell death on optic lobe development. Our data demonstrate that, in the optic lobe of Drosophila, cell death occurs in neural precursor cells and neurons before neurite formation and functions to prevent various developmental abnormalities. When neuronal cell death was inhibited by an effector caspase inhibitor, p35, multiple abnormal neuropil structures arose during optic lobe development-e.g., enlarged or fused neuropils, misrouted neurons and abnormal neurite lumps. Inhibition of cell death also induced morphogenetic defects in the lamina and medulla development-e.g., failures in the separation of the lamina and medulla cortices and the medulla rotation. These defects were reproduced in the mutant of an initiator caspase, dronc. If cell death was a mechanism for removing the abnormal neuropil structures, we would also expect to observe them in mutants defective for corpse clearance. However, they were not observed in these mutants. When dead cell-membranes were visualized with Apoliner, they were observed only in cortices and not in neuropils. These results suggest that the cell death occurs before mature neurite formation. Moreover, we found that inhibition of cell death induced ectopic neuroepithelial cells, neuroblasts and ganglion mother cells in late pupal stages, at sites where the outer and inner proliferation centers were located at earlier developmental stages. Caspase-3 activation was observed in the neuroepithelial cells and neuroblasts in the proliferation centers. These results indicate that cell death is required for elimination of the precursor cells composing the proliferation centers. This study substantiates an essential role of early neural cell death for ensuring normal development of the central nervous system. Copyright © 2018 Elsevier Inc. All rights reserved.

Developmental Structural Tooth Defects in Dogs – Experience From Veterinary Dental Referral Practice and Review of the Literature

PubMed Central

Boy, Sonja; Crossley, David; Steenkamp, Gerhard

2016-01-01

Developmental tooth abnormalities in dogs are uncommon in general veterinary practice but understanding thereof is important for optimal management in order to maintain masticatory function through preservation of the dentition. The purpose of this review is to discuss clinical abnormalities of the enamel and general anatomy of dog teeth encountered in veterinary dental referral practice and described in the literature. More than 900 referral cases are seen annually between the two referral practices. The basis of the pathogenesis, resultant clinical appearance, and the principles of management for each anomaly will be described. Future research should be aimed toward a more detailed analysis of these conditions so rarely described in the literature. PMID:26904551

Velo-cardio-facial and partial DiGeorge phenotype in a child with interstitial deletion at 10p13 - implications for cytogenetics and molecular biology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lipson, A.; Sholler, G.; Issacs, D.

We report on a female with a interstitial deletion of 10p13 and a phenotype similar to that seen with the 22q deletion syndromes (DiGeorge/velo-cardio-facial). She had a posterior cleft palate, perimembranous ventricular septal defect, dyscoordinate swallowing, T-cell subset abnormalities, small ears, maxillary and mandibular hypoplasia, broad nasal bridge, deficient alae nasi, contractures of fingers and developmental delay. This could indicate homology of some developmental genes at 22q and 10p so that patients with the velocardiofacial phenotype who do not prove to be deleted on 22q are candidates for a 10p deletion. 58 refs., 3 figs.

GABA-CREB signalling regulates maturation and survival of newly generated neurons in the adult hippocampus

PubMed Central

Jagasia, Ravi; Steib, Kathrin; Englberger, Elisabeth; Herold, Sabine; Faus-Kessler, Theresa; Saxe, Michael; Gage, Fred H.; Song, Hongjun; Lie, D. Chichung

2009-01-01

Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signalling pathways. Here, we investigate the role of CREB signalling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous fashion impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule associated protein, DCX, and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects following loss of GABA-mediated excitation can be compensated by enhanced CREB signalling. These results indicate that CREB signalling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation. PMID:19553437

Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.

PubMed

Bolton, Helen; Graham, Sarah J L; Van der Aa, Niels; Kumar, Parveen; Theunis, Koen; Fernandez Gallardo, Elia; Voet, Thierry; Zernicka-Goetz, Magdalena

2016-03-29

Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic.

Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

PubMed

Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

2010-10-01

To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. © Wiley-Liss, Inc.

Improved safety margin for embryotoxicity in rats for the new endoperoxide artefenomel (OZ439) as compared to artesunate.

PubMed

Clark, Robert L; Edwards, Tammye L; Longo, Monica; Kinney, Joseph; Walker, Don K; Rhodes, Jon; Clode, Sally A; Rückle, Thomas; Wells, Timothy; Andenmatten, Nicole; Huber, Anna Christine

2018-04-17

Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo-fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single-dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel-related material in plasma was determined after the administration of 14 C-artefenomel. Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose-response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250-fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100-fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant. The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype.

PubMed

Yabe, Miharu; Yabe, Hiromasa; Morimoto, Tsuyoshi; Fukumura, Akiko; Ohtsubo, Keisuke; Koike, Takashi; Yoshida, Kenichi; Ogawa, Seishi; Ito, Etsuro; Okuno, Yusuke; Muramatsu, Hideki; Kojima, Seiji; Matsuo, Keitaro; Hira, Asuka; Takata, Minoru

2016-11-01

Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients. © 2016 John Wiley & Sons Ltd.

PAK4 kinase is essential for embryonic viability and for proper neuronal development.

PubMed

Qu, Jian; Li, Xiaofan; Novitch, Bennet G; Zheng, Ye; Kohn, Matthew; Xie, Jian-Ming; Kozinn, Spencer; Bronson, Roderick; Beg, Amer A; Minden, Audrey

2003-10-01

The serine/threonine kinase PAK4 is a target for the Rho GTPase Cdc42 and has been shown to regulate cell morphology and cytoskeletal organization in mammalian cells. To examine the physiological and developmental functions of PAK4, we have disrupted the PAK4 gene in mice. The absence of PAK4 led to lethality by embryonic day 11.5, a result most likely due to a defect in the fetal heart. Striking abnormalities were also evident in the nervous systems of PAK4-deficient embryos. These embryos had dramatic defects in neuronal development and axonal outgrowth. In particular, spinal cord motor neurons and interneurons failed to differentiate and migrate to their proper positions. This is probably related to the role for PAK4 in the regulation of cytoskeletal organization and cell and/or extracellular matrix adhesion. PAK4-null embryos also had defects in proper folding of the caudal portion of the neural tube, suggesting an important role for PAK4 in neural tube development.

Right upper limb bud triplication and polythelia, left sided hemihypertrophy and congenital hip dislocation, facial dysmorphism, congenital heart disease, and scoliosis: disorganisation-like spectrum or patterning gene defect?

PubMed

Sabry, M A; al-Saleh, Q; al-Saw'an, R; al-Awadi, S A; Farag, T I

1995-07-01

A Somali female baby with right upper limb triplication, polythelia, left sided hemihypertrophy, congenital hip dislocation, facial dysmorphism, congenital heart disease, and scoliosis is described. It seems that the above described pattern of anomalies has not been reported before. The possible developmental genetic mechanism responsible for this phenotype is briefly discussed.

Perinatal Autopsy Findings in a Case of De Novo Hypohidrotic Ectodermal Dysplasia.

PubMed

Chikkannaiah, Panduranga; Nagaraju, Smitha; Kangle, Rajit; Gosavi, Mansi

2015-01-01

Ectodermal dysplasia are group of inherited disorders involving the developmental defects of ectodermal structures like hair, teeth, nails, sweat glands, and others. X-linked recessive inheritance is most common. Here we describe perinatal autopsy findings in a case of de novo ectodermal dysplasia in a female fetus. To the best of our knowledge, this is the first fetal autopsy description in a case of ectodermal dysplasia.