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Sample records for ganglioneuromas implicates hedgehog

  1. [Giant retroperitoneal ganglioneuroma].

    PubMed

    Sarf, Ismail; el Mejjad, Amine; Badre, Latifa; Mani, Ahmed; Aboutaieb, Rachid; Meziane, Fethi

    2003-06-01

    The authors report a new case of retroperitoneal ganglioneuroma in an 18-year-old girl presenting with abdominal mass and lumbosciatica. The diagnosis of retroperitoneal tumour was based on computed tomography and magnetic resonance imaging. Treatment consisted of complete resection of the tumour. The postoperative course was favourable with no recurrence after one year of follow-up. The authors discuss the diagnostic, therapeutic and prognostic aspects of this disease. PMID:12940207

  2. Lipomatous ganglioneuroma of the retroperitoneum.

    PubMed

    Meng, Qing-Da; Ma, Xiao-Ning; Wei, Hong; Pan, Rong-Hui; Jiang, Wei; Chen, Fang-Shu

    2016-04-01

    Lipomatous ganglioneuroma (LG) is a rare variant of ganglioneuroma that is histologically characterized by a mature adipocytic component admixed with a conventional ganglioneuroma. We report the clinicopathological and immunohistochemical features of an LG in a 44-year-old Chinese male; additionally, we review the literature regarding this type of tumor. Magnetic resonance imaging revealed a left paravertebral soft-tissue mass at the T11-L3 levels. Grossly, the encapsulated neoplasm had a white to yellowish cut surface and rubbery consistency. Microscopic evaluation revealed an encapsulated lesion that consisted of areas of ganglioneuroma admixed with areas of mature fat. By immunohistochemistry, the ganglion cells were positive for chromogranin and synaptophysin, whereas the Schwann cells were positive for vimentin, S-100 protein, and glial fibrillary acidic protein (GFAP). This is the second known report of a retroperitoneal LG. The patient was well and without evidence of disease at 2 years' follow-up. PMID:23978430

  3. DS-03SONIC HEDGEHOG ANTAGONISTS POTENTLY INDUCE APOPTOSIS IN THE CEREBELLAR EXTERNAL GRANULE LAYER: IMPLICATIONS FOR MEDULLOBLASTOMA TREATMENT

    PubMed Central

    Noguchi, Kevin; Cabrera, Omar; Swiney, Brant; Smith, Julie; Farber, Nuri

    2014-01-01

    There is a great interest in Hedgehog signaling both for its role in cerebellar development and medulloblastoma (MB) treatment. The cerebellum maintains its own proliferative layer called the external granule layer (EGL) that produces over 90% of its neurons. During development, the established dogma views Hedgehog signaling as a robust mitogenic stimulator of EGL proliferation. However, in other regions of the body, Hedgehog stimulation acts as a survival signal by potently inducing NPC apoptosis when signaling is lost. In this manner, the sonic hedgehog ligand's concentration gradient determines NPC survival or death thereby morphologically sculpting the developing nervous system. Therefore, we tested whether Hedgehog signaling also acts as a survival signal in the EGL by administering several Hedgehog antagonists (vismodegib, cyclopamine, and jervine). Remarkably, we found all Hedgehog antagonists (HAs) potently induced EGL apoptosis within a few hours of administration. This suggests a large portion of the HAs' anti-proliferative effects are due to the apoptotic loss of a large number of EGL NPCs. This research may also have important implications for MB formation and treatment. There is convincing evidence that EGL neural progenitor cells (NPCs) can be the tumor initiating cells for MBs (the most common malignant brain tumor in children). Therefore, we examined if HAs can also produce apoptosis in Patched mice which exhibit constitutive Hedgehog stimulation and are prone to MB formation. We found HA administration also potently increased apoptosis in both EGL NPCs and preneoplasms. This may have important implications for the treatment of MBs with HAs. For example, apoptosis involves signaling mechanisms distinct from proliferation that may need to be disabled for malignant transformation. In addition, the requirement for Hedgehog signaling may prevent metastasis by killing tumor cells as they spread to regions where such signaling is absent.

  4. Ganglioneuroma

    MedlinePlus

    ... may come back after it is removed. Possible Complications If the tumor has been present for a long time and has pressed on the spinal cord or caused other symptoms, surgery to remove the tumor may not reverse the ...

  5. The Hedgehog gene family of the cnidarian, Nematostella vectensis, and implications for understanding metazoan Hedgehog pathway evolution

    PubMed Central

    Matus, David Q.; Magie, Craig; Pang, Kevin; Martindale, Mark Q; Thomsen, Gerald H.

    2008-01-01

    Hedgehog signaling is an important component of cell-cell communication during bilaterian development, and abnormal Hedgehog signaling contributes to disease and birth defects. Hedgehog genes are composed of a ligand (“hedge”) domain and an autocatalytic intein (“hog”) domain. Hedgehog (hh) ligands bind to a conserved set of receptors and activate downstream signal transduction pathways terminating with Gli/Ci transcription factors. We have identified five intein-containing genes in the anthozoan cnidarian Nematostella vectensis, two of which (NvHh1 and NvHh2) contain definitive hedgehog ligand domains, suggesting that to date, cnidarians are the earliest branching metazoan phylum to possess definitive Hh orthologs. Expression analysis of NvHh1 and NvHh2, the receptor NvPatched and a downstream transcription factor NvGli (a Gli3/Ci ortholog) indicate that these genes may have conserved roles in planar and trans-epithelial signaling during gut and germline development, while the three remaining intein-containing genes (NvHint1,2,3) are expressed in a cell-type specific manner in putative neural precursors. Metazoan intein-containing genes that lack a ligand domain have previously only been identified within nematodes. However, phylogenetic analyses suggest that these nematode inteins may be derived from an ancestral nematode true hedgehog gene, and that the non-bilaterian intein-containing genes identified here may represent an ancestral state prior to the domain swapping events that resulted in the formation of true hedgehog genes in the cnidarian-bilaterian ancestor. Genomic surveys of N. vectensis suggest that most of the components of both protostome and deuterostome Hh signaling pathways are present in anthozoans and that some appear to have been lost in ecdysozoan lineages. Cnidarians possess many bilaterian cell-cell signaling pathways (Wnt, TGFß, FGF and Hh) that appear to act in concert to pattern tissues along the oral-aboral axis of the polyp

  6. Cardiac ganglioneuroma in a juvenile pig.

    PubMed

    Inoue, Ryoko; Joma, Ikumi; Otsubo, Koji; Matsutake, Hiroshi; Yanai, Tokuma; Sakai, Hiroki

    2016-02-01

    A cardiac mass (3 × 5 × 3 cm) was detected at the base between the right auricular wall and right vena cava of a slaughtered 6-month-old female mixed-breed pig during a meat inspection. The tumor comprised infiltrative prominent interweaving fascicles of Schwann cells with Verocay bodies. Moreover, the ganglion cells were scattered or aggregated throughout the neoplastic tissue. The ganglion and Schwann cells had neither cellular atypism nor mitosis. On the basis of the bearing site as well as the morphological and immunohistochemical features, this is the first case of a cardiac ganglioneuroma in a pig. PMID:26256406

  7. Cardiac ganglioneuroma in a juvenile pig

    PubMed Central

    INOUE, Ryoko; JOMA, Ikumi; OTSUBO, Koji; MATSUTAKE, Hiroshi; YANAI, Tokuma; SAKAI, Hiroki

    2015-01-01

    A cardiac mass (3 × 5 × 3 cm) was detected at the base between the right auricular wall and right vena cava of a slaughtered 6-month-old female mixed-breed pig during a meat inspection. The tumor comprised infiltrative prominent interweaving fascicles of Schwann cells with Verocay bodies. Moreover, the ganglion cells were scattered or aggregated throughout the neoplastic tissue. The ganglion and Schwann cells had neither cellular atypism nor mitosis. On the basis of the bearing site as well as the morphological and immunohistochemical features, this is the first case of a cardiac ganglioneuroma in a pig. PMID:26256406

  8. Hedgehog Zoonoses

    PubMed Central

    Riley, Patricia Y.

    2005-01-01

    Exotic pets, including hedgehogs, have become popular in recent years among pet owners, especially in North America. Such animals can carry and introduce zoonotic agents, a fact well illustrated by the recent outbreak of monkeypox in pet prairie dogs. We reviewed known and potential zoonotic diseases that could be carried and transmitted by pet hedgehogs or when rescuing and caring for wild-caught hedgehogs. PMID:15705314

  9. Antiferromagnetic hedgehogs with superconducting cores

    NASA Astrophysics Data System (ADS)

    Goldbart, Paul M.; Sheehy, Daniel E.

    1998-09-01

    Excitations of the antiferromagnetic state that resemble antiferromagnetic hedgehogs at large distances but are predominantly superconducting inside a core region are discussed within the context of Zhang's SO(5)-symmetry-based approach to the physics of high-temperature superconducting materials. Nonsingular, in contrast with their hedgehog cousins in pure antiferromagnetism, these texture excitations are what hedgehogs become when the antiferromagnetic order parameter is permitted to ``escape'' into superconducting directions. The structure of such excitations is determined in a simple setting, and a number of their experimental implications are examined.

  10. Antiferromagnetic hedgehogs with superconducting cores

    SciTech Connect

    Goldbart, P.M.; Sheehy, D.E.

    1998-09-01

    Excitations of the antiferromagnetic state that resemble antiferromagnetic hedgehogs at large distances but are predominantly superconducting inside a core region are discussed within the context of Zhang{close_quote}s SO(5)-symmetry-based approach to the physics of high-temperature superconducting materials. Nonsingular, in contrast with their hedgehog cousins in pure antiferromagnetism, these texture excitations are what hedgehogs become when the antiferromagnetic order parameter is permitted to {open_quotes}escape{close_quotes} into superconducting directions. The structure of such excitations is determined in a simple setting, and a number of their experimental implications are examined. {copyright} {ital 1998} {ital The American Physical Society}

  11. Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): implications for mental illness.

    PubMed

    Boyd, Penelope J; Cunliffe, Vincent T; Roy, Sudipto; Wood, Jonathan D

    2015-01-01

    DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness. PMID:26405049

  12. Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): implications for mental illness

    PubMed Central

    Boyd, Penelope J.; Cunliffe, Vincent T.; Roy, Sudipto; Wood, Jonathan D.

    2015-01-01

    ABSTRACT DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness. PMID

  13. Transcriptome Changes Affecting Hedgehog and Cytokine Signalling in the Umbilical Cord: Implications for Disease Risk

    PubMed Central

    Stünkel, Walter; Tng, Emilia; Tan, Jun Hao; Chen, Li; Joseph, Roy; Cheong, Clara Y.; Ong, Mei-Lyn; Lee, Yung Seng; Chong, Yap-Seng; Saw, Seang Mei; Meaney, Michael J.; Kwek, Kenneth; Sheppard, Allan M.; Gluckman, Peter D.; Holbrook, Joanna D.

    2012-01-01

    Background Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA. Methods The gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698–4151 g) and gestational ages (35–41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity. Results We found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome. Conclusions We studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk. PMID:22808055

  14. Unsuspected Ganglioneuroma of the Choroid Diagnosed after Enucleation

    PubMed Central

    Mbagwu, Michael; Rahmani, Bahram; Srivastava, Arth; Burrowes, Delilah; Bryar, Paul J.

    2015-01-01

    We report a case of an unsuspected ganglioneuroma of the choroid in a patient with neurofibromatosis type 1. A 5-year-old girl presented from an outside institution with right proptosis and glaucoma since birth. Magnetic resonance imaging was obtained and showed a cavernous sinus mass extending into the right orbit and multiple orbital lesions. Additionally, increased signal in the posterior globe of the right eye was noted, but its etiology was unclear at the time. She was lost to follow-up for 3 years and later returned with a blind painful eye. Enucleation was performed, and histopathology was significant for diffuse choroidal ganglioneuroma and advanced glaucoma. We report the atypical history, examination findings, and histopathology to support the diagnosis. PMID:27171204

  15. [Mature cystic teratoma of the ovary with a small ganglioneuroma].

    PubMed

    Marucci, G; Collina, G

    2006-02-01

    A case of ganglioneuroma arising within a cystic mature teratoma of the ovary in a 34-year-old woman is reported. Patient underwent right adnexectomy. The ovary was completely replaced by a bilocular cystic lesion, measuring 8 cm in diameter and filled with adipose tissue and pilosebaceous material. Microscopically the cyst was composed by a mature cystic teratoma containing skin with dermal appendages, fatty tissue and bronchial epithelium. Furthermore a nodule (0.5 cm in size) composed of mature ganglion cells, axons and Schwann cells, was identified. Ganglion cells were positive for NSE and synaptophysin, while Schwann cells stained positively with S100 protein and GFAP. To the best of our knowledgment this is the first reported cases of ganglioneuroma arisen within a cystic mature teratoma of the ovary. PMID:16789685

  16. Paracrine Hedgehog signaling in stomach and intestine: new roles for Hedgehog in gastrointestinal patterning

    PubMed Central

    Kolterud, Åsa; Grosse, Ann S.; Zacharias, William J.; Walton, Katherine D.; Kretovich, Katherine E.; Madison, Blair; Waghray, Meghna; Ferris, Jennifer E.; Hu, Chunbo; Merchant, Juanita L.; Dlugosz, Andrzej; Kottmann, Andreas H.; Gumucio, Deborah L.

    2009-01-01

    Background & Aims Hedgehog signaling is critical in gastrointestinal patterning. Mice deficient in Hedgehog signaling exhibit abnormalities that mirror deformities seen in the human VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, limb) association. However, the direction of Hedgehog signal flow is controversial and the cellular targets of Hedgehog signaling change with time during development. We profiled cellular Hedgehog response patterns from embryonic day 10.5 (E10.5) to adult in murine antrum, pyloric region, small intestine and colon. Methods Hedgehog signaling was profiled using Hedgehog pathway reporter mice and in situ hybridization. Cellular targets were identified by immunostaining. Ihh-overexpressing transgenic animals were generated and analyzed. Results Hedgehog signaling is strictly paracrine from antrum to colon throughout embryonic and adult life. Novel findings include: mesothelial cells of the serosa transduce Hedgehog signals in fetal life; the hindgut epithelium expresses Ptch but not Gli1 at E10.5; the two layers of the muscularis externa respond differently to Hedgehog signals; organogenesis of the pyloric sphincter is associated with robust Hedgehog signaling; dramatically different Hedgehog responses characterize stomach and intestine at E16; after birth, the muscularis mucosa and villus smooth muscle (SM) consist primarily of Hedgehog responsive cells and Hh levels actively modulate villus core SM. Conclusions These studies reveal a previously unrecognized association of paracrine Hedgehog signaling with several gastrointestinal patterning events involving the serosa, pylorus and villus smooth muscle. The results may have implications for several human anomalies and could potentially expand the spectrum of the human VACTERL association. PMID:19445942

  17. Hedgehog signalling.

    PubMed

    Lee, Raymond Teck Ho; Zhao, Zhonghua; Ingham, Philip W

    2016-02-01

    The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species. PMID:26839340

  18. Non-Functional Adrenal Gland Ganglioneuroma Masquerading as Chronic Calculus Cholecystitis.

    PubMed

    Patel, Rashmi D; Vanikar, Aruna V; Trivedi, H L

    2015-09-01

    Adrenal ganglioneuromas in young adults are rare and ill-understood. We report an incidentally detected adrenal gland tumor diagnosed as ganglioneuroma (mature type) in 33 years old man who presented with vomiting and epigastric pain for 2 months. Histopathology examination revealed a well-encapsulated benign tumor of mature ganglion cells and Schwann-like cells arranged in fascicles, staining strongly with NSE and s-100 proteins, with adjacent unremarkable adrenal cortex and medulla. PMID:27608876

  19. Conus medullaris ganglioneuroma with syringomyelia radiologically mimicking ependymoma: A case report

    PubMed Central

    WANG, KAI; DAI, JIANPING

    2015-01-01

    Ganglioneuromas are rare, benign, well-differentiated tumors of the conus medullaris. Approximately 20 cases of spinal cord ganglioneuroma, and only 1 case of mixed chemodectoma-ganglioneuroma of the conus medullaris have been previously reported. The present study presents the case of a 38-year-old man with a histopathological diagnosis of conus medullaris ganglioneuroma. The patient presented with hypoesthesia in the lower limbs, muscle atrophy of the right lower limb and dysuria. Magnetic resonance imaging analysis led to a diagnosis of ependymoma. Histopathological analysis of the excised mass revealed typical, well-differentiated ganglion cells, consistent with a ganglioneuroma. The mass was associated with a neighboring syringomyelia. At an 18 month follow-up the patient had recovered, although some remaining difficulty in walking and urinating remained. The aim of the present report was to raise awareness that when ganglioneuromas present in unusual locations, analogous radiological findings may mislead investigators to consider more common pathologies and thus result in misdiagnosis. The present case demonstrates the importance of considering the potential differential diagnoses for neural tissue neoplasms. PMID:26788212

  20. Intermittent Fever, Progressive Weight Gain, and Personality Changes in a Five-Year-Old Girl: Unusual Paraneoplastic Syndrome due to Presacral Ganglioneuroma

    PubMed Central

    Yang, Chao; Li, Chang-chun; Zhang, Jun; Kong, Xiang-ru; Zhao, Zhenzhen; Deng, Xiao-bin; Peng, Liang; Wang, Shan

    2016-01-01

    Ganglioneuromas are rare tumors in the neuroblastoma group. Paraneoplastic syndrome (PNS) due to presacral ganglioneuromas was hardly reported in previous literature. Here, we reported that a case of a 5-year-old girl with a presacral ganglioneuroma presented with PNS, who presented with intermittent fever, progressive weight gain, and personality changes. Our report revealed intermittent fever, progressive weight gain, and personality changes may represent rare paraneoplastic syndromes in ganglioneuromas. PMID:27413558

  1. Ganglioneuroma of the Internal Auditory Canal Presenting as a Vestibular Schwannoma

    PubMed Central

    Bekelis, Kimon; Meiklejohn, Duncan A.; Missios, Symeon; Harris, Brent; Saunders, James E.; Erkmen, Kadir

    2011-01-01

    In most series, 90% of cerebellopontine angle tumors are vestibular schwannomas. Meningiomas and epidermoid tumors follow with decreased frequency. Ganglioneuroma is a benign tumor usually found in the retroperitoneum and posterior mediastinum. We report a case of a 21-year-old man with gradual sensorineural hearing loss and a minimally enhancing lesion of the internal auditory canal, which was excised through a middle fossa approach and found histologically to be a ganglioneuroma. Like vestibular schwannomas, these lesions are benign in nature and may be managed in a similar fashion, although the possibility of malignant transformation may support surgical resection over conservative management or radiosurgery. Ganglioneuromas should be considered in patients with atypical radiographic findings for vestibular schwannomas. PMID:23984208

  2. Adrenal ganglioneuroma in a patient with polycystic ovarian disease (PCOD): a rare association.

    PubMed

    Kumar, Arvind; Singh, Vishwajeet; Sankhwar, Satyanarayan; Babu, Suresh

    2013-01-01

    Adrenal ganglioneuromas are rare, benign incidentalomas of a neural crest origin. A majority of these tumours are clinically silent and discovered on imaging for unrelated reasons. Polycystic ovarian disease (PCOD) is an endocrine disorder characterised by bilateral polycystic ovaries, anovulation leading to infertility, irregular menstrual cycles and features of androgen hormone excess. Herein we report a rare case of adrenal ganglioneuroma in a 14-year-old girl with PCOD. She was referred to us by the gynaecologist after incidental detection of adrenal mass on ultrasonography. Except for raised 24 h urinary metanephrines, rest of the hormones measured were in normal range. Transperitoneal adrenalectomy was performed and histopathology was suggestive of ganglioneuroma. Postoperative recovery was excellent and she is doing well. To our knowledge it is the first such type of case to be reported. PMID:24145507

  3. Scoliosis secondary to ganglioneuroma: a case report and up to date literature review.

    PubMed

    D'Eufemia, Patrizia; Properzi, Enrico; Palombaro, Marta; Lodato, Valentina; Mellino, Loretta; Tetti, Martina; Martini, Lorena; Persiani, Pietro

    2014-07-01

    Idiopathic scoliosis is the most common form of spinal deformity in children. However, secondary causes of scoliosis, such as ganglioneuroma, should be always considered to avoid wrong diagnosis, and further investigations are required when there are atypical signs. We report a case of ganglioneuroma misdiagnosed as idiopathic scoliosis and review the literature to identify the red flags useful for physicians during the evaluation of a child with scoliosis. On the basis of both clinical and radiographic criteria that emerged from this study, we propose an algorithm that could help in the differential diagnosis, suggesting when to perform an MRI. PMID:24681491

  4. Hedgehog signaling update.

    PubMed

    Cohen, M Michael

    2010-08-01

    In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith-Lemli-Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Carpenter syndrome, and Rubinstein-Taybi syndrome. PMID:20635334

  5. Outfoxing the Hedgehog

    ERIC Educational Resources Information Center

    Barbieri, Richard

    2011-01-01

    Jim Collins's "Good to Great" has attained near-scriptural status in organizations, including nonprofits, which Collins says constitute a third of his readers. The pivot point in "Good to Great" is the Hedgehog Concept. The "Hedgehog Concept" (HC), this author claims, is dangerous for schools because it distorts the nature of education. As Collins…

  6. A Comparison of Raman Spectral Features of Frozen and Deparaffinized Tissues in Neuroblastoma and Ganglioneuroma

    NASA Astrophysics Data System (ADS)

    Devpura, Suneetha; Thakur, Jagdish S.; Poulik, Janet M.; Rabah, Raja; Naik, Vaman M.; Naik, Ratna

    2012-02-01

    We have investigated the cellular regions in neuroblastoma and ganglioneuroma using Raman spectroscopy and compared their spectral characteristics with those of normal adrenal gland. Thin sections from both frozen and deparaffinized tissues, obtained from the same tissue specimen, were studied in conjunction with the pathological examination of the tissues. We found a significant difference in the spectral features of frozen sections of normal adrenal gland, neuroblastoma, and ganglioneuroma when compared to deparaffinized tissues. The quantitative analysis of the Raman data using chemometric methods of principal component analysis and discriminant function analysis obtained from the frozen tissues show a sensitivity and specificity of 100% each. The biochemical identification based on the spectral differences shows that the normal adrenal gland tissues have higher levels of carotenoids, lipids, and cholesterol compared to the neuroblastoma and ganglioneuroma frozen tissues. However, deparaffinized tissues show complete removal of these biochemicals in adrenal tissues. This study demonstrates that Raman spectroscopy combined with chemometric methods can successfully distinguish neuroblastoma and ganglioneuroma at cellular level.

  7. Metastable nematic hedgehogs

    NASA Astrophysics Data System (ADS)

    Rosso, Riccardo; Virga, Epifanio G.

    1996-07-01

    For nematic liquid crystals, we study the local stability of a radial hedgehog against biaxial perturbations. Our analysis employs the Landau - de Gennes functional to describe the free energy stored in a ball, whose radius is a parameter of the model. We find that a radial hedgehog may be either unstable or metastable, depending on the values of the elastic constants. For unstable hedgehogs, we give an explicit expression for the radius of the ball within which the instability manifests itself: it can be interpreted as the size of the biaxial core of the defect; it is of the same order of magnitude as the radius of the disclination ring predicted by Penzenstadler and Trebin's model. The metastable hedgehogs predicted by our model are the major novelty of the paper. They tell us that we may also expect truly uniaxial point defects, whose core contains no biaxial structure.

  8. Paraneoplastic cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma.

    PubMed

    Fancellu, Roberto; Corsini, Elena; Bernardi, Giorgio; Buzzo, Paolo; Ferrari, Maria Luisa; Lamantea, Eleonora; Garaventa, Alberto; Truini, Mauro; Salvarani, Sandro

    2014-01-01

    We describe a case of cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma. A 28-year-old woman developed progressive ataxia with hyporeflexia at the age of 19. Brain MRI showed progressive cerebellar atrophy. Neurophysiological studies, screening of immune-mediated ataxias, oncological markers, vitamin E and genetic tests for spinocerebellar ataxia types 1,2,3, Friedreich ataxia and POLG1 were negative. Anti-Hu antibodies were positive in Western blot and indirect immunofluorescence (1:640). Total-body computed tomography revealed a mediastinum mass; the histological diagnosis was maturing ganglioneuroma. Immunohistochemistry showed a mild reaction between the tumor and the patient's serum, and no reaction between the tumor and control serum. After surgery, serum anti-Hu titer decreased, while ataxic symptoms initially worsened and then stabilized. Ganglioneuroma is a benign tumor, usually derived from the maturation of a neuroblastoma. The benign histology and the presence of anti-Hu antibodies could be related to the positive oncological prognosis and to the slow clinical course mimicking a degenerative ataxia. PMID:25764259

  9. Hedgehog signaling in skin cancers

    PubMed Central

    Li, Chengxin; Chi, Sumin; Xie, Jingwu

    2011-01-01

    An increasing progress on the role of Hedgehog (Hh) signaling for carcinogenesis has been achieved since the link of Hh pathway to human cancer was firstly established. In particular, the critical role of Hh signaling in the development of Basal cell carcinoma (BCC) has been convincingly demonstrated by genetic mutation analyses, mouse models of BCCs, and successful clinical trials of BCCs using Hh signaling inhibitors. In addition, the Hh pathway activity is also reported to be involved in the pathogenesis of Squamous Cell Carcinoma (SCC), melanoma and Merkel Cell Carcinoma. These findings have significant new paradigm on Hh signaling transduction, its mechanisms in skin cancer and even therapeutic approaches for BCC. In this review, we will summarize the major advances in the understanding of Hh signaling transduction, the roles of Hh signaling in skin cancer development, and the current implications of “mechanism-based” therapeutic strategies. PMID:21397013

  10. Hedgehog Pathway Inhibition.

    PubMed

    Sekulic, Aleksandar; Von Hoff, Daniel

    2016-02-25

    The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC). PMID:26919418

  11. Functionally active ganglioneuroma with increased plasma and urinary catecholamines and positive iodine 131-meta-iodobenzylguanidine scintigraphy

    SciTech Connect

    Clerico, A.; Jenkner, A.; Castello, M.A.; Ciofetta, G.; Lucarelli, C.; Codini, M. )

    1991-01-01

    Ganglioneuromas are usually considered not to be functionally active. Studies of their catecholamine excretory pattern and of their imaging by means of the adrenergic tracing agent 131-I-MIBG have been therefore sparse. We report on a case of secretory ganglioneuroma, as demonstrated by the increased urinary excretion of the catecholamine metabolites HVA and VMA, increased plasma dopamine and epinephrine levels, and positive 131-I-MIBG scintigraphy. We must therefore be aware that a functionally active tumor is not necessarily a neuroblastoma, and that the diagnosis should be biopsy proven.

  12. Sonic Hedgehog Signaling and VACTERL Association

    PubMed Central

    Ngan, E.S.-W.; Kim, K.-H.; Hui, C.-c.

    2013-01-01

    Hedgehog (Hh) signaling is vital for the patterning and organogenesis of almost every system. The specificity of these developmental processes is achieved through a tight spatio-temporal regulation of Hh signaling. Mice with defective Hh signal exhibit a wide spectrum of anomalies, including Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Renal dysplasia, and Limb defects, that resemble strikingly the phenotypes observed in VACTERL association in humans. In this review, we summarize our current understanding of mammalian Hh signaling and highlight the relevance of various mouse models for studying the etiology and pathogenesis of VACTERL association. In addition, recent advances in genetic study for unraveling the complexity of genetic inheritance of VACTERL and the implication of the Sonic hedgehog pathway in disease pathogenesis are also discussed. PMID:23653575

  13. Dopamine-secreting giant adrenal ganglioneuroma: clinical and diffusion-weighted magnetic resonance imaging findings.

    PubMed

    Polat, A V; Polat, A Kamali; Aslan, K; Atmaca, H; Karagoz, F

    2014-01-01

    We report a case of a dopamine-secreting giant primary adrenal ganglioneuroma (GN) in a 29-year-old male patient. Although the patient was clinically silent, the 24-hour urine levels of dopamine, normetanephrine, homovanillic acid and vanillyl mandelic acid were elevated. Abdominal ultrasonography and magnetic resonance imaging showed a large solid tumor with calcifications and a slightly lobular edge on the left adrenal gland. A tumor, 13 x 23 x 25 cm in size, was completely resected without morbidity. A 2-year follow-up with computed tomography showed that the postoperative course of the patient was uneventful. PMID:25073244

  14. Hedgehog Excitations and their Superconducting Cores in the Antiferromagnetic State of SO(5) Materials

    NASA Astrophysics Data System (ADS)

    Goldbart, Paul M.

    1998-03-01

    Zhang's SO(5) approach to the physics of high-temperature superconducting materials(S.-C. Zhang, Science 275), 1089 (1997). contains the possibility that the antiferromagnetic state should support novel excitations that resemble antiferromagnetic hedgehogs at large distances but are predominantly superconducting inside a core region(P. M. Goldbart, Antiferromagnetic hedgehogs with superconducting cores); cond- mat/9711088 (UIUC Preprint P-97-10-030-iii).. Neither singular nor topologically stable, in contrast with their hedgehog cousins in pure antiferromagnetism, these excitations are what hedgehogs become when antiferromagnetic order is permitted to `` escape'' toward superconductivity---a central element in Zhang's approach. We describe the structure of antiferromagnetic hedgehog excitations with superconducting cores within the context of Zhang's approach to high-temperature superconducting materials, and touch upon a number of the experimental implications that these excitations engender.

  15. Crossed thalamocortical connections in the Madagascan hedgehog tenrec: dissimilarities to erinaceous hedgehog, similarities to mammals with more differentiated brains.

    PubMed

    Künzle, H

    1995-04-14

    The adult erinaceous hedgehog, unlike other mammals, has recently been shown to have prominent crossed projections from the thalamus to the motor cortex. There are suggestions relating this unique pattern of connectivity to the overall degree of brain differentiation and/or the poorly developed corpus callosum. The present tracing study demonstrates that the Madagascan lesser hedgehog tenrec, with its tiny corpus callosum and one of the lowest neocorticalization indices among insectivores, has extensive crossed cortico-thalamic projections, but essentially the same sparse thalamic projections to the contralateral cortex as have placental mammals with more differentiated brains. The implications of the findings and the relevance of extracallosal pathways are discussed. PMID:7541906

  16. Hedgehog signaling and steroidogenesis.

    PubMed

    Finco, Isabella; LaPensee, Christopher R; Krill, Kenneth T; Hammer, Gary D

    2015-01-01

    Since its discovery nearly 30 years ago, the Hedgehog (Hh) signaling pathway has been shown to be pivotal in many developmental and pathophysiological processes in several steroidogenic tissues, including the testis, ovary, adrenal cortex, and placenta. New evidence links the evolutionarily conserved Hh pathway to the steroidogenic organs, demonstrating how Hh signaling can influence their development and homeostasis and can act in concert with steroids to mediate physiological functions. In this review, we highlight the role of the components of the Hh signaling pathway in steroidogenesis of endocrine tissues. PMID:25668018

  17. Palmitoylation of Hedgehog proteins.

    PubMed

    Buglino, John A; Resh, Marilyn D

    2012-01-01

    Hedgehog (Hh) proteins are secreted signaling proteins that contain amide-linked palmitate at the N-terminus and cholesterol at the C-terminus. Palmitoylation of Hh proteins is critical for effective long- and short-range signaling. The palmitoylation reaction occurs during transit of Hh through the secretory pathway, most likely in the lumen of the ER. Attachment of palmitate to Hh proteins is independent of cholesterol modification and autoprocessing and is catalyzed by Hhat (Hedgehog acyltransferase). Hhat is a member of the membrane bound O-acyltransferase (MBOAT) family, a subgroup of multipass membrane proteins that catalyze transfer of fatty acyl groups to lipids and proteins. Several classes of secreted proteins have recently been shown to be substrates for MBOAT acyltransferases, including Hh proteins and Spitz (palmitoylated by Hhat), Wg/Wnt proteins (modified with palmitate and/or palmitoleate by Porcupine) and ghrelin (octanoylated by ghrelin O-acyltransferase). These findings highlight protein fatty acylation as a mechanism that not only influences membrane binding of intracellular proteins but also regulates the signaling range and efficacy of secreted proteins. PMID:22391306

  18. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling.

    PubMed

    Petrova, Elissaveta; Rios-Esteves, Jessica; Ouerfelli, Ouathek; Glickman, J Fraser; Resh, Marilyn D

    2013-04-01

    Inhibition of Sonic hedgehog (Shh) signaling is of great clinical interest. Here we exploit Hedgehog acyltransferase (Hhat)-mediated Shh palmitoylation, a modification critical for Shh signaling, as a new target for Shh pathway inhibition. A target-oriented high-throughput screen was used to identify small-molecule inhibitors of Hhat. In cells, these Hhat inhibitors specifically block Shh palmitoylation and inhibit autocrine and paracrine Shh signaling. PMID:23416332

  19. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    PubMed Central

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2012-01-01

    Purpose Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of KrasG12D-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radio-sensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer. PMID:23182391

  20. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  1. Homeodomains, Hedgehogs, and Happiness.

    PubMed

    Scott, Matthew P

    2016-01-01

    Developmental biologists have had a spectacular quarter century of discoveries, building on many decades of work earlier, discovering molecular, cellular, and genetic mechanisms that underlie the magical process by which an egg becomes a plant or animal. Among the discoveries were homeodomains, DNA-binding domains that allow transcription factors to recognize their target genes, and the Hedgehog signaling pathway, which is used in many organs and tissues for communication among cells. The experience of unveiling the mechanisms and molecules connected to both of these findings has been remarkable, joyful, difficult, and a time of great teamwork and collaboration within and between laboratory groups. More than ever it is possible to discern the evolutionary processes, and their mechanisms, that led to the diversity of life on earth. A huge amount of work remains to be done to obtain a broad understanding of what happened and how development works. PMID:26969987

  2. Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.

    PubMed

    D'Amico, Davide; Antonucci, Laura; Di Magno, Laura; Coni, Sonia; Sdruscia, Giulia; Macone, Alberto; Miele, Evelina; Infante, Paola; Di Marcotullio, Lucia; De Smaele, Enrico; Ferretti, Elisabetta; Ciapponi, Laura; Giangaspero, Felice; Yates, John R; Agostinelli, Enzo; Cardinali, Beatrice; Screpanti, Isabella; Gulino, Alberto; Canettieri, Gianluca

    2015-10-12

    Developmental Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs), and its aberrant activation is a leading cause of medulloblastoma. We show here that Hedgehog promotes polyamine biosynthesis in GCPs by engaging a non-canonical axis leading to the translation of ornithine decarboxylase (ODC). This process is governed by AMPK, which phosphorylates threonine 173 of the zinc finger protein CNBP in response to Hedgehog activation. Phosphorylated CNBP increases its association with Sufu, followed by CNBP stabilization, ODC translation, and polyamine biosynthesis. Notably, CNBP, ODC, and polyamines are elevated in Hedgehog-dependent medulloblastoma, and genetic or pharmacological inhibition of this axis efficiently blocks Hedgehog-dependent proliferation of medulloblastoma cells in vitro and in vivo. Together, these data illustrate an auxiliary mechanism of metabolic control by a morphogenic pathway with relevant implications in development and cancer. PMID:26460945

  3. Canonical and non-canonical Hedgehog signalling and the control of metabolism

    PubMed Central

    Teperino, Raffaele; Aberger, Fritz; Esterbauer, Harald; Riobo, Natalia; Pospisilik, John Andrew

    2014-01-01

    Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease. PMID:24862854

  4. Zinc Inhibits Hedgehog Autoprocessing

    PubMed Central

    Xie, Jian; Owen, Timothy; Xia, Ke; Singh, Ajay Vikram; Tou, Emiley; Li, Lingyun; Arduini, Brigitte; Li, Hongmin; Wan, Leo Q.; Callahan, Brian; Wang, Chunyu

    2015-01-01

    Zinc is an essential trace element with wide-ranging biological functions, whereas the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. The upstream activator of Hh signaling, the Hh ligand, originates from Hh autoprocessing, which converts the Hh precursor protein to the Hh ligand. In an in vitro Hh autoprocessing assay we show that zinc inhibits Hh autoprocessing with a Ki of 2 μm. We then demonstrate that zinc inhibits Hh autoprocessing in a cellular environment with experiments in primary rat astrocyte culture. Solution NMR reveals that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing, and isothermal titration calorimetry provided the thermodynamics of the binding. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand. PMID:25787080

  5. Hedgehog Signaling in the Liver

    PubMed Central

    Omenetti, Alessia; Choi, Steve; Michelotti, Gregory; Diehl, Anna Mae

    2010-01-01

    Reactivation of Hedgehog (Hh), a morphogenic signaling pathway that controls progenitor cell fate and tissue construction during embryogenesis occurs during many types of liver injury in adult. The net effects of activating the Hedgehog pathway include expansion of liver progenitor populations to promote liver regeneration, but also hepatic accumulation of inflammatory cells, liver fibrogenesis, and vascular remodeling. All of these latter responses are known to be involved in the pathogenesis of cirrhosis. In addition, Hh signaling may play a role in primary liver cancers, such as cholangiocarcinoma and hepatocellular carcinoma. Study of Hedgehog signaling in liver cells is in its infancy. Additional research in this area is justified given growing experimental and clinical data supporting a role for the pathway in regulating outcomes of liver injury. PMID:21093090

  6. Intestinal lymphosarcoma in captive African hedgehogs.

    PubMed

    Raymond, J T; Clarke, K A; Schafer, K A

    1998-10-01

    Two captive adult female African hedgehogs (Atelerix albiventris) had inappetance and bloody diarrhea for several days prior to death. Both hedgehogs had ulceration of the small intestine and hepatic lipidosis. Histopathology revealed small intestinal lymphosarcoma with metastasis to the liver. Extracellular particles that had characteristics of retroviruses were observed associated with the surface of some neoplastic lymphoid cells by transmission electron microscopy. These are the first reported cases of intestinal lymphosarcoma in African hedgehogs. PMID:9813852

  7. Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling.

    PubMed

    Callahan, Brian P; Wang, Chunyu

    2015-01-01

    Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog's biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. PMID:26473928

  8. Mammary gland tumors in captive African hedgehogs.

    PubMed

    Raymond, J T; Gerner, M

    2000-04-01

    From December 1995 to July 1999, eight mammary gland tumors were diagnosed in eight adult captive female African hedgehogs (Atelerix albiventris). The tumors presented as single or multiple subcutaneous masses along the cranial or caudal abdomen that varied in size for each hedgehog. Histologically, seven of eight (88%) mammary gland tumors were malignant. Tumors were classified as solid (4 cases), tubular (2 cases), and papillary (2 cases). Seven tumors had infiltrated into the surrounding stroma and three tumors had histologic evidence of neoplastic vascular invasion. Three hedgehogs had concurrent neoplasms. These are believed to be the first reported cases of mammary gland tumors in African hedgehogs. PMID:10813628

  9. A Polyamine Twist on Hedgehog Signaling.

    PubMed

    Zhao, Xuesong; Segal, Rosalind A

    2015-10-12

    The Hedgehog pathway plays important roles in embryonic development and oncogenesis, but how it affects metabolism is less clear. D'Amico et al. (2015) now demonstrate that the Hedgehog pathway regulates translation of ornithine decarboxylase, thereby enhancing polyamine biosynthesis and cell proliferation in neural precursor cells and in brain tumors. PMID:26460938

  10. Cytologic diagnosis of diseases of hedgehogs.

    PubMed

    Juan-Sallés, Carles; Garner, Michael M

    2007-01-01

    This article focuses on neoplastic diseases because they may be the most frequent disease processes in captive hedgehogs according to the literature and authors' case files and the most common cases submitted for cytologic diagnosis in these species, particularly the African hedgehog (Atelerix albiventris). PMID:17198959

  11. Hedgehog Signaling in Pancreatic Fibrosis and Cancer

    PubMed Central

    Bai, Yongyu; Bai, Yongheng; Dong, Jiaojiao; Li, Qiang; Jin, Yuepeng; Chen, Bicheng; Zhou, Mengtao

    2016-01-01

    Abstract The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies. PMID:26962810

  12. Cardiac assessment of African hedgehogs (Atelerix albiventris).

    PubMed

    Black, Peter A; Marshall, Cecilia; Seyfried, Alice W; Bartin, Anne M

    2011-03-01

    Cardiomyopathy is a common finding in captive African hedgehogs (Atelerix albiventris) at postmortem exam. To date, treatment attempts have been mostly empirical and unrewarding. The objective of this study was to determine reference cardiac values for captive African hedgehogs based on echocardiogram, electrocardiogram (ECG), and radiographs. Adult African hedgehogs with no clinical signs of cardiac disease (n = 13) were selected. Each animal was anesthetized with isoflurane via facemask and an echocardiogram, ECG, and radiographs were performed. Standard measurements were taken and the descriptive statistics performed. Values were comparable to limited data available in other hedgehog species and other similar-sized exotic species. Two animals were removed from consideration of reference values due to valvular defects that were considered significant. These data are the first establishing cardiac parameters in normal African hedgehogs using radiographic cardiac measurement, echocardiogram, and ECG. Evaluating animals with possible cardiomyopathy may allow for earlier diagnosis and more successful treatment. PMID:22946370

  13. Hedgehog Signaling in Pancreatic Fibrosis and Cancer.

    PubMed

    Bai, Yongyu; Bai, Yongheng; Dong, Jiaojiao; Li, Qiang; Jin, Yuepeng; Chen, Bicheng; Zhou, Mengtao

    2016-03-01

    The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies. PMID:26962810

  14. Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines

    PubMed Central

    Kim, H-A; Kim, M-C; Kim, N-Y; Kim, Y

    2015-01-01

    Deregulation of crucial embryonic pathways, including hedgehog signaling, has been frequently implicated in a variety of human cancers and is emerging as an important target for anticancer therapy. This study evaluated the potential anticancer effects of cyclopamine, a chemical inhibitor of hedgehog signaling, in human malignant mesothelioma (HMM) cell lines. Cyclopamine treatment significantly decreased the proliferation of HMM cells by promoting apoptosis and shifting the cell cycle toward dormant phase. The clonogenicity and mobility of HMM cells were significantly decreased by cyclopamine treatment. Treatment of HMM cells with cyclopamine significantly reduced the abundance of side population cells, which were measured using an assay composed of Hoechst 33342 dye staining and subsequent flow cytometry. Furthermore, the expression levels of stemness-related genes were significantly affected by cyclopamine treatment. Taken together, the present study showed that targeting hedgehog signaling could reduce a more aggressive subpopulation of the cancer cells, suggesting an alternative approach for HMM therapy. PMID:26206198

  15. Sonic Hedgehog Signalling Pathway and Ameloblastoma - A Review.

    PubMed

    Mishra, Pallavi; Panda, Abikshyeet; Bandyopadhyay, Alokenath; Kumar, Harish; Mohiddin, Gouse

    2015-11-01

    Ameloblastoma is a benign but aggressive odontogenic neoplasm arising from odontogenic epithelium. Many theories have been proposed to explain the pathogenesis of ameloblatoma. Numerous signalling pathways have been implicated to be associated in the development and progression of this neoplasm. Studies have found association of various signalling molecules of Sonic Hedgehog Pathway, namely SHH, PTCH1, SMO, Gli 1, Gli 2, Gli 3, with ameloblastoma. Knowledge about this pathway will help us to understand the nature and behaviour of this neoplasm. This will open the door towards new treatment modalities. PMID:26674664

  16. Cholesterol and its derivatives in Sonic Hedgehog signaling and Cancer

    PubMed Central

    Riobo, Natalia A.

    2012-01-01

    The connection between the Hedgehog pathway and cholesterol has been recognized since the early days that shaped our current understanding of this unique pathway. Cholesterol and related lipids are intricately linked to HH signaling: from the role of cholesterol in HH biosynthesis to the modulation of HH signal reception and transduction by other sterols, passing by the phylogenetic relationships among many components of the HH pathway that resemble or contain lipid-binding domains. Here I review the connections between HH signaling, cholesterol and its derivatives and analyze the potential implications for HH-dependent cancers. PMID:22832232

  17. Sonic Hedgehog Signalling Pathway and Ameloblastoma – A Review

    PubMed Central

    Mishra, Pallavi; Bandyopadhyay, Alokenath; Kumar, Harish; Mohiddin, Gouse

    2015-01-01

    Ameloblastoma is a benign but aggressive odontogenic neoplasm arising from odontogenic epithelium. Many theories have been proposed to explain the pathogenesis of ameloblatoma. Numerous signalling pathways have been implicated to be associated in the development and progression of this neoplasm. Studies have found association of various signalling molecules of Sonic Hedgehog Pathway, namely SHH, PTCH1, SMO, Gli 1, Gli 2, Gli 3, with ameloblastoma. Knowledge about this pathway will help us to understand the nature and behaviour of this neoplasm. This will open the door towards new treatment modalities. PMID:26674664

  18. Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion

    PubMed Central

    Nochioka, Katsunori; Okuda, Hiroaki; Tatsumi, Kouko; Morita, Shoko; Ogata, Nahoko; Wanaka, Akio

    2016-01-01

    Choroidal neovascularization is one of the major pathological changes in age-related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser-induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration. PMID:27239075

  19. Functional Interaction between HEXIM and Hedgehog Signaling during Drosophila Wing Development

    PubMed Central

    Nguyen, Duy; Fayol, Olivier; Buisine, Nicolas; Lecorre, Pierrette; Uguen, Patricia

    2016-01-01

    Studying the dynamic of gene regulatory networks is essential in order to understand the specific signals and factors that govern cell proliferation and differentiation during development. This also has direct implication in human health and cancer biology. The general transcriptional elongation regulator P-TEFb regulates the transcriptional status of many developmental genes. Its biological activity is controlled by an inhibitory complex composed of HEXIM and the 7SK snRNA. Here, we examine the function of HEXIM during Drosophila development. Our key finding is that HEXIM affects the Hedgehog signaling pathway. HEXIM knockdown flies display strong phenotypes and organ failures. In the wing imaginal disc, HEXIM knockdown initially induces ectopic expression of Hedgehog (Hh) and its transcriptional effector Cubitus interuptus (Ci). In turn, deregulated Hedgehog signaling provokes apoptosis, which is continuously compensated by apoptosis-induced cell proliferation. Thus, the HEXIM knockdown mutant phenotype does not result from the apoptotic ablation of imaginal disc; but rather from the failure of dividing cells to commit to a proper developmental program due to Hedgehog signaling defects. Furthermore, we show that ci is a genetic suppressor of hexim. Thus, HEXIM ensures the integrity of Hedgehog signaling in wing imaginal disc, by a yet unknown mechanism. To our knowledge, this is the first time that the physiological function of HEXIM has been addressed in such details in vivo. PMID:27176767

  20. Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion.

    PubMed

    Nochioka, Katsunori; Okuda, Hiroaki; Tatsumi, Kouko; Morita, Shoko; Ogata, Nahoko; Wanaka, Akio

    2016-04-28

    Choroidal neovascularization is one of the major pathological changes in age-related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser-induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration. PMID:27239075

  1. Thyroid, Renal, and Breast Carcinomas, Chondrosarcoma, Colon Adenomas, and Ganglioneuroma: A New Cancer Syndrome, FAP, or Just Coincidence.

    PubMed

    Atta, Ihab Shafek; AlQahtani, Fahd Nasser

    2016-01-01

    We are presenting a case associated with papillary thyroid carcinoma, renal cell carcinoma, invasive mammary carcinoma, chondrosarcoma, benign ganglioneuroma, and numerous colon adenomas. The patient had a family history of colon cancer, kidney and bladder cancers, lung cancer, thyroid cancer, leukemia, and throat and mouth cancers. She was diagnosed with colonic villous adenoma at the age of 41 followed by thyroid, renal, and breast cancers and chondrosarcoma at the ages of 48, 64, 71, and 74, respectively. Additionally, we included a table with the most common familial cancer syndromes with one or more benign or malignant tumors diagnosed in our case, namely, FAP, HNPCC, Cowden, Peutz-Jeghers, renal cancer, tuberous sclerosis, VHL, breast/other, breast/ovarian, Carney, Werner's, Bloom, Li-Fraumeni, xeroderma pigmentosum, ataxia-telangiectasia, osteochondromatosis, retinoblastoma, and MEN2A. PMID:27087812

  2. Thyroid, Renal, and Breast Carcinomas, Chondrosarcoma, Colon Adenomas, and Ganglioneuroma: A New Cancer Syndrome, FAP, or Just Coincidence

    PubMed Central

    Atta, Ihab Shafek; AlQahtani, Fahd Nasser

    2016-01-01

    We are presenting a case associated with papillary thyroid carcinoma, renal cell carcinoma, invasive mammary carcinoma, chondrosarcoma, benign ganglioneuroma, and numerous colon adenomas. The patient had a family history of colon cancer, kidney and bladder cancers, lung cancer, thyroid cancer, leukemia, and throat and mouth cancers. She was diagnosed with colonic villous adenoma at the age of 41 followed by thyroid, renal, and breast cancers and chondrosarcoma at the ages of 48, 64, 71, and 74, respectively. Additionally, we included a table with the most common familial cancer syndromes with one or more benign or malignant tumors diagnosed in our case, namely, FAP, HNPCC, Cowden, Peutz-Jeghers, renal cancer, tuberous sclerosis, VHL, breast/other, breast/ovarian, Carney, Werner's, Bloom, Li-Fraumeni, xeroderma pigmentosum, ataxia-telangiectasia, osteochondromatosis, retinoblastoma, and MEN2A. PMID:27087812

  3. Cardiomyopathy in captive African hedgehogs (Atelerix albiventris).

    PubMed

    Raymond, J T; Garner, M M

    2000-09-01

    From 1994 to 1999, 16 captive African hedgehogs (Atelerix albiventris), from among 42 necropsy cases, were diagnosed with cardiomyopathy. The incidence of cardiomyopathy in this study population was 38%. Fourteen of 16 hedgehogs with cardiomyopathy were males and all hedgehogs were adult (>1 year old). Nine hedgehogs exhibited 1 or more of the following clinical signs before death: heart murmur, lethargy, icterus, moist rales, anorexia, dyspnea, dehydration, and weight loss. The remaining 7 hedgehogs died without premonitory clinical signs. Gross findings were cardiomegaly (6 cases), hepatomegaly (5 cases), pulmonary edema (5 cases), pulmonary congestion (4 cases), hydrothorax (3 cases), pulmonary infarct (1 case), renal infarcts (1 case), ascites (1 case), and 5 cases showed no changes. Histologic lesions were found mainly within the left ventricular myocardium and consisted primarily of myodegeneration, myonecrosis, atrophy, hypertrophy, and disarray of myofibers. All hedgehogs with cardiomyopathy had myocardial fibrosis, myocardial edema, or both. Other common histopathologic findings were acute and chronic passive congestion of the lungs, acute passive congestion of the liver, renal tubular necrosis, vascular thrombosis, splenic extramedullary hematopoiesis, and hepatic lipidosis. This is the first report of cardiomyopathy in African hedgehogs. PMID:11021439

  4. [Hedgehog signaling pathway and human disorders].

    PubMed

    Fujii, Katsunori; Miyashita, Toshiyuki

    2009-07-01

    The hedgehog signaling pathway plays pivotal roles in embryonic development and cancer formation. This pathway in mammals consists of multiple molecules such as Sonic Hedgehog, PTCH, SMO, and GLI. Mutations of these components result in various human malformations or tumors, i.e., holoprosencephaly, Gorlin syndrome, Greig encephalopolysyndactyly, Pallister-Hall syndrome, Rubinstein-Taybi syndrome, basal cell carcinomas, and medulloblastomas. Recently, small molecules that inhibit this signaling pathway were developed, and clinically applied to cancer therapy. Thus, understanding of these molecular relationships may facilitate the development of new therapies and treatments for diseases caused by hedgehog signaling disorders. PMID:19618878

  5. Astrocytoma in an African hedgehog (Atelerix albiventris) suspected wobbly hedgehog syndrome.

    PubMed

    Nakata, Makoto; Miwa, Yasutsugu; Itou, Takuya; Uchida, Kazuyuki; Nakayama, Hiroyuki; Sakai, Takeo

    2011-10-01

    A 28-month-old African hedgehog was referred to our hospital with progressive tetraparesis. On the first presentation, the hedgehog was suspected as having wobbly hedgehog syndrome (WHS) and the animal was treated with medication and rehabilitation. The animal died 22 days after onset. Pathological examination revealed that the animal was involved in astrocytoma between the medulla oblongata and the spinal cord (C1). This report indicates that a primary central nervous system tumor should be considered as one of the differential diagnoses for hedgehogs presenting with progressive paresis, together with WHS. PMID:21628867

  6. Anomalous dispersions of `hedgehog' particles

    NASA Astrophysics Data System (ADS)

    Bahng, Joong Hwan; Yeom, Bongjun; Wang, Yichun; Tung, Siu On; Hoff, J. Damon; Kotov, Nicholas

    2015-01-01

    Hydrophobic particles in water and hydrophilic particles in oil aggregate, but can form colloidal dispersions if their surfaces are chemically camouflaged with surfactants, organic tethers, adsorbed polymers or other particles that impart affinity for the solvent and increase interparticle repulsion. A different strategy for modulating the interaction between a solid and a liquid uses surface corrugation, which gives rise to unique wetting behaviour. Here we show that this topographical effect can also be used to disperse particles in a wide range of solvents without recourse to chemicals to camouflage the particles' surfaces: we produce micrometre-sized particles that are coated with stiff, nanoscale spikes and exhibit long-term colloidal stability in both hydrophilic and hydrophobic media. We find that these `hedgehog' particles do not interpenetrate each other with their spikes, which markedly decreases the contact area between the particles and, therefore, the attractive forces between them. The trapping of air in aqueous dispersions, solvent autoionization at highly developed interfaces, and long-range electrostatic repulsion in organic media also contribute to the colloidal stability of our particles. The unusual dispersion behaviour of our hedgehog particles, overturning the notion that like dissolves like, might help to mitigate adverse environmental effects of the use of surfactants and volatile organic solvents, and deepens our understanding of interparticle interactions and nanoscale colloidal chemistry.

  7. Regulation of Thalamic Development by Sonic Hedgehog

    PubMed Central

    Epstein, Douglas J.

    2012-01-01

    The thalamus is strategically positioned within the caudal diencephalic area of the forebrain, between the mesencephalon and telencephalon. This location is important for unique aspects of thalamic function, to process and relay sensory and motor information to and from the cerebral cortex. How the thalamus comes to reside within this region of the central nervous system has been the subject of much investigation. Extracellular signals secreted from key locations both extrinsic and intrinsic to the thalamic primordium have recently been identified and shown to play important roles in the growth, regionalization, and specification of thalamic progenitors. One factor in particular, the secreted morphogen Sonic hedgehog (Shh), has been implicated in spatiotemporal and threshold models of thalamic development that differ from other areas of the CNS due, in large part, to its expression within two signaling centers, the basal plate and the zona limitans intrathalamica, a dorsally projecting spike that separates the thalamus from the subthalamic region. Shh signaling from these dual sources exhibit unique and overlapping functions in the control of thalamic progenitor identity and nuclei specification. This review will highlight recent advances in our understanding of Shh function during thalamic development, revealing similarities, and differences that exist between species. PMID:22529771

  8. Twist transition of nematic hyperbolic hedgehogs.

    PubMed

    James, Richard; Fukuda, Jun-ichi

    2014-04-01

    Stability of an idealized hyperbolic hedgehog in a nematic liquid crystal against a twist transition is investigated by extending the methodology of Rüdinger and Stark [Liq. Cryst. 26, 753 (1999)], where the hedgehog is confined between two concentric spheres. In the ideal hyperbolic-hedgehog the molecular orientation is assumed to rotate proportionally with respect to the inclination angle, θ (and in the opposite sense). However, when splay, k11, and bend, k33, moduli differ this proportionality is lost and the liquid crystal deforms relative to the ideal with bend and splay. Although slight, these deformations are shown to significantly shift the transition if k11/k33 is small. By increasing the degree of confinement the twist transition can be inhibited, a characteristic both hyperbolic and radial hedgehogs have in common. The twist transition of a hyperbolic defect that accompanies a particle is found to be well predicted by the earlier stability analysis of a thick shell. PMID:24827263

  9. Corynebacterial pneumonia in an African hedgehog.

    PubMed

    Raymond, J T; Williams, C; Wu, C C

    1998-04-01

    A 3-mo-old, male African hedgehog (Atelerix albiventris) was anorectic and lethargic for a period of 3 days prior to death. Necropys revealed lungs that were diffusely firm, dark red, and dorsally adhered by fibrinous tags to the pericardial sac. Histopathology revealed necrosuppurative bronchopneumonia with pulmonary abscesses and suppurative pericarditis and myocarditis. A Corynebacterium sp. was isolated from the lungs. We believe this is the first reported case of corynebacterial pneumonia in an African hedgehog. PMID:9577794

  10. Intestinal plasmacytoma in an African hedgehog.

    PubMed

    Ramos-Vara, J A; Miller, M A; Craft, D

    1998-04-01

    A 3-yr-old male African hedgehog (Atelerix albiventris) had anorexia and weight loss for 1 wk before its death. The colon and mesocolon were diffusely infiltrated by a neoplastic proliferation of round cells with plasmacytoid features. A diagnosis of intestinal plasmacytoma was made and confirmed by electron microscopy. No other organs appeared to be affected. This is the first description of intestinal plasmacytoma in a hedgehog. PMID:9577789

  11. Foxf Genes Integrate Tbx5 and Hedgehog Pathways in the Second Heart Field for Cardiac Septation

    PubMed Central

    Hoffmann, Andrew D.; Yang, Xinan Holly; Burnicka-Turek, Ozanna; Bosman, Joshua D.; Ren, Xiaomeng; Steimle, Jeffrey D.; Vokes, Steven A.; McMahon, Andrew P.; Kalinichenko, Vladimir V.; Moskowitz, Ivan P.

    2014-01-01

    The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation. PMID:25356765

  12. Hedgehog inhibitors from Withania somnifera.

    PubMed

    Yoneyama, Tatsuro; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2015-09-01

    The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA. PMID:26169123

  13. Magnetic hedgehog-like nanostructures

    NASA Astrophysics Data System (ADS)

    Brombacher, C.; Falke, M.; Springer, F.; Rohrmann, H.; Goncharov, A.; Schrefl, T.; Bleloch, A.; Albrecht, M.

    2010-09-01

    Granular CoCrPt-SiO2 films with perpendicular magnetic anisotropy were deposited onto arrays of SiO2 nanoparticles with diameters down to 10 nm. Columnar CoCrPt grains with their c-axis pointing perpendicular to the particle surface were formed, creating a unique hedgehog-like cap structure. This peculiar structure induced by the curvature of the particles substantially modifies the magnetic properties. Underneath the CoCrPt pillars a continuous Co-rich layer was observed, which gives rise to enhanced intergranular exchange coupling resulting in single domain states. The temperature dependence of the coercivity and the angular dependence of the switching field were extracted and correlated with the microstructure.

  14. Membrane topology of hedgehog acyltransferase.

    PubMed

    Matevossian, Armine; Resh, Marilyn D

    2015-01-23

    Hedgehog acyltransferase (Hhat) is a multipass transmembrane enzyme that mediates the covalent attachment of the 16-carbon fatty acid palmitate to the N-terminal cysteine of Sonic Hedgehog (Shh). Palmitoylation of Shh by Hhat is critical for short and long range signaling. Knowledge of the topological organization of Hhat transmembrane helices would enhance our understanding of Hhat-mediated Shh palmitoylation. Bioinformatics analysis of transmembrane domains within human Hhat using 10 different algorithms resulted in highly consistent predictions in the C-terminal, but not in the N-terminal, region of Hhat. To empirically determine the topology of Hhat, we designed and exploited Hhat constructs containing either terminal or 12 different internal epitope tags. We used selective permeabilization coupled with immunofluorescence as well as a protease protection assay to demonstrate that Hhat contains 10 transmembrane domains and 2 re-entrant loops. The invariant His and highly conserved Asp residues within the membrane-bound O-acyltransferase (MBOAT) homology domain are segregated on opposite sides of the endoplasmic reticulum membrane. The localization of His-379 on the lumenal membrane surface is consistent with a role for this invariant residue in catalysis. Analysis of the activity and stability of the Hhat constructs revealed that the C-terminal MBOAT domain is especially sensitive to manipulation. Moreover, there was remarkable similarity in the overall topological organization of Hhat and ghrelin O-acyltransferase, another MBOAT family member. Knowledge of the topological organization of Hhat could serve as an important tool for further design of selective Hhat inhibitors. PMID:25488661

  15. Hedgehog Signaling in the Maintenance of Cancer Stem Cells

    PubMed Central

    Cochrane, Catherine R.; Szczepny, Anette; Watkins, D. Neil; Cain, Jason E.

    2015-01-01

    Cancer stem cells (CSCs) represent a rare population of cells with the capacity to self-renew and give rise to heterogeneous cell lineages within a tumour. Whilst the mechanisms underlying the regulation of CSCs are poorly defined, key developmental signaling pathways required for normal stem and progenitor functions have been strongly implicated. Hedgehog (Hh) signaling is an evolutionarily-conserved pathway essential for self-renewal and cell fate determination. Aberrant Hh signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumourigenesis, including the maintenance of CSCs. Here, we discuss the mounting evidence suggestive of Hh-driven CSCs in the context of haematological malignancies and solid tumours and the novel strategies that hold the potential to block many aspects of the transformation attributed to the CSC phenotype, including chemotherapeutic resistance, relapse and metastasis. PMID:26270676

  16. Characterization of two patched receptors for the vertebrate hedgehog protein family

    PubMed Central

    Carpenter, David; Stone, Donna M.; Brush, Jennifer; Ryan, Anne; Armanini, Mark; Frantz, Gretchen; Rosenthal, Arnon; de Sauvage, Frederic J.

    1998-01-01

    The multitransmembrane protein Patched (PTCH) is the receptor for Sonic Hedgehog (Shh), a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. According to this model, the inhibition of SMO signaling is relieved after mutational inactivation of PTCH in the basal cell nevus syndrome. Recently, PTCH2, a molecule with sequence homology to PTCH, has been identified. To characterize both PTCH molecules with respect to the various Hedgehog proteins, we have isolated the human PTCH2 gene. Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. However, the expression patterns of PTCH and PTCH2 do not fully overlap. While PTCH is expressed throughout the mouse embryo, PTCH2 is found at high levels in the skin and in spermatocytes. Because Desert Hedgehog (Dhh) is expressed specifically in the testis and is required for germ cell development, it is likely that PTCH2 mediates its activity in vivo. Chromosomal localization of PTCH2 places it on chromosome 1p33–34, a region deleted in some germ cell tumors, raising the possibility that PTCH2 may be a tumor suppressor in Dhh target cells. PMID:9811851

  17. Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling

    PubMed Central

    Callahan, Brian P.; Wang, Chunyu

    2015-01-01

    Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog’s biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. PMID:26473928

  18. Chylous ascites in a hedgehog (Atelerix albiventris).

    PubMed

    Roh, Yoon-Seok; Kim, Eun-Ju; Cho, Ara; Kim, Min-Su; Cho, Ho-Seong; Lim, Chae Woong; Kim, Bumseok

    2014-12-01

    An African pygmy hedgehog (Atelerix albiventris) was diagnosed as chylous ascites with biliary cirrhosis. Abdomenocentesis revealed a milky fluid with a 324 mg/dl triglyceride level. On serum biochemical examination, the hedgehog had hypoalbuminemia, hypoglycemia, and high blood urea nitrogen. There was no cytologic or genomic evidence of infection, and a blood culture was negative. Histopathologic examination revealed a liver with proliferative bile ducts that were often surrounded by prominent septa of fibrous connective tissue. In the area of ductular reaction, proliferative cells positive for CD66, an embryogenic antigen of epithelial cells, were revealed. The potential association between chylous ascites and liver cirrhosis is undetermined but could be an aspect of future study. This is the first description of chylous ascites in a hedgehog. PMID:25632690

  19. The role of ciliary trafficking in Hedgehog receptor signaling

    PubMed Central

    Kim, Jynho; Hsia, Elaine Y. C.; Brigui, Amira; Plessis, Anne; Beachy, Philip A.; Zheng, Xiaoyan

    2016-01-01

    Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor, Patched, negatively regulates the activity and ciliary accumulation of Smoothened, a seven transmembrane protein that is essential for transducing the Hedgehog signal. We found that this negative regulation of Smoothened required the ciliary localization of Patched, as specified either by its own cytoplasmic tail or by provision of heterologous ciliary localization signals. Surprisingly, given that Hedgehog binding promotes the exit of Patched from the cilium, we observed that an altered form of Patched that is retained in the cilium nevertheless responded to Hedgehog, resulting in Smoothened activation. Our results indicate that, whereas ciliary localization of Patched is essential for suppression of Smoothened activation, the primary event enabling Smoothened activation is binding of Hedgehog to Patched, and Patched ciliary removal is secondary. PMID:26038600

  20. Detection of a pneumonia virus of mice (PVM) in an African hedgehog (Atelerix arbiventris) with suspected wobbly hedgehog syndrome (WHS).

    PubMed

    Madarame, Hiroo; Ogihara, Kikumi; Kimura, Moe; Nagai, Makoto; Omatsu, Tsutomu; Ochiai, Hideharu; Mizutani, Tetsyuya

    2014-09-17

    A pneumonia virus of mice (PVM) from an African hedgehog (Atelerix arbiventris) with suspected wobbly hedgehog syndrome (WHS) was detected and genetically characterized. The affected hedgehog had a nonsuppurative encephalitis with vacuolization of the white matter, and the brain samples yielded RNA reads highly homogeneous to PVM strain 15 (96.5% of full genomic sequence homology by analysis of next generation sequencing). PVM antigen was also detected in the brain and the lungs immunohistochemically. A PVM was strongly suggested as a causative agent of encephalitis of a hedgehog with suspected WHS. This is a first report of PVM infection in hedgehogs. PMID:25129384

  1. Endometrial polyps in 2 African pygmy hedgehogs

    PubMed Central

    2005-01-01

    Abstract Reports of spontaneously occurring endometrial polyps in animals are rare and have only involved a few species. This report is intended to advise veterinarians that older African pygmy hedgehogs may develop endometrial polyps and that these lesions can be a cause of bloody vaginal discharge, sometimes interpreted as hematuria. PMID:16048013

  2. Ectoparasites of hedgehogs (Erinaceus concolor) from Turkey.

    PubMed

    Girisgin, Ahmet Onur; Senlik, Bayram; Aydin, Levent; Cirak, Veli Y

    2015-01-01

    Hedgehogs are small, nocturnal, spiny-coated animals that have been growing in popularity as exotic pets. However, these animals are host to a wide variety of viruses, bacteria, fungi and parasites, some of which are of zoonotic character. Thus, because hedgehogs have a potential role to transmit zoonoses including arthropod-borne diseases, we examined them for their ectoparasites. The study was carried out on hedgehogs found dead mainly due to road casualties in the Bursa province of Turkey. The ectoparasites were collected by both insecticide spraying of the body and inspection on a white paper carefully. Totally three species of ticks (Rhipicephalus sanguineus, Hyalomma aegyptium, Haemophysalis parvo) and one flea species (Archeopsylla erinacei) were detected. The prevalence of mixed infestation with both ticks and fleas was 45.5%. Haemaphysalis parva was reported for the first time from hedgehogs (Erinaceus concolor) in Turkey. The occurrence of ectoparasites and their potential role as vectors of certain zoonotic diseases are briefly discussed. PMID:26281445

  3. Twist transition of nematic hyperbolic hedgehogs

    NASA Astrophysics Data System (ADS)

    James, Richard; Fukuda, Jun-ichi

    2014-04-01

    Stability of an idealized hyperbolic hedgehog in a nematic liquid crystal against a twist transition is investigated by extending the methodology of Rüdinger and Stark [Liq. Cryst. 26, 753 (1999), 10.1080/026782999204840], where the hedgehog is confined between two concentric spheres. In the ideal hyperbolic-hedgehog the molecular orientation is assumed to rotate proportionally with respect to the inclination angle, θ (and in the opposite sense). However, when splay, k11, and bend, k33, moduli differ this proportionality is lost and the liquid crystal deforms relative to the ideal with bend and splay. Although slight, these deformations are shown to significantly shift the transition if k11/k33 is small. By increasing the degree of confinement the twist transition can be inhibited, a characteristic both hyperbolic and radial hedgehogs have in common. The twist transition of a hyperbolic defect that accompanies a particle is found to be well predicted by the earlier stability analysis of a thick shell.

  4. Protein kinase A activity and Hedgehog signaling pathway.

    PubMed

    Kotani, Tomoya

    2012-01-01

    Protein kinase A (PKA) is a well-known kinase that plays fundamental roles in a variety of biological processes. In Hedgehog-responsive cells, PKA plays key roles in proliferation and fate specification by modulating the transduction of Hedgehog signaling. In the absence of Hedgehog, a basal level of PKA activity represses the transcription of Hedgehog target genes. The main substrates of PKA in this process are the Ci/Gli family of bipotential transcription factors, which activate and repress Hedgehog target gene expression. PKA phosphorylates Ci/Gli, promoting the production of the repressor forms of Ci/Gli and thus repressing Hedgehog target gene expression. In contrast, the activation of Hedgehog signaling in response to Hedgehog increases the active forms of Ci/Gli, resulting in Hedgehog target gene expression. Because both decreased and increased levels of PKA activity cause abnormal cell proliferation and alter cell fate specification, the basal level of PKA activity in Hedgehog-responsive cells should be precisely regulated. However, the mechanism by which PKA activity is regulated remains obscure and appears to vary between cell types, tissues, and organisms. To date, two mechanisms have been proposed. One is a classical mechanism in which PKA activity is regulated by a small second messenger, cAMP; the other is a novel mechanism in which PKA activity is regulated by a protein, Misty somites. PMID:22391308

  5. The hedgehog/Gli signaling paradigm in prostate cancer

    PubMed Central

    Chen, Mengqian; Carkner, Richard; Buttyan, Ralph

    2011-01-01

    Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone. PMID:21776292

  6. Hedgehog signaling: networking to nurture a promalignant tumor microenvironment.

    PubMed

    Harris, Lillianne G; Samant, Rajeev S; Shevde, Lalita A

    2011-09-01

    In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors. PMID:21775419

  7. Hedgehog signaling in development and homeostasis of the gastrointestinal tract.

    PubMed

    van den Brink, Gijs R

    2007-10-01

    The Hedgehog family of secreted morphogenetic proteins acts through a complex evolutionary conserved signaling pathway to regulate patterning events during development and in the adult organism. In this review I discuss the role of Hedgehog signaling in the development, postnatal maintenance, and carcinogenesis of the gastrointestinal tract. Three mammalian hedgehog genes, sonic hedgehog (Shh), indian hedgehog (Ihh), and desert hedgehog (Dhh) have been identified. Shh and Ihh are important endodermal signals in the endodermal-mesodermal cross-talk that patterns the developing gut tube along different axes. Mutations in Shh, Ihh, and downstream signaling molecules lead to a variety of gross malformations of the murine gastrointestinal tract including esophageal atresia, tracheoesophageal fistula, annular pancreas, midgut malrotation, and duodenal and anal atresia. These congenital malformations are also found in varying constellations in humans, suggesting a possible role for defective Hedgehog signaling in these patients. In the adult, Hedgehog signaling regulates homeostasis in several endoderm-derived epithelia, for example, the stomach, intestine, and pancreas. Finally, growth of carcinomas of the proximal gastrointestinal tract such as esophageal, gastric, biliary duct, and pancreatic cancers may depend on Hedgehog signaling offering a potential avenue for novel therapy for these aggressive cancers. PMID:17928586

  8. RAS and Hedgehog--partners in crime.

    PubMed

    Lauth, Matthias

    2011-01-01

    Both RAS and Hedgehog (HH) pathway activation can be found in approximately one third of all cancers. In many cases, this activation occurs in the same tumor types, suggesting a positive impact of a simultaneous activation of RAS and HH on tumor development. This review aims to summarize the current knowledge about the molecular and functional crosstalk of RAS and HH signaling in the development of hyperproliferative disease. PMID:21622175

  9. Hedgehog Signalling in the Embryonic Mouse Thymus

    PubMed Central

    Saldaña, José Ignacio; Crompton, Tessa

    2016-01-01

    T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC)-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC) development, and thymocyte–TEC cross-talk in the embryonic mouse thymus during the last week of gestation. PMID:27504268

  10. [Endoparasitic infestation of wild hedgehogs and hedgehogs in human care with a contribution to therapy].

    PubMed

    Barutzki, D; Laubmeier, E; Forstner, M J

    1987-01-01

    In order to confirm the prevalence of endoparasites fecal samples from 127 hedgehogs living outdoors as well as from 85 in an animal home and from 542 hedgehogs hibernating in private homes were examined. 52.0%-72.3% of the animals from natural surroundings proved to be infested with the lung worm and 72.3%-74.0% with Capillaria species of the intestine, respectively. Capillaria aerophila were found in 15.1%-40.7%, whereas coccidia (1.4%-12.9%) were less frequent. In animal homes and private care hibernating hedgehogs excreted larvae of Crenosoma striatum (23.5% and 21.0%, respectively), eggs of Capillaria species of the intestine (47.1% and 37.1%), and eggs of Capillaria aerophila (7.1% and 19.4%), but oocysts of Isospora rastegaievae were found to be predominant (44.7% and 32.3%). Proglottides of Hymenolepis erinacei and eggs of Brachylaemus erinacei appeared only in the faeces of 3 and 2 hedgehogs, respectively. Helminths of the lung and gut were already found in May, therefore it must be concluded that these parasites are able to survive the winter in the host during the hibernation period. Even young hedgehogs (400-500 g) were infected with Crenosoma and/or Capillaria spp. of the intestine, however, compared with the adults the excretion of eggs and larvae was rather low. The antiparasitic agent Ivermectin (0.3 mg/100 g body-weight) was effective against Crenosoma striatum (efficacy: 95.9%) and Capillaria spp. (100%); therefore it can be recommended as a new, well tolerated anthelmintic against nematodes of the hedgehog. PMID:3424361

  11. Role of Hedgehog Signaling Pathway in NASH.

    PubMed

    Verdelho Machado, Mariana; Diehl, Anna Mae

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease. PMID:27258259

  12. The Hedgehog signalling pathway in bone formation

    PubMed Central

    Yang, Jing; Andre, Philipp; Ye, Ling; Yang, Ying-Zi

    2015-01-01

    The Hedgehog (Hh) signalling pathway plays many important roles in development, homeostasis and tumorigenesis. The critical function of Hh signalling in bone formation has been identified in the past two decades. Here, we review the evolutionarily conserved Hh signalling mechanisms with an emphasis on the functions of the Hh signalling pathway in bone development, homeostasis and diseases. In the early stages of embryonic limb development, Sonic Hedgehog (Shh) acts as a major morphogen in patterning the limb buds. Indian Hedgehog (Ihh) has an essential function in endochondral ossification and induces osteoblast differentiation in the perichondrium. Hh signalling is also involved intramembrane ossification. Interactions between Hh and Wnt signalling regulate cartilage development, endochondral bone formation and synovial joint formation. Hh also plays an important role in bone homeostasis, and reducing Hh signalling protects against age-related bone loss. Disruption of Hh signalling regulation leads to multiple bone diseases, such as progressive osseous heteroplasia. Therefore, understanding the signalling mechanisms and functions of Hh signalling in bone development, homeostasis and diseases will provide important insights into bone disease prevention, diagnoses and therapeutics. PMID:26023726

  13. Hedgehog receptor function during craniofacial development.

    PubMed

    Xavier, Guilherme M; Seppala, Maisa; Barrell, William; Birjandi, Anahid A; Geoghegan, Finn; Cobourne, Martyn T

    2016-07-15

    The Hedgehog signalling pathway plays a fundamental role in orchestrating normal craniofacial development in vertebrates. In particular, Sonic hedgehog (Shh) is produced in three key domains during the early formation of the head; neuroectoderm of the ventral forebrain, facial ectoderm and the pharyngeal endoderm; with signal transduction evident in both ectodermal and mesenchymal tissue compartments. Shh signalling from the prechordal plate and ventral midline of the diencephalon is required for appropriate division of the eyefield and forebrain, with mutation in a number of pathway components associated with Holoprosencephaly, a clinically heterogeneous developmental defect characterized by a failure of the early forebrain vesicle to divide into distinct halves. In addition, signalling from the pharyngeal endoderm and facial ectoderm plays an essential role during development of the face, influencing cranial neural crest cells that migrate into the early facial processes. In recent years, the complexity of Shh signalling has been highlighted by the identification of multiple novel proteins that are involved in regulating both the release and reception of this protein. Here, we review the contributions of Shh signalling during early craniofacial development, focusing on Hedgehog receptor function and describing the consequences of disruption for inherited anomalies of this region in both mouse models and human populations. PMID:26875496

  14. Role of Hedgehog Signaling Pathway in NASH

    PubMed Central

    Verdelho Machado, Mariana; Diehl, Anna Mae

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease. PMID:27258259

  15. Hedgehog signaling in prostate epithelial-mesenchymal growth regulation

    PubMed Central

    Peng, Yu-Ching; Joyner, Alexandra L.

    2015-01-01

    The prostate gland plays an important role in male reproduction, and is also an organ prone to diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. The prostate consists of ducts with an inner layer of epithelium surrounded by stroma. Reciprocal signaling between these two cell compartments is instrumental to normal prostatic development, homeostasis, regeneration, as well as tumor formation. Hedgehog (HH) signaling is a master regulator in numerous developmental processes. In many organs, HH plays a key role in epithelial-mesenchymal signaling that regulates organ growth and tissue differentiation, and abnormal HH signaling has been implicated in the progression of various epithelial carcinomas. In this review, we focus on recent studies exploring the multipotency of endogenous postnatal and adult epithelial and stromal stem cells and studies addressing the role of HH in prostate development and cancer. We discuss the implications of the results for a new understanding of prostate development and disease. Insight into the cellular and molecular mechanisms underlying epithelial-mesenchymal growth regulation should provide a basis for devising innovative therapies to combat diseases of the prostate. PMID:25641695

  16. Hedgehogs in a three-dimensional anisotropic spin system

    NASA Astrophysics Data System (ADS)

    Jonsson, Thordur

    1983-06-01

    We study a continuum version of a classical anisotropic spin model in three dimensions with three component spins. We prove the existence of topological defects, called hedgehogs, which are analogous to the vortices in the two-dimensional xy-model and have a logarithmically divergent action. Bounds for the interaction energy of a hedgehog and an antihedgehog are derived.

  17. Hedgehog signaling pathway in small bovine ovarian follicles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The hedgehog signaling pathway is involved in the regulation of cell proliferation, differentiation, and turnover in a variety of mammalian embryonic and adult tissues including bovine ovarian granulosa and theca cells. Binding of hedgehog to the patch receptor derepresses smoothened resulting in t...

  18. Downregulating Hedgehog Signaling Reduces Renal Cystogenic Potential of Mouse Models

    PubMed Central

    Talbott, George C.; Turbe-Doan, Annick; Jacobs, Damon T.; Schonfeld, Michael P.; Silva, Luciane M.; Chatterjee, Anindita; Prysak, Mary; Allard, Bailey A.; Beier, David R.

    2014-01-01

    Renal cystic diseases are a leading cause of renal failure. Mutations associated with renal cystic diseases reside in genes encoding proteins that localize to primary cilia. These cystoproteins can disrupt ciliary structure or cilia-mediated signaling, although molecular mechanisms connecting cilia function to renal cystogenesis remain unclear. The ciliary gene, Thm1(Ttc21b), negatively regulates Hedgehog signaling and is most commonly mutated in ciliopathies. We report that loss of murine Thm1 causes cystic kidney disease, with persistent proliferation of renal cells, elevated cAMP levels, and enhanced expression of Hedgehog signaling genes. Notably, the cAMP-mediated cystogenic potential of Thm1-null kidney explants was reduced by genetically deleting Gli2, a major transcriptional activator of the Hedgehog pathway, or by culturing with small molecule Hedgehog inhibitors. These Hedgehog inhibitors acted independently of protein kinase A and Wnt inhibitors. Furthermore, simultaneous deletion of Gli2 attenuated the renal cystic disease associated with deletion of Thm1. Finally, transcripts of Hedgehog target genes increased in cystic kidneys of two other orthologous mouse mutants, jck and Pkd1, and Hedgehog inhibitors reduced cystogenesis in jck and Pkd1 cultured kidneys. Thus, enhanced Hedgehog activity may have a general role in renal cystogenesis and thereby present a novel therapeutic target. PMID:24700869

  19. Sonic Hedgehog regulates thymic epithelial cell differentiation.

    PubMed

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-04-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  20. Sonic Hedgehog regulates thymic epithelial cell differentiation

    PubMed Central

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L.; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-01-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  1. Sonic hedgehog patterning during cerebellar development.

    PubMed

    De Luca, Annarita; Cerrato, Valentina; Fucà, Elisa; Parmigiani, Elena; Buffo, Annalisa; Leto, Ketty

    2016-01-01

    The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions. PMID:26499980

  2. Localizing global hedgehogs on the brane

    NASA Astrophysics Data System (ADS)

    Cho, Inyong

    2004-10-01

    We investigate the localization of 4D topological global defects on the brane embedded in 5D. The defects are induced by 5D scalar fields with a symmetry-breaking potential. Taking an Ansatz which separates the scalar field into the 4D and the extra-D part, we find that the static-hedgehog configuration is accomplished and the defects are formed only in the AdS4/AdS5 background. In the extra dimension, the localization amplitude for the 4D defects is high where the warp factor is high.

  3. Where Are the Hedgehogs in Quenched Nematics?

    NASA Astrophysics Data System (ADS)

    Hindmarsh, Mark

    1995-09-01

    In experiments which take a liquid crystal rapidly from the isotropic to the nematic phase, a dense tangle of defects is formed. In nematics, there are, in principle, both line and point defects (``hedgehogs''), but no point defects are observed until the defect network has coarsened appreciably. In this Letter the expected density of point defects is shown to be extremely low, approximately 10-8 per initially correlated domain, as a result of the topology (specifically, the homology) of the order-parameter space.

  4. Localizing global hedgehogs on the brane

    SciTech Connect

    Cho, Inyong

    2004-10-15

    We investigate the localization of 4D topological global defects on the brane embedded in 5D. The defects are induced by 5D scalar fields with a symmetry-breaking potential. Taking an Ansatz which separates the scalar field into the 4D and the extra-D part, we find that the static-hedgehog configuration is accomplished and the defects are formed only in the AdS{sub 4}/AdS{sub 5} background. In the extra dimension, the localization amplitude for the 4D defects is high where the warp factor is high.

  5. Regulation of Hedgehog signaling by ubiquitination

    PubMed Central

    Hsia, Elaine Y. C.; Gui, Yirui; Zheng, Xiaoyan

    2015-01-01

    The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components. PMID:26366162

  6. Transcriptional Regulation of Graded Hedgehog Signaling

    PubMed Central

    Falkenstein, Kristin N.; Vokes, Steven A.

    2014-01-01

    The Hedgehog (Hh) pathway plays conserved roles in regulating a diverse spectrum of developmental processes. In some developmental contexts, a gradient of Hh protein specifies multiple cell types in a dose-dependent fashion, thereby acting as a morphogen. Hh signaling ultimately acts on the transcriptional level through GLI proteins. In the presence of Hh signaling full length GLI proteins act as transcriptional activators of target genes. Conversely, in the absence of Hh, GLI proteins act as transcriptional repressors. This review will highlight mechanisms contributing to how graded Hh signaling might translate to differential GLI activity and be interpreted into distinct transcriptional responses. PMID:24862856

  7. Endocannabinoids are conserved inhibitors of the Hedgehog pathway

    PubMed Central

    Khaliullina, Helena; Bilgin, Mesut; Sampaio, Julio L.; Shevchenko, Andrej; Eaton, Suzanne

    2015-01-01

    Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids. PMID:25733905

  8. Perturbations to the hedgehog pathway in sea urchin embryos.

    PubMed

    Warner, Jacob F; McClay, David R

    2014-01-01

    The Hedgehog pathway has been shown to be an important developmental signaling pathway in many organisms (Ingham and McMahon. Genes Dev 15:3059-3087, 2001). Recently that work has been extended to developing echinoderm embryos (Walton et al. Dev Biol 331(1):26-37, 2009). Here we describe several methods to perturb the Hedgehog signaling pathway in the sea urchin. These include microinjection of Morpholinos and mRNA constructs as well as treatments with small molecule inhibitors. Finally we provide simple methods for assaying Hedgehog phenotypes in the sea urchin embryo. PMID:24567217

  9. Acinic cell carcinoma in an African pygmy hedgehog (Atelerix albiventris).

    PubMed

    Fukuzawa, Ryuji; Fukuzawa, Kazuhiro; Abe, Hitoshi; Nagai, Toshihiro; Kameyama, Kaori

    2004-01-01

    A male African pygmy hedgehog (Atelerix albiventris), estimated to be 3 years old, presented with exophthalmos and fixed abduction of the right eye. Radiographic examination revealed a retrobulbar tumor in the right orbital cavity. The mass was surgically resected but recurred 3 months later and the hedgehog died. There was no gross or microscopic evidence of salivary or lacrimal gland involvement of the tumor at surgery or at necropsy. The histopathologic, immunohistochemical, and ultrastructural findings were those of acinic cell carcinoma, the origin of which was unknown. This is the first known case of acinic cell carcinoma in an African hedgehog. PMID:15048626

  10. Semiclassical projection of hedgehog models with quarks

    SciTech Connect

    Cohen, T.D.; Broniowski, W.

    1986-12-01

    A simple semiclassical method is presented for calculating physical observables in states with good angular momentum and isospin for models whose mean-field solutions are hedgehogs. The method is applicable for theories which have both quark and meson degrees of freedom. The basic approach is to find slowly rotating solutions to the time-dependent mean-field equations. A nontrivial set of differential equations must be solved to find the quark configuration for these rotating hedgehogs. The parameters which specify the rotating solutions are treated as the collective degrees of freedom. They are requantized by imposing a set of commutation relations which ensures the correct algebra for the SU(2) x SU(2) group of angular momentum and isospin. Collective wave functions can then be found and with these wave functions all matrix elements can be calculated. The method is applied to a simple version of the chiral quark-meson model. A number of physical quantities such as magnetic moments, charge distributions, g/sub A/, g/sub ..pi..//sub N//sub N/, N-..delta.. mass splitting, properties of the N-..delta.. transition, etc., are calculated.

  11. Semiclassical projection of hedgehog models with quarks

    NASA Astrophysics Data System (ADS)

    Cohen, Thomas D.; Broniowski, Wojciech

    1986-12-01

    A simple semiclassical method is presented for calculating physical observables in states with good angular momentum and isospin for models whose mean-field solutions are hedgehogs. The method is applicable for theories which have both quark and meson degrees of freedom. The basic approach is to find slowly rotating solutions to the time-dependent mean-field equations. A nontrivial set of differential equations must be solved to find the quark configuration for these rotating hedgehogs. The parameters which specify the rotating solutions are treated as the collective degrees of freedom. They are requantized by imposing a set of commutation relations which ensures the correct algebra for the SU(2)×SU(2) group of angular momentum and isospin. Collective wave functions can then be found and with these wave functions all matrix elements can be calculated. The method is applied to a simple version of the chiral quark-meson model. A number of physical quantities such as magnetic moments, charge distributions, gA, gπNN, N-Δ mass splitting, properties of the N-Δ transition, etc., are calculated.

  12. Hedgehog Signaling during Appendage Development and Regeneration

    PubMed Central

    Singh, Bhairab N.; Koyano-Nakagawa, Naoko; Donaldson, Andrew; Weaver, Cyprian V.; Garry, Mary G.; Garry, Daniel J.

    2015-01-01

    Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration. PMID:26110318

  13. Targeting the Hedgehog Pathway in Pediatric Medulloblastoma

    PubMed Central

    Huang, Sherri Y.; Yang, Jer-Yen

    2015-01-01

    Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical. PMID:26512695

  14. Hedgehog Signaling during Appendage Development and Regeneration.

    PubMed

    Singh, Bhairab N; Koyano-Nakagawa, Naoko; Donaldson, Andrew; Weaver, Cyprian V; Garry, Mary G; Garry, Daniel J

    2015-01-01

    Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration. PMID:26110318

  15. Ontogenetic Expression of Sonic Hedgehog in the Chicken Subpallium

    PubMed Central

    Bardet, Sylvia M.; Ferran, José L. E.; Sanchez-Arrones, Luisa; Puelles, Luis

    2010-01-01

    Sonic hedgehog (SHH) is a secreted signaling factor that is implicated in the molecular patterning of the central nervous system (CNS), somites, and limbs in vertebrates. SHH has a crucial role in the generation of ventral cell types along the entire rostrocaudal axis of the neural tube. It is secreted early in development by the axial mesoderm (prechordal plate and notochord) and the overlying ventral neural tube. Recent studies clarified the impact of SHH signaling mechanisms on dorsoventral patterning of the spinal cord, but the corresponding phenomena in the rostral forebrain are slightly different and more complex. This notably involves separate Shh expression in the preoptic part of the forebrain alar plate, as well as in the hypothalamic floor and basal plates. The present work includes a detailed spatiotemporal description of the singular alar Shh expression pattern in the rostral preoptic forebrain of chick embryos, comparing it with FoxG1, Dlx5, Nkx2.1, and Nkx2.2 mRNA expression at diverse stages of development. As a result of this mapping, we report a subdivision of the preoptic region in dorsal and ventral zones; only the dorsal part shows Shh expression. The positive area impinges as well upon a median septocommissural preoptic domain. Our study strongly suggests tangential migration of Shh-positive cells from the preoptic region into other subpallial domains, particularly into the pallidal mantle and the intermediate septum. PMID:20700498

  16. Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HIP

    PubMed Central

    Bishop, Benjamin; Aricescu, A. Radu; Harlos, Karl; O’Callaghan, Chris A.; Jones, E. Yvonne; Siebold, Christian

    2009-01-01

    Hedgehog (Hh) morphogens play fundamental roles in development whilst dysregulation of Hh signaling leads to disease. Multiple cell surface receptors are responsible for transducing and/or regulating Hh signals. Among these, the hedgehog-interacting protein (HIP) is a highly conserved, vertebrate-specific, inhibitor of Hh signaling. We have solved a series of crystal structures for the human HIP ectodomain and Desert Hh in isolation, as well as Sonic and Desert Hh-HIP complexes, with and without calcium. The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal novel and distinct functions for Hh zinc- and calcium-binding sites; functions which appear common to all vertebrate Hhs. Zinc makes a key contribution to the Hh-HIP interface while calcium prevents electrostatic repulsion between the two proteins, thus playing a major modulatory role. This interplay of several metal-binding sites suggests a tuneable mechanism for regulation of Hh signaling. PMID:19561611

  17. Sweet on Hedgehogs: regulatory roles of heparan sulfate proteoglycans in Hedgehog-dependent cell proliferation and differentiation.

    PubMed

    Bandari, Shyam; Exner, Sebastian; Ortmann, Corinna; Bachvarova, Velina; Vortkamp, Andrea; Grobe, Kay

    2015-01-01

    Morphogens exert their effects over long distances, typically by spreading from cell to cell to activate signal transduction in surrounding tissues in concentration-dependent manner. One example of a morphogen is the signaling molecule Hedgehog (Hh), which controls growth and patterning during development and has also been implicated in the progression of numerous cancers. To this end, accessory mechanisms that release, transport, and receive Hhs are required to elicit temporally and spatially specific responses in cells and tissues. The Hh spreading mechanism is especially intriguing, because all Hhs are released from the producing cells despite being synthesized as dually lipidated, membrane-tethered molecules. In addition to this cellular association, Hhs bind strongly to extracellular heparan sulfate proteoglycans (HSPGs), which is expected to further reduce their spreading. Paradoxically, several lines of evidence suggest that Hh gradient formation actually requires HSPG expression, and that HSPGs act as both positive and negative regulators of Hh function. This article reviews the multiple roles that HSPGs play in Hh morphogen function, and discusses their congruity with proposed mechanisms of Hh solubilization, transport, and signal reception in vertebrate and invertebrate tissues. PMID:25692848

  18. Impacts of removing badgers on localised counts of hedgehogs.

    PubMed

    Trewby, Iain D; Young, Richard; McDonald, Robbie A; Wilson, Gavin J; Davison, John; Walker, Neil; Robertson, Andrew; Doncaster, C Patrick; Delahay, Richard J

    2014-01-01

    Experimental evidence of the interactions among mammalian predators that eat or compete with one another is rare, due to the ethical and logistical challenges of managing wild populations in a controlled and replicated way. Here, we report on the opportunistic use of a replicated and controlled culling experiment (the Randomised Badger Culling Trial) to investigate the relationship between two sympatric predators: European badgers Meles meles and western European hedgehogs Erinaceus europaeus. In areas of preferred habitat (amenity grassland), counts of hedgehogs more than doubled over a 5-year period from the start of badger culling (from 0.9 ha-1 pre-cull to 2.4 ha-1 post-cull), whereas hedgehog counts did not change where there was no badger culling (0.3-0.3 hedgehogs ha-1). This trial provides experimental evidence for mesopredator release as an outcome of management of a top predator. PMID:24736454

  19. Spontaneous neoplasia in four captive greater hedgehog tenrecs (Setifer setosus).

    PubMed

    Khoii, Mina K; Howerth, Elizabeth W; Burns, Roy B; Carmichael, K Paige; Gyimesi, Zoltan S

    2008-09-01

    Little information is available about diseases and pathology of species within the family Tenrecidae, including the greater hedgehog tenrec (Setifer setosus), a Madagascan insectivore. This report summarizes necropsy and histopathologic findings of neoplasia in four captive greater hedgehog tenrecs. Although only four animals are included in this report, neoplasia seems to be a common and significant source of morbidity and mortality in greater hedgehog tenrecs. Types of neoplasia identified include a thyroid follicular-solid carcinoma, two urinary bladder transitional cell carcinomas, uterine endometrial polyps, and multicentric B-cell lymphoma. Due to small sample size, no etiology could be determined, but genetics, viral infection, pesticide treatment, nutrition, or other environmental factors might contribute to the development of neoplasia in this species. This is the first report of neoplasia in greater hedgehog tenrecs. PMID:18817002

  20. Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling.

    PubMed

    Huang, Pengxiang; Nedelcu, Daniel; Watanabe, Miyako; Jao, Cindy; Kim, Youngchang; Liu, Jing; Salic, Adrian

    2016-08-25

    In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and is unique among CRD-containing receptors. We demonstrate that Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol. PMID:27545348

  1. Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Gradilone, Sergio A.; Smoot, Rory L.; Mertens, Joachim C.; Bronk, Steven F.; Sirica, Alphonse E.; Gores, Gregory J.

    2014-01-01

    Background & Aims: The Hedgehog signaling pathway contributes to cholangiocarcinoma biology. However, canonical Hedgehog signaling requires cilia, and cholangiocarcinoma cells often do not express cilia. To resolve this paradox, we examined non-canonical (G-protein coupled, pertussis toxin sensitive) Hedgehog signaling in cholangiocarcinoma cells. Methods: Human [non-malignant (H69), malignant (HuCC-T1 and Mz-ChA-1)] and rat [non-malignant (BDE1 and NRC), and malignant (BDEneu)] cell lines were employed for this study. A BDEΔLoop2 cell line with the dominant-negative receptor Patched-1 was generated with the Sleeping Beauty transposon transfection system. Results: Cilia expression was readily identified in non-malignant, but not in malignant cholangiocarcinoma cell lines. Although the canonical Hh signaling pathway was markedly attenuated in cholangiocarcinoma cells, they were chemotactic to purmorphamine, a small-molecule direct Smoothened agonist. Purmorphamine also induced remodeling of the actin cytoskeleton with formation of filopodia and lamellipodia-like protrusions. All these biological features of cell migration were pertussis toxin sensitive, a feature of G-protein coupled (Gis) receptors. To further test the role of Hedgehog signaling in vivo, we employed a syngeneic orthotopic rat model of cholangiocarcinoma. In vivo, genetic inhibition of the Hedgehog signaling pathway employing BDEΔLoop2 cells or pharmacological inhibition with a small-molecule antagonist of Smoothened, vismodegib, was tumor and metastasis suppressive. Conclusions: Cholangiocarcinoma cells exhibit non-canonical Hedgehog signaling with chemotaxis despite impaired cilia expression. This non-canonical Hedgehog signaling pathway appears to contribute to cholangiocarcinoma progression, thereby, supporting a role for Hedgehog pathway inhibition in human cholangiocarcinoma. PMID:24239776

  2. Hedgehog-Gli pathway activation during kidney fibrosis.

    PubMed

    Fabian, Steven L; Penchev, Radostin R; St-Jacques, Benoit; Rao, Anjali N; Sipilä, Petra; West, Kip A; McMahon, Andrew P; Humphreys, Benjamin D

    2012-04-01

    The Hedgehog (Hh) signaling pathway regulates tissue patterning during development, including patterning and growth of limbs and face, but whether Hh signaling plays a role in adult kidney remains undefined. In this study, using a panel of hedgehog-reporter mice, we show that the two Hh ligands (Indian hedgehog and sonic hedgehog ligands) are expressed in tubular epithelial cells. We report that the Hh effectors (Gli1 and Gli2) are expressed exclusively in adjacent platelet-derived growth factor receptor-β-positive interstitial pericytes and perivascular fibroblasts, suggesting a paracrine signaling loop. In two models of renal fibrosis, Indian Hh ligand was upregulated with a dramatic activation of downstream Gli effector expression. Hh-responsive Gli1-positive interstitial cells underwent 11-fold proliferative expansion during fibrosis, and both Gli1- and Gli2-positive cells differentiated into α-smooth muscle actin-positive myofibroblasts. In the pericyte-like cell line 10T1/2, hedgehog ligand triggered cell proliferation, suggesting a possible role for this pathway in the regulation of cell cycle progression of myofibroblast progenitors during the development of renal fibrosis. The hedgehog antagonist IPI-926 abolished Gli1 induction in vivo but did not decrease kidney fibrosis. However, the transcriptional induction of Gli2 was unaffected by IPI-926, suggesting the existence of smoothened-independent Gli activation in this model. This study is the first detailed description of paracrine hedgehog signaling in adult kidney, which indicates a possible role for hedgehog-Gli signaling in fibrotic chronic kidney disease. PMID:22342522

  3. Hedgehog-Gli Pathway Activation during Kidney Fibrosis

    PubMed Central

    Fabian, Steven L.; Penchev, Radostin R.; St-Jacques, Benoit; Rao, Anjali N.; Sipilä, Petra; West, Kip A.; McMahon, Andrew P.; Humphreys, Benjamin D.

    2012-01-01

    The Hedgehog (Hh) signaling pathway regulates tissue patterning during development, including patterning and growth of limbs and face, but whether Hh signaling plays a role in adult kidney remains undefined. In this study, using a panel of hedgehog-reporter mice, we show that the two Hh ligands (Indian hedgehog and sonic hedgehog ligands) are expressed in tubular epithelial cells. We report that the Hh effectors (Gli1 and Gli2) are expressed exclusively in adjacent platelet-derived growth factor receptor-β-positive interstitial pericytes and perivascular fibroblasts, suggesting a paracrine signaling loop. In two models of renal fibrosis, Indian Hh ligand was upregulated with a dramatic activation of downstream Gli effector expression. Hh-responsive Gli1-positive interstitial cells underwent 11-fold proliferative expansion during fibrosis, and both Gli1- and Gli2-positive cells differentiated into α-smooth muscle actin-positive myofibroblasts. In the pericyte-like cell line 10T1/2, hedgehog ligand triggered cell proliferation, suggesting a possible role for this pathway in the regulation of cell cycle progression of myofibroblast progenitors during the development of renal fibrosis. The hedgehog antagonist IPI-926 abolished Gli1 induction in vivo but did not decrease kidney fibrosis. However, the transcriptional induction of Gli2 was unaffected by IPI-926, suggesting the existence of smoothened-independent Gli activation in this model. This study is the first detailed description of paracrine hedgehog signaling in adult kidney, which indicates a possible role for hedgehog-Gli signaling in fibrotic chronic kidney disease. PMID:22342522

  4. Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma.

    PubMed

    Satheesha, S; Manzella, G; Bovay, A; Casanova, E A; Bode, P K; Belle, R; Feuchtgruber, S; Jaaks, P; Dogan, N; Koscielniak, E; Schäfer, B W

    2016-04-21

    Current treatment regimens for rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer, rely on conventional chemotherapy, and although they show clinical benefit, there is a significant risk of adverse side effects and secondary tumors later in life. Therefore, identifying and targeting sub-populations with higher tumorigenic potential and self-renewing capacity would offer improved patient management strategies. Hedgehog signaling has been linked to the development of embryonal RMS (ERMS) through mouse genetics and rare human syndromes. However, activating mutations in this pathway in sporadic RMS are rare and therefore the contribution of hedgehog signaling to oncogenesis remains unclear. Here, we show by genetic loss- and gain-of-function experiments and the use of clinically relevant small molecule modulators that hedgehog signaling is important for controlling self-renewal of a subpopulation of RMS cells in vitro and tumor initiation in vivo. In addition, hedgehog activity altered chemoresistance, motility and differentiation status. The core stem cell gene NANOG was determined to be important for ERMS self-renewal, possibly acting downstream of hedgehog signaling. Crucially, evaluating the presence of a subpopulation of tumor-propagating cells in patient biopsies identified by GLI1 and NANOG expression had prognostic significance. Hence, this work identifies novel functional aspects of hedgehog signaling in ERMS, redefines the rationale for its targeting as means to control ERMS self-renewal and underscores the importance of studying functional tumor heterogeneity in pediatric cancers. PMID:26189795

  5. Rickettsiae in arthropods collected from the North African Hedgehog (Atelerix algirus) and the desert hedgehog (Paraechinus aethiopicus) in Algeria.

    PubMed

    Khaldi, Mourad; Socolovschi, Cristina; Benyettou, Meryam; Barech, Ghania; Biche, Mohamed; Kernif, Tahar; Raoult, Didier; Parola, Philippe

    2012-03-01

    Hedgehogs have become a popular pet despite their potential role in zoonotic disease transmission. We conducted an entomological study in a mountainous region of northeast Algeria in which we collected 387 fleas (Archeopsylla erinacei) and 342 ticks (Rhipicephalus sanguineus and Haemaphysalis erinacei) from Paraechinus aethiopicus and Atelerix algirus hedgehogs. Of the hedgehogs sampled, 77.7% and 91% were infested with fleas and ticks, respectively. Significantly more ticks and fleas were collected from A. algirus than from P. aethiopicus. Rickettsia felis was detected in 95.5% of fleas and R. massiliae was detected in 6.25% of Rh. sanguineus ticks by molecular tools. A new Rickettsia species of the spotted fever group was detected in 11.25% of Rh. sanguineus and in 77% of H. erinacei ticks. Overall, we show that hedgehogs can act as hosts for ectoparasites infected with several rickettsial agents. These data justify a more detailed investigation of animal reservoirs for Rickettsiae. PMID:22222114

  6. The role of glypicans in Hedgehog signaling.

    PubMed

    Filmus, Jorge; Capurro, Mariana

    2014-04-01

    Glypicans (GPCs) are a family of proteoglycans that are bound to the cell surface by a glycosylphosphatidylinositol anchor. Six glypicans have been found in the mammalian genome (GPC1 to GPC6). GPCs regulate several signaling pathways, including the pathway triggered by Hedgehogs (Hhs). This regulation, which could be stimulatory or inhibitory, occurs at the signal reception level. In addition, GPCs have been shown to be involved in the formation of Hh gradients in the imaginal wing disks in Drosophila. In this review we will discuss the role of various glypicans in specific developmental events in the embryo that are regulated by Hh signaling. In addition, we will discuss the mechanism by which loss-of-function GPC3 mutations alter Hh signaling in the Simpson-Golabi-Behmel overgrowth syndrome, and the molecular basis of the GPC5-induced stimulation of Hh signaling and tumor progression in rhabdomyosarcomas. PMID:24412155

  7. Developmental pathways: Sonic hedgehog-Patched-GLI.

    PubMed Central

    Walterhouse, D O; Yoon, J W; Iannaccone, P M

    1999-01-01

    Developmental pathways are networks of genes that act coordinately to establish the body plan. Disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Environmental exposures can be associated with poor pregnancy outcomes, including dysmorphic offspring or children with a variety of diseases. An important goal of environmental science should be reduction of these poor outcomes. This will require an understanding of the genes affected by specific exposures and the consequence of alterations in these genes or their products, which in turn will require an understanding of the pathways critical in development. The ligand Sonic hedgehog, the receptors Patched and Smoothened, and the GLI family of transcription factors represent one such pathway. This pathway illustrates several operating principles important in the consideration of developmental consequences of environmental exposures to toxins. Images Figure 1 Figure 2 PMID:10064544

  8. Hedgehog and Resident Vascular Stem Cell Fate

    PubMed Central

    Mooney, Ciaran J.; Hakimjavadi, Roya; Fitzpatrick, Emma; Kennedy, Eimear; Walls, Dermot; Morrow, David; Redmond, Eileen M.; Cahill, Paul A.

    2015-01-01

    The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall. PMID:26064136

  9. Smoothened regulation in response to Hedgehog stimulation

    PubMed Central

    Jiang, Kai; Jia, Jianhang

    2016-01-01

    The Hedgehog (Hh) signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched (Ptc) inhibits the atypical G protein-coupled receptor Smoothened (Smo) in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI(4)P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation. PMID:26973699

  10. Catecholaminergic and serotoninergic fibres innervate the ventricular system of the hedgehog CNS.

    PubMed Central

    Michaloudi, H C; Papadopoulos, G C

    1996-01-01

    Immunocytochemistry with antisera against serotonin (5-HT), dopamine (DA) and noradrenaline (NA) was used to detect monoaminergic (MA) fibres in the ventricular system of the hedgehog Erinaceus europaeus. Light microscopic examination of immunocytochemically stained sections revealed that the ventricular system of the hedgehog is unique among mammals in that the choroid plexuses receive CA axons and that the supraependyma and subependyma of the cerebral ventricles and the spinal central canal are innervated both by serotoninergic and catecholaminergic (CA) fibres. Supraependymal 5-HT axons were generally more abundant and created at places a large number of interconnected basket-like structures, whereas CA fibres were usually directed towards the ventricular lumen. In the lateral ventricles, CA fibres were more numerous in the ependyma lining grey matter, whereas a higher 5-HT innervation density was observed in the area between the corpus callosum and the caudate nucleus or the septum. In the 3rd ventricle, the ependyma of its dorsal part exhibited a higher 5-HT and NA innervation density, whereas DA fibres were preferentially distributed in the ventral half of the basal region. The ependyma lining the cerebral aqueduct displayed a higher MA innervation density in its ventral part. The ependymal wall of the 4th ventricle exhibited an extremely dense 5-HT innervation, mainly in the floor of the ventricle, relatively fewer NA fibres and only sparse DA ones. Few NA and relatively more 5-HT fibres were detected in the ependyma of the central canal. Finally, the circumventricular organs were unevenly innervated by the 3 types of MA fibres. The extensive monoaminergic innervation of the hedgehog ventricular system described here probably reflects a transitory evolutionary stage in the phylogeny of the MA systems with presently unknown functional implications. Images Fig. 1 Fig. 2 Figs 3-8 Figs 9-14 Figs 15-20 PMID:8886949

  11. Serotonin Regulates Calcium Homeostasis in Lactation by Epigenetic Activation of Hedgehog Signaling

    PubMed Central

    Laporta, Jimena; Keil, Kimberly P.; Weaver, Samantha R.; Cronick, Callyssa M.; Prichard, Austin P.; Crenshaw, Thomas D.; Heyne, Galen W.; Vezina, Chad M.; Lipinski, Robert J.

    2014-01-01

    Calcium homeostasis during lactation is critical for maternal and neonatal health. We previously showed that nonneuronal/peripheral serotonin [5-hydroxytryptamine (5-HT)] causes the lactating mammary gland to synthesize and secrete PTHrP in an acute fashion. Here, using a mouse model, we found that genetic inactivation of tryptophan hydroxylase 1 (Tph1), which catalyzes the rate-limiting step in peripheral 5-HT synthesis, reduced circulating and mammary PTHrP expression, osteoclast activity, and maternal circulating calcium concentrations during the transition from pregnancy to lactation. Tph1 inactivation also reduced sonic hedgehog signaling in the mammary gland during lactation. Each of these deficiencies was rescued by daily injections of 5-hydroxy-L-tryptophan (an immediate precursor of 5-HT) to Tph1-deficient dams. We used immortalized mouse embryonic fibroblasts to demonstrate that 5-HT induces PTHrP through a sonic hedgehog-dependent signal transduction mechanism. We also found that 5-HT altered DNA methylation of the Shh gene locus, leading to transcriptional initiation at an alternate start site and formation of a variant transcript in mouse embryonic fibroblasts in vitro and in mammary tissue in vivo. These results support a new paradigm of 5-HT-mediated Shh regulation involving DNA methylation remodeling and promoter switching. In addition to having immediate implications for lactation biology, identification and characterization of a novel functional regulatory relationship between nonneuronal 5-HT, hedgehog signaling, and PTHrP offers new avenues for the study of these important factors in development and disease. PMID:25192038

  12. Expression pattern of the Hedgehog signaling pathway in pituitary adenomas.

    PubMed

    Yavropoulou, Maria P; Maladaki, Anna; Topouridou, Konstantina; Kotoula, Vasiliki; Poulios, Chris; Daskalaki, Emily; Foroglou, Nikolaos; Karkavelas, George; Yovos, John G

    2016-01-12

    Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged-1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway. PMID:26620835

  13. Gastroenteritis caused by the Cryptosporidium hedgehog genotype in an immunocompetent man.

    PubMed

    Kváč, Martin; Saková, Kamila; Kvĕtoňová, Dana; Kicia, Marta; Wesołowska, Maria; McEvoy, John; Sak, Bohumil

    2014-01-01

    The Cryptosporidium hedgehog genotype, which has been reported previously in hedgehogs and horses, was identified as the cause of the diarrheal disease cryptosporidiosis in an immunocompetent man in the Czech Republic. This is the first report of human illness caused by the Cryptosporidium hedgehog genotype. PMID:24131692

  14. Ectoparasite loads in sympatric urban populations of the northern white-breasted and the European hedgehog.

    PubMed

    Dziemian, Sylwia; Sikora, Bożena; Piłacińska, Barbara; Michalik, Jerzy; Zwolak, Rafał

    2015-06-01

    We investigated abundance and prevalence of ticks and fleas infesting urban populations of two species of hedgehogs: the northern white-breasted hedgehog (Erinaceus roumanicus) and the European hedgehog (Erinaceus europaeus). The hedgehogs were captured in the city of Poznań (western Poland) over the period of 4 years. Both species of hedgehogs were infested with the castor bean tick (Ixodes ricinus), the hedgehog tick (Ixodes hexagonus), and the hedgehog flea (Archeopsylla erinacei). The northern white-breasted hedgehog had higher loads of I. ricinus and A. erinacei than the European hedgehog. The abundance and prevalence of I. hexagonus were similar on both species of hosts. Co-infestation with the two species of ticks was more frequent on the northern white-breasted hedgehog than on the European hedgehog. Therefore, these two closely related species of hedgehogs differ in their importance as hosts of arthropod vectors of pathogens in urban areas and might play a different role in the dynamics of zoonotic diseases. PMID:25820646

  15. Regulation of Patched by Sonic Hedgehog in the Developing Neural Tube

    NASA Astrophysics Data System (ADS)

    Marigo, Valeria; Tabin, Clifford J.

    1996-09-01

    Ventral cell fates in the central nervous system are induced by Sonic hedgehog, a homolog of hedgehog, a secreted Drosophila protein. In the central nervous system, Sonic hedgehog has been identified as the signal inducing floor plate, motor neurons, and dopaminergic neurons. Sonic hedgehog is also involved in the induction of ventral cell type in the developing somites. ptc is a key gene in the Drosophila hedgehog signaling pathway where it is involved in transducing the hedgehog signal and is also a transcriptional target of the signal. PTC, a vertebrate homolog of this Drosophila gene, is genetically downstream of Sonic hedgehog (Shh) in the limb bud. We analyze PTC expression during chicken neural and somite development and find it expressed in all regions of these tissues known to be responsive to Sonic hedgehog signal. As in the limb bud, ectopic expression of Sonic hedgehog leads to ectopic induction of PTC in the neural tube and paraxial mesoderm. This conservation of regulation allows us to use PTC as a marker for Sonic hedgehog response. The pattern of PTC expression suggests that Sonic hedgehog may play an inductive role in more dorsal regions of the neural tube than have been previously demonstrated. Examination of the pattern of PTC expression also suggests that PTC may act in a negative feedback loop to attenuate hedgehog signaling.

  16. Habenular Neurogenesis in Zebrafish Is Regulated by a Hedgehog, Pax6 Proneural Gene Cascade

    PubMed Central

    Naye, François; Peers, Bernard; Roussigné, Myriam; Blader, Patrick

    2016-01-01

    The habenulae are highly conserved nuclei in the dorsal diencephalon that connect the forebrain to the midbrain and hindbrain. These nuclei have been implicated in a broad variety of behaviours in humans, primates, rodents and zebrafish. Despite this, the molecular mechanisms that control the genesis and differentiation of neural progenitors in the habenulae remain relatively unknown. We have previously shown that, in zebrafish, the timing of habenular neurogenesis is left-right asymmetric and that in the absence of Nodal signalling this asymmetry is lost. Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4. We present evidence that Hedgehog signalling is required for the expression of pax6a, which is in turn necessary for the expression of neurog1 and neurod4. Finally, we demonstrate by pharmacological inhibition that Hedgehog signalling is required continuously during habenular neurogenesis and by cell transplantation experiments that pathway activation is required cell autonomously. Our data sheds light on the mechanism underlying habenular development that may provide insights into how Nodal signalling imposes asymmetry on the timing of habenular neurogenesis. PMID:27387288

  17. Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

    PubMed Central

    Seppala, Maisa; Depew, Michael J.; Martinelli, David C.; Fan, Chen-Ming; Sharpe, Paul T.; Cobourne, Martyn T.

    2007-01-01

    Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest–specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1–/– mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1–/– background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3–q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations. PMID:17525797

  18. An essential role for Grk2 in Hedgehog signalling downstream of Smoothened.

    PubMed

    Zhao, Zhonghua; Lee, Raymond Teck Ho; Pusapati, Ganesh V; Iyu, Audrey; Rohatgi, Rajat; Ingham, Philip W

    2016-05-01

    The G-protein-coupled receptor kinase 2 (adrbk2/GRK2) has been implicated in vertebrate Hedgehog (Hh) signalling based on the effects of its transient knock-down in mammalian cells and zebrafish embryos. Here, we show that the response to Hh signalling is effectively abolished in the absence of Grk2 activity. Zebrafish embryos lacking all Grk2 activity are refractory to both Sonic hedgehog (Shh) and oncogenic Smoothened (Smo) activity, but remain responsive to inhibition of cAMP-dependent protein kinase (PKA) activity. Mutation of the kinase domain abrogates the rescuing activity of grk2 mRNA, suggesting that Grk2 acts in a kinase-dependent manner to regulate the response to Hh. Previous studies have suggested that Grk2 potentiates Smo activity by phosphorylating its C-terminal tail (CTT). In the zebrafish embryo, however, phosphomimetic Smo does not display constitutive activity, whereas phospho-null mutants retain activity, implying phosphorylation is neither sufficient nor necessary for Smo function. Since Grk2 rescuing activity requires the integrity of domains essential for its interaction with GPCRs, we speculate that Grk2 may regulate Hh pathway activity by downregulation of a GPCR. PMID:27113758

  19. Evolution of the Hedgehog Gene Family

    PubMed Central

    Kumar, S.; Balczarek, K. A.; Lai, Z. C.

    1996-01-01

    Effective intercellular communication is an important feature in the development of multicellular organisms. Secreted hedgehog (hh) protein is essential for both long- and short-range cellular signaling required for body pattern formation in animals. In a molecular evolutionary study, we find that the vertebrate homologs of the Drosophila hh gene arose by two gene duplications: the first gave rise to Desert hh, whereas the second produced the Indian and Sonic hh genes. Both duplications occurred before the emergence of vertebrates and probably before the evolution of chordates. The amino-terminal fragment of the hh precursor, crucial in long- and short-range intercellular communication, evolves two to four times slower than the carboxyl-terminal fragment in both Drosophila hh and its vertebrate homologues, suggesting conservation of mechanism of hh action in animals. A majority of amino acid substitutions in the amino- and carboxyl-terminal fragments are conservative, but the carboxyl-terminal domain has undergone extensive insertion-deletion events while maintaining its autocleavage protease activity. Our results point to similarity of evolutionary constraints among sites of Drosophila and vertebrate hh homologs and suggest some future directions for understanding the role of hh genes in the evolution of developmental complexity in animals. PMID:8849902

  20. The dawn of hedgehog inhibitors: Vismodegib.

    PubMed

    Sandhiya, Selvarajan; Melvin, George; Kumar, Srinivasamurthy Suresh; Dkhar, Steven Aibor

    2013-01-01

    Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib. PMID:23662017

  1. Probing extracellular Sonic hedgehog in neurons

    PubMed Central

    Eitan, Erez; Petralia, Ronald S.; Wang, Ya-Xian; Indig, Fred E.; Mattson, Mark P.

    2016-01-01

    ABSTRACT The bioactivity of Sonic hedgehog (Shh) depends on specific lipid modifications; a palmitate at its N-terminus and a cholesterol at its C-terminus. This dual-lipid modification makes Shh molecules lipophilic, which prevents them from diffusing freely in extracellular space. Multiple lines of evidence indicate that Shh proteins are carried by various forms of extracellular vesicles (EVs). It also has been shown, for instance, that in some tissues Shh proteins are transported to neighboring cells directly via filopodia. We have previously reported that Shh proteins are expressed in hippocampal neurons. In this study we show that, in the hippocampus and cerebellum of postnatal day (P)2 rats, Shh is mostly found near or on the membrane surface of small neurites or filopodia. We also examined cultured hippocampal neurons where we observed noticeable and widespread Shh-immunolabeled vesicles located outside neurons. Through immunoelectron microscopy and biochemical analysis, we find Shh-containing EVs with a wide range of sizes. Unlike robust Shh activity in EVs isolated from cells overexpressing an N-terminal Shh fragment construct, we did not detect measurable Shh activity in EVs purified from the medium of cultured hippocampal neurons. These results suggest the complexity of the transcellular Shh signaling mechanisms in neurons. PMID:27387534

  2. dachshund Potentiates Hedgehog Signaling during Drosophila Retinogenesis

    PubMed Central

    Aerts, Stein; Casares, Fernando; Janody, Florence

    2016-01-01

    Proper organ patterning depends on a tight coordination between cell proliferation and differentiation. The patterning of Drosophila retina occurs both very fast and with high precision. This process is driven by the dynamic changes in signaling activity of the conserved Hedgehog (Hh) pathway, which coordinates cell fate determination, cell cycle and tissue morphogenesis. Here we show that during Drosophila retinogenesis, the retinal determination gene dachshund (dac) is not only a target of the Hh signaling pathway, but is also a modulator of its activity. Using developmental genetics techniques, we demonstrate that dac enhances Hh signaling by promoting the accumulation of the Gli transcription factor Cubitus interruptus (Ci) parallel to or downstream of fused. In the absence of dac, all Hh-mediated events associated to the morphogenetic furrow are delayed. One of the consequences is that, posterior to the furrow, dac- cells cannot activate a Roadkill-Cullin3 negative feedback loop that attenuates Hh signaling and which is necessary for retinal cells to continue normal differentiation. Therefore, dac is part of an essential positive feedback loop in the Hh pathway, guaranteeing the speed and the accuracy of Drosophila retinogenesis. PMID:27442438

  3. Probing extracellular Sonic hedgehog in neurons.

    PubMed

    Eitan, Erez; Petralia, Ronald S; Wang, Ya-Xian; Indig, Fred E; Mattson, Mark P; Yao, Pamela J

    2016-01-01

    The bioactivity of Sonic hedgehog (Shh) depends on specific lipid modifications; a palmitate at its N-terminus and a cholesterol at its C-terminus. This dual-lipid modification makes Shh molecules lipophilic, which prevents them from diffusing freely in extracellular space. Multiple lines of evidence indicate that Shh proteins are carried by various forms of extracellular vesicles (EVs). It also has been shown, for instance, that in some tissues Shh proteins are transported to neighboring cells directly via filopodia. We have previously reported that Shh proteins are expressed in hippocampal neurons. In this study we show that, in the hippocampus and cerebellum of postnatal day (P)2 rats, Shh is mostly found near or on the membrane surface of small neurites or filopodia. We also examined cultured hippocampal neurons where we observed noticeable and widespread Shh-immunolabeled vesicles located outside neurons. Through immunoelectron microscopy and biochemical analysis, we find Shh-containing EVs with a wide range of sizes. Unlike robust Shh activity in EVs isolated from cells overexpressing an N-terminal Shh fragment construct, we did not detect measurable Shh activity in EVs purified from the medium of cultured hippocampal neurons. These results suggest the complexity of the transcellular Shh signaling mechanisms in neurons. PMID:27387534

  4. Aberrant Hedgehog Signaling and Clinical Outcome in Osteosarcoma

    PubMed Central

    Lo, Winnie W.; Pinnaduwage, Dushanthi; Gokgoz, Nalan; Wunder, Jay S.; Andrulis, Irene L.

    2014-01-01

    Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration. PMID:24799831

  5. Novel Hedgehog pathway targets against basal cell carcinoma

    SciTech Connect

    Tang, Jean Y. So, P.-L.; Epstein, Ervin H.

    2007-11-01

    The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.

  6. Hedgehog ansatz and its generalization for self-gravitating Skyrmions

    NASA Astrophysics Data System (ADS)

    Canfora, Fabrizio; Maeda, Hideki

    2013-04-01

    The hedgehog ansatz for spherically symmetric spacetimes in self-gravitating nonlinear sigma models and Skyrme models is revisited and its generalization for nonspherically symmetric spacetimes is proposed. The key idea behind our construction is that, even if the matter fields depend on the Killing coordinates in a nontrivial way, the corresponding energy-momentum tensor can still be compatible with spacetime symmetries. Our generalized hedgehog ansatz reduces the Skyrme equations to coupled differential equations for two scalar fields together with several constraint equations between them. Some particular field configurations satisfying those constraints are presented in several physically important spacetimes, including stationary and axisymmetric spacetimes. Incidentally, new exact solutions are obtained under the standard hedgehog ansatz, one of which represents a global monopole inside a black hole with the Skyrme effect.

  7. Piperazic acid derivatives inhibit Gli1 in Hedgehog signaling pathway.

    PubMed

    Khatra, Harleen; Kundu, Jayanta; Khan, Pragya Paramita; Duttagupta, Indranil; Pattanayak, Sankha; Sinha, Surajit

    2016-09-15

    Piperazic acid, a non-proteinogenic amino acid, found in complex secondary metabolites and peptide natural substances, has shown down regulation of Gli1 expression in Hedgehog signaling pathway in cell based assays. Further structure activity relationship study indicated that amide derivatives of piperazic acid are more potent than piperazic acid itself, with little to no toxicity. However, other cellular components involved in the pathway were not affected. To the best of our knowledge, this is the first report on the inhibitory property of piperazic acid in this pathway. Hence, this molecule could serve as a useful tool for studying Hedgehog signaling. PMID:27528433

  8. A different kind of hedgehog pathway: tinea manus due to Trichophyton erinacei transmitted by an African pygmy hedgehog (Atelerix albiventris).

    PubMed

    Weishaupt, Julia; Kolb-Mäurer, Annette; Lempert, Sigrid; Nenoff, Pietro; Uhrlaß, Silke; Hamm, Henning; Goebeler, Matthias

    2014-02-01

    The unusual case of a 29-year-old woman with tinea manus caused by infection due to Trichophyton erinacei is described. The patient presented with marked erosive inflammation of the entire fifth finger of her right hand. Mycological and genomic diagnostics resulted in identification of T. erinacei as the responsible pathogen, which had been transmitted by a domestic African pygmy hedgehog, Atelerix albiventris. Upon prolonged treatment with topical and systemic antifungal agents skin lesions slowly resolved. This case illustrates that the increasingly popular keeping of extraordinary pets such as hedgehogs may bear the risk of infections with uncommon dermatophytes. PMID:23889168

  9. Pyrvinium attenuates Hedgehog signaling downstream of smoothened.

    PubMed

    Li, Bin; Fei, Dennis Liang; Flaveny, Colin A; Dahmane, Nadia; Baubet, Valérie; Wang, Zhiqiang; Bai, Feng; Pei, Xin-Hai; Rodriguez-Blanco, Jezabel; Hang, Brian; Orton, Darren; Han, Lu; Wang, Baolin; Capobianco, Anthony J; Lee, Ethan; Robbins, David J

    2014-09-01

    The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. PMID:24994715

  10. Hedgehog and extramacrochaetae in the Drosophila eye

    PubMed Central

    Spratford, Carrie M; Kumar, Justin P

    2014-01-01

    During the third and final larval instar stage, thousands of pluripotent cells within the Drosophila eye imaginal disc are transformed into a near perfect neurocrystalline lattice of 800 unit eyes called ommatidia. This transformation begins with the initiation of the morphogenetic furrow at the posterior margin of the eye field. The furrow, which marks the leading edge of a wave of differentiation, passes across the epithelium transforming unpatterned and undifferentiated cells into rows of periodically spaced clusters of photoreceptor neurons. As cells enter and exit the furrow they undergo dramatic alterations in cellular architecture and gene expression, many of which are required to propel the furrow forward and for proper cell fate specification. The Decapentaplegic (Dpp) and Hedgehog (Hh) signaling pathways are required for the initiation and progression of the furrow, respectively. Consistent with a role in furrow progression, the loss of Hh pathway activity results in a “furrow stop” phenotype. In contrast, reductions in levels of the helix-loop-helix transcription factor, Extramacrochaetae (Emc), lead to the polar opposite phenotype—the furrow accelerates. Recently, we demonstrated that the furrow stop and furrow acceleration phenotypes are molecularly connected. Emc appears to serve as a brake on the furrow by dampening the activity of the Hh pathway. Loss of Emc leads to an upsurge in Hh pathway activity and a faster moving furrow. The acceleration of the furrow appears to be due to an increase in levels of the full-length isoform of Cubitus Interruptus (Ci155) and Suppressor of Fused [Su(fu)]. Here we will briefly review the mechanisms by which Hh drives and Emc impedes the progression of the furrow across the developing retina. PMID:24406336

  11. Amygdalar connections in the lesser hedgehog tenrec.

    PubMed

    Künzle, Heinz

    2012-01-01

    The present study analyses the overall extrinsic connectivity of the non-olfactory amygdala (Ay) in the lesser hedgehog tenrec. The data were obtained from tracer injections into the lateral and intermediate portions of the Ay as well as several non-amygdalar brain regions. Both the solitary and the parabrachial nucleus receive descending projections from the central nucleus of the Ay, but only the parabrachial nucleus appears to project to the Ay. There is one prominent region in the ventromedial hypothalamus connected reciprocally with the medial and central Ay. Amygdalar afferents clearly arise from the dorsomedial thalamus, the subparafascicular nuclei and the medial geniculate complex (GM). Similar to other subprimate species, the latter projections originate in the dorsal and most caudal geniculate portions and terminate in the dorsolateral Ay. Unusual is the presence of amygdalo-projecting cells in the marginal geniculate zone and their virtual absence in the medial GM. As in other species, amygdalo-striatal projections mainly originate in the basolateral Ay and terminate predominantly in the ventral striatum. Given the poor differentiation of the tenrec's neocortex, there is a remarkable similarity with regard to the amygdalo-cortical connectivity between tenrec and rat, particularly as to prefrontal, limbic and somatosensorimotor areas as well as the rhinal cortex throughout its length. The tenrec's isocortex dorsomedial to the caudal rhinal cortex, on the other hand, may not be connected with the Ay. An absence of such connections is expected for primary auditory and visual fields, but it is unusual for their secondary fields. PMID:21638204

  12. Sonic hedgehog: restricted expression and limb dysmorphologies.

    PubMed

    Hill, Robert E; Heaney, Simon J H; Lettice, Laura A

    2003-01-01

    Sonic hedgehog, SHH, is required for patterning the limb. The array of skeletal elements that compose the hands and feet, and the ordered arrangement of these bones to form the pattern of fingers and toes are dependent on SHH. The mechanism of action of SHH in the limb is not fully understood; however, an aspect that appears to be important is the localized, asymmetric expression of Shh. Shh is expressed in the posterior margin of the limb bud in a region defined as the zone of polarizing activity (ZPA). Analysis of mouse mutants which have polydactyly (extra toes) shows that asymmetric expression of Shh is lost due to the appearance of an ectopic domain of expression in the anterior limb margin. One such polydactylous mouse mutant, sasquatch (Ssq), maps to the corresponding chromosomal region of the human condition pre-axial polydactyly (PPD) and thus represents a model for this condition. The mutation responsible for Ssq is located 1 Mb away from the Shh gene; however, the mutation disrupts a long-range cis-acting regulator of Shh expression. By inference, human pre-axial polydactyly results from a similar disruption of Shh expression. Other human congenital abnormalities also map near the pre-axial polydactyly locus, suggesting a major chromosomal region for limb dysmorphologies. The distinct phenotypes range from loss of all bones of the hands and feet to syndactyly of the soft tissue and fusion of the digits. We discuss the role played by Shh expression in mouse mutant phenotypes and the human limb dysmorphologies. PMID:12587915

  13. Sonic hedgehog: restricted expression and limb dysmorphologies

    PubMed Central

    Hill, Robert E; Heaney, Simon JH; Lettice, Laura A

    2003-01-01

    Sonic hedgehog, SHH, is required for patterning the limb. The array of skeletal elements that compose the hands and feet, and the ordered arrangement of these bones to form the pattern of fingers and toes are dependent on SHH. The mechanism of action of SHH in the limb is not fully understood; however, an aspect that appears to be important is the localized, asymmetric expression of Shh. Shh is expressed in the posterior margin of the limb bud in a region defined as the zone of polarizing activity (ZPA). Analysis of mouse mutants which have polydactyly (extra toes) shows that asymmetric expression of Shh is lost due to the appearance of an ectopic domain of expression in the anterior limb margin. One such polydactylous mouse mutant, sasquatch (Ssq), maps to the corresponding chromosomal region of the human condition pre-axial polydactyly (PPD) and thus represents a model for this condition. The mutation responsible for Ssq is located 1 Mb away from the Shh gene; however, the mutation disrupts a long-range cis-acting regulator of Shh expression. By inference, human pre-axial polydactyly results from a similar disruption of Shh expression. Other human congenital abnormalities also map near the pre-axial polydactyly locus, suggesting a major chromosomal region for limb dysmorphologies. The distinct phenotypes range from loss of all bones of the hands and feet to syndactyly of the soft tissue and fusion of the digits. We discuss the role played by Shh expression in mouse mutant phenotypes and the human limb dysmorphologies. PMID:12587915

  14. Structural insights into human Kif7, a kinesin involved in Hedgehog signalling

    PubMed Central

    Klejnot, Marta; Kozielski, Frank

    2012-01-01

    Kif7, a member of the kinesin 4 superfamily, is implicated in a variety of diseases including Joubert, hydrolethalus and acrocallosal syndromes. It is also involved in primary cilium formation and the Hedgehog signalling pathway and may play a role in cancer. Its activity is crucial for embryonic development. Kif7 and Kif27, a closely related kinesin in the same subfamily, are orthologues of the Drosophila melano­gaster kinesin-like protein Costal-2 (Cos2). In vertebrates, they work together to fulfil the role of the single Cos2 gene in Drosophila. Here, the high-resolution structure of the human Kif7 motor domain is reported and is compared with that of conventional kinesin, the founding member of the kinesin superfamily. These data are a first step towards structural characterization of a kinesin-4 family member and of this interesting molecular motor of medical significance. PMID:22281744

  15. The Hedgehog Signalling Pathway in Cell Migration and Guidance: What We Have Learned from Drosophila melanogaster

    PubMed Central

    Araújo, Sofia J.

    2015-01-01

    Cell migration and guidance are complex processes required for morphogenesis, the formation of tumor metastases, and the progression of human cancer. During migration, guidance molecules induce cell directionality and movement through complex intracellular mechanisms. Expression of these molecules has to be tightly regulated and their signals properly interpreted by the receiving cells so as to ensure correct navigation. This molecular control is fundamental for both normal morphogenesis and human disease. The Hedgehog (Hh) signaling pathway is evolutionarily conserved and known to be crucial for normal cellular growth and differentiation throughout the animal kingdom. The relevance of Hh signaling for human disease is emphasized by its activation in many cancers. Here, I review the current knowledge regarding the involvement of the Hh pathway in cell migration and guidance during Drosophila development and discuss its implications for human cancer origin and progression. PMID:26445062

  16. Stage-specific effects of sonic hedgehog expression in the epidermis.

    PubMed

    Morgan, B A; Orkin, R W; Noramly, S; Perez, A

    1998-09-01

    Sonic hedgehog (Shh) is expressed in the ectoderm of the forming hair follicle and feather bud during normal development. However, inappropriate activation of the Shh signal transduction cascade in human epidermis can cause basal cell carcinoma. Here we show that during normal development of avian skin, Shh is first expressed only after the responsiveness to this protein has been suppressed in most of the surrounding ectodermal cells. Forced expression of Shh in avian skin prior to this time causes a disorganized ectodermal proliferation. However, as skin begins to differentiate, the forced expression of Shh causes feather bud formation. Subsequently, expression of Shh in interfollicular epidermis has little or no morphological effect. Restricted responsiveness to Shh in developing skin has functional consequences for morphogenesis and may have important implications for cutaneous pathologies as well. PMID:9733569

  17. Sonic Hedgehog functions by localizing the region of proliferation in early developing feather buds.

    PubMed

    McKinnell, Iain W; Turmaine, Mark; Patel, Ketan

    2004-08-01

    Feathers are formed following a series of reciprocal signals between the epithelium and the mesenchyme. Initially, the formation of a dense dermis leads to the induction of a placode in the overlying ectoderm. The ectoderm subsequently signals back to the dermis to promote cell division. Sonic Hedgehog (Shh) is a secreted protein expressed in the ectoderm that has previously been implicated in mitogenic and morphogenetic processes throughout feather bud development. We therefore interfered with Shh signaling during early feather bud development and observed a dramatic change in feather form and prominence. Surprisingly, outgrowth did occur and was manifest as irregular, fused, and ectopic feather domains at both molecular and morphological levels. Experiments with Di-I and BrdU indicated that this effect was at least in part caused by the dispersal of previously aggregated proliferating dermal cells. We propose that Shh maintains bud development by localizing the dermal feather progenitors. PMID:15242792

  18. Gene expression analysis uncovers novel Hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells

    PubMed Central

    Zhou, Xiaobo; Qiu, Weiliang; Sathirapongsasuti, J. Fah.; Cho, Michael H.; Mancini, John D.; Lao, Taotao; Thibault, Derek M.; Litonjua, Gus; Bakke, Per S.; Gulsvik, Amund; Lomas, David A.; Beaty, Terri H.; Hersh, Craig P.; Anderson, Christopher; Geigenmuller, Ute; Raby, Benjamin A.; Rennard, Stephen I.; Perrella, Mark A.; Choi, Augustine M.K.; Quackenbush, John; Silverman, Edwin K.

    2013-01-01

    Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis. PMID:23459001

  19. Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology

    PubMed Central

    Singh, Nandini; Dutka, Tara; Devenney, Benjamin M.; Kawasaki, Kazuhiko; Reeves, Roger H.; Richtsmeier, Joan T.

    2015-01-01

    Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS. PMID:25540129

  20. Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology.

    PubMed

    Singh, Nandini; Dutka, Tara; Devenney, Benjamin M; Kawasaki, Kazuhiko; Reeves, Roger H; Richtsmeier, Joan T

    2015-03-01

    Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS. PMID:25540129

  1. Cryptosporidium erinacei n. sp. (Apicomplexa: Cryptosporidiidae) in hedgehogs.

    PubMed

    Kváč, Martin; Hofmannová, Lada; Hlásková, Lenka; Květoňová, Dana; Vítovec, Jiří; McEvoy, John; Sak, Bohumil

    2014-03-17

    The morphological, biological, and molecular characteristics of Cryptosporidium hedgehog genotype are described, and the species name Cryptosporidium erinacei n. sp. is proposed to reflect its specificity for hedgehogs under natural and experimental conditions. Oocysts of C. erinacei are morphologically indistinguishable from Cryptosporidium parvum, measuring 4.5-5.8 μm (mean=4.9 μm) × 4.0-4.8 μm (mean=4.4 μm) with a length to width ratio of 1.13 (1.02-1.35) (n=100). Oocysts of C. erinacei obtained from a naturally infected European hedgehog (Erinaceus europaeus) were infectious for naïve 8-week-old four-toed hedgehogs (Atelerix albiventris); the prepatent period was 4-5 days post infection (DPI) and the patent period was longer than 20 days. C. erinacei was not infectious for 8-week-old SCID and BALB/c mice (Mus musculus), Mongolian gerbils (Meriones unguiculatus), or golden hamsters (Mesocricetus auratus). Phylogenetic analyses based on small subunit rRNA, 60 kDa glycoprotein, actin, Cryptosporidium oocyst wall protein, thrombospondin-related adhesive protein of Cryptosporidium-1, and heat shock protein 70 gene sequences revealed that C. erinacei is genetically distinct from previously described Cryptosporidium species. PMID:24529828

  2. Common Emergencies in Small Rodents, Hedgehogs, and Sugar Gliders.

    PubMed

    McLaughlin, Alicia; Strunk, Anneliese

    2016-05-01

    Small exotic mammal pets such as rats, mice, hamsters, gerbils, degus, hedgehogs, and sugar gliders are becoming more popular. Because these animals are prone to a variety of health problems, and require specialized husbandry care to remain healthy, they may present to emergency hospitals in critical condition. This article provides a basic overview of common emergency presentations of these species. PMID:27131160

  3. Learning to Play: A "Hedgehog Concept" for Physical Education

    ERIC Educational Resources Information Center

    Johnson, Tyler

    2014-01-01

    What is physical education and why does it exist? Despite its relatively long and storied history, consensus about the main purpose of physical education remains minimal. This article explores three questions, developed by Jim Collins in his best-selling book Good to Great, to help organizations identify a hedgehog concept, or primary reason for…

  4. Malignant mast cell tumor in an African hedgehog (Atelerix albiventris).

    PubMed

    Raymond, J T; White, M R; Janovitz, E B

    1997-01-01

    In November 1995, a malignant mast cell tumor (mastocytoma) was diagnosed in an adult African hedgehog (Atelerix albiventris) from a zoological park (West Lafayette, Indiana, USA). The primary mast cell tumor presented as a firm subcutaneous mass along the ventrum of the neck. Metastasis to the right submandibular lymph node occurred. PMID:9027702

  5. Spinal osteosarcoma in a hedgehog with pedal self-mutilation.

    PubMed

    Rhody, Jeffrey L; Schiller, Chris A

    2006-09-01

    An African pygmy hedgehog (Atelerix albiventris) was diagnosed with osteosarcoma of vertebral origin with compression of the spinal cord and spinal nerves. The only presenting sign was a self-mutilation of rear feet. Additional diagnoses included a well-differentiated splenic hemangiosarcoma, an undifferentiated sarcoma of the ascending colon, and membranoproliferative glomerulonephritis. PMID:16931383

  6. Brown adipocyte differentiation is regulated by hedgehog signaling during development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During development, brown fat tissue arises from mesenchymal precursor cells under the control of signaling networks that are not yet well understood. The Hedgehog (Hh) signaling pathway is one of the major signaling pathways that regulate mesenchymal cell fate. However, whether the Hh pathway contr...

  7. Dissecting the Role of Hedgehog Pathway in Murine Gonadal Development

    ERIC Educational Resources Information Center

    Barsoum, Ivraym Boshra

    2009-01-01

    Hedgehog (Hh) signaling pathway is one of the universal pathways involved in animal development. This dissertation focuses on Hh role in the mammalian gonad development, which is a central part of mammalian sexual development and identity. The central dogma of mammalian sex development is that genetic sex determines the gonadal sex, which in turn…

  8. Ectoparasitic infestations of the European hedgehog (Erinaceus europaeus) in Urmia city, Iran: First report

    PubMed Central

    Gorgani-Firouzjaee, Tahmineh; Pour-Reza, Behzad; Naem, Soraya; Tavassoli, Mousa

    2013-01-01

    Hedgehogs are small, nocturnal mammals that become popular in the world and have significant role in transmission of zoonotic agents. Some of the agents are transmitted by ticks and fleas such as rickettsial agents. For these reason, a survey on ectoparasites in European hedgehog (Erinaceus europaeus) carried out between April 2006 and December 2007 from different parts of Urmia city, west Azerbaijan, Iran. After being euthanized external surface of body of animals was precisely considered for ectoparasites, and arthropods were collected and stored in 70% ethanol solution. Out of 34 hedgehogs 23 hedgehogs (67.70%) were infested with ticks (Rhipicephalus turanicus). Fleas of the species Archaeopsylla erinacei were found on 19 hedgehogs of 34 hedgehogs (55.90%). There was no significant differences between sex of ticks (p > 0.05) but found in fleas (p < 0.05). The prevalence of infestation in sexes and the body condition of hedgehogs (small, medium and large) with ticks and fleas did not show significant differences (p > 0.05). Highest occurrence of infestation in both tick and flea was in June. Among three seasons of hedgehog collection significant differences was observed (p < 0.05). The result of our survey revealed that infestation rate in hedgehog was high. According to zoonotic importance of this ectoparasite and ability to transmission of some pathogens, more studies are needed to investigate hedgehog parasites in different parts of Iran. PMID:25653796

  9. The hedgehog system in ovarian follicles of cattle selected for twin ovulations and births: evidence of a link between the IGF and hedgehog systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hedgehog signaling is involved in regulation of ovarian function in Drosophila but its role in regulating mammalian ovarian folliculogenesis is less clear. Therefore, gene expression of Indian hedgehog (IHH) and its type 1 receptor, patched 1 (PTCH1), were quantified in bovine granulosa (GC) or the...

  10. The hedgehog system in ovarian follicles of cattle selected for twin ovulations and births: evidence of a link between the IGF and hedgehog systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The hedgehog system is involved in the regulation of ovarian function in drosophila, but its role in regulating ovarian follicular function in mammals is unclear. Therefore, gene expression of Indian hedgehog ligand (Ihh), its type 1 receptor (patched 1; Patch1), and IGF type 2 receptor (IGF2R) were...

  11. Hedgehog excitations in double-exchange magnetism: Energetics and electronic structure

    NASA Astrophysics Data System (ADS)

    Pekker, David; Goldbart, Paul; Salamon, Myron; Abanov, Alexander

    2004-03-01

    Topological hedgehog excitations of the magnetic state are believed to play an important role in the three-dimensional ferromagnet-to-paramagnet phase transition. This is true not only in Heisenberg magnets but also in double-exchange magnets, for which the transition is accompanied by a metal-insulator transition. The energetics and electronic structure of hedgehog excitations in double-exchange systems are investigated using a model in which the electrons move through a lattice of classical spins, to which they are coupled via Hund's Rule interactions. The core energy of hedgehog excitations is determined, as is the extent to which charge is expelled from the hedgehog cores. In settings involving pairs of hedgehogs, the manner in which the electronic energetics determines the magnetic structure is explored variationally, especially in the region between the hedgehogs.

  12. Axon Targeting of Olfactory Receptor Neurons is Patterned by Coupled Hedgehog Signaling at Two Distinct Steps

    PubMed Central

    Chou, Ya-Hui; Zheng, Xiaoyan; Beachy, Philip A.; Luo, Liqun

    2010-01-01

    SUMMARY We present evidence for a novel, coupled two-step action of Hedgehog signaling in patterning axon targeting of Drosophila olfactory receptor neurons (ORNs). In the first step, differential Hedgehog pathway activity in peripheral sensory organ precursors creates ORN populations with different levels of the Patched receptor. Different Patched levels in ORNs then determine axonal responsiveness to target-derived Hedgehog in the brain: only ORN axons that do not express high levels of Patched are responsive to and require a second-step of Hedgehog signaling for target selection. Hedgehog signaling in the imaginal sensory organ precursors thus confers differential ORN responsiveness to Hedgehog-mediated axon targeting in the brain. This mechanism contributes to the spatial coordination of ORN cell bodies in the periphery and their glomerular targets in the brain. Such coupled two-step signaling may be more generally used to coordinate other spatially and temporally segregated developmental events. PMID:20850015

  13. Requirements for Hedgehog, a Segmental Polarity Gene, in Patterning Larval and Adult Cuticle of Drosophila

    PubMed Central

    Mohler, J.

    1988-01-01

    Mutations of the hedgehog gene are generally embryonic lethal, resulting in a lawn of denticles on the ventral surface. In strong alleles, no segmentation is obvious and the anteroposterior polarity of ventral denticles is lost. Temperature shift analysis of a temperature-sensitive allele indicates an embryonic activity period for hedgehog between 2.5 and 6 hr of embryonic development (at 25°) and a larval/pupal period from 4 to 7 days of development (at 25°). Mosaic analysis of hedgehog mutations in the adult cuticle indicates a series of defined defects associated with the failure of appropriate hedgehog expression. In particular, defects in the distal portions of the legs and antenna occur in association with homozygous hedgehog clones in the posterior compartment of those structures. Because the defects are associated with homozygous clones, but are not co-extensive, a type of ``domineering'' nonautonomy is proposed for the activity of the hedgehog gene. PMID:3147217

  14. Cloning and bioinformatical analysis of the N-terminus of the sonic hedgehog gene.

    PubMed

    Zhang, Yi; Zhao, Shu; Dong, Weiren; He, Suifen; Wang, Haihong; Zhang, Lihua; Tang, Yinjuan; Guo, Jiasong; Guo, Suiqun

    2013-01-25

    The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation, migration and neuronal axon guidance. The N-terminal fragment of sonic hedgehog is the key functional element in this process. Therefore, this study aimed to clone and analyze the N-terminal fragment of the sonic hedgehog gene. Total RNA was extracted from the notochord of a Sprague-Dawley rat at embryonic day 9 and the N-terminal fragment of sonic hedgehog was amplified by nested reverse transcription-PCR. The N-terminal fragment of the sonic hedgehog gene was successfully cloned. The secondary and tertiary structures of the N-terminal fragment of the sonic hedgehog protein were predicted using Jpred and Phyre online. PMID:25206596

  15. A directed mutagenesis screen in Drosophila melanogaster reveals new mutants that influence hedgehog signaling.

    PubMed Central

    Haines, N; van den Heuvel, M

    2000-01-01

    The Hedgehog signaling pathway has been recognized as essential for patterning processes in development of metazoan animal species. The signaling pathway is, however, not entirely understood. To start to address this problem, we set out to isolate new mutations that influence Hedgehog signaling. We performed a mutagenesis screen for mutations that dominantly suppress Hedgehog overexpression phenotypes in the Drosophila melanogaster wing. We isolated four mutations that influence Hedgehog signaling. These were analyzed in the amenable wing system using genetic and molecular techniques. One of these four mutations affects the stability of the Hedgehog expression domain boundary, also known as the organizer in the developing wing. Another mutation affects a possible Hedgehog autoregulation mechanism, which stabilizes the same boundary. PMID:11102373

  16. Unraveling the therapeutic potential of the LncRNA-dependent noncanonical Hedgehog pathway in cancer

    PubMed Central

    Xing, Zhen; Lin, Chunru; Yang, Liuqing

    2015-01-01

    Acquired resistance to Hedgehog pathway inhibitors has been reported in the clinical setting and upregulation of noncanonical Hedgehog signaling is one of the major underlying mechanisms behind this resistance. As demonstrated in our recent study, greater clinical efficacy might be achieved by focusing on downstream targets of the chemokine-activated noncanonical Hedgehog signaling pathway such as BCAR4 and phospho-GLI2 (Ser149). PMID:27308519

  17. The Mode of Hedgehog Binding to Ihog Homologues is Not Conserved Across Different Phyla

    SciTech Connect

    McLellan, J.; Zheng, X; Hauk, G; Ghirlando, R; Beachy, P; Leahy, D

    2008-01-01

    Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses1, 2. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer3, 4, 5, 6, 7. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle8, 9, 10. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner12, 13. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO12, 14. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.

  18. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

    SciTech Connect

    Hirose, Yoshikazu; Itoh, Tohru; Miyajima, Atsushi

    2009-09-10

    Hedgehog (Hh) signaling plays crucial roles in development and homeostasis of various organs. In the adult liver, it regulates proliferation and/or viability of several types of cells, particularly under injured conditions, and is also implicated in stem/progenitor cell maintenance. However, the role of this signaling pathway during the normal developmental process of the liver remains elusive. Although Sonic hedgehog (Shh) is expressed in the ventral foregut endoderm from which the liver derives, the expression disappears at the onset of the liver bud formation, and its possible recurrence at the later stages has not been investigated. Here we analyzed the activation and functional relevance of Hh signaling during the mouse fetal liver development. At E11.5, Shh and an activation marker gene for Hh signaling, Gli1, were expressed in Dlk{sup +} hepatoblasts, the fetal liver progenitor cells, and the expression was rapidly decreased thereafter as the development proceeded. In the culture of Dlk{sup +} hepatoblasts isolated from the E11.5 liver, activation of Hh signaling stimulated their proliferation and this effect was cancelled by a chemical Hh signaling inhibitor, cyclopamine. In contrast, hepatocyte differentiation of Dlk{sup +} hepatoblasts in vitro as manifested by the marker gene expression and acquisition of ammonia clearance activity was significantly inhibited by forced activation of Hh signaling. Taken together, these results demonstrate the temporally restricted manner of Hh signal activation and its role in promoting the hepatoblast proliferation, and further suggest that the pathway needs to be shut off for the subsequent hepatic differentiation of hepatoblasts to proceed normally.

  19. Two Lamprey Hedgehog Genes Share Non-Coding Regulatory Sequences and Expression Patterns with Gnathostome Hedgehogs

    PubMed Central

    Ekker, Marc; Hadzhiev, Yavor; Müller, Ferenc; Casane, Didier; Magdelenat, Ghislaine; Rétaux, Sylvie

    2010-01-01

    Hedgehog (Hh) genes play major roles in animal development and studies of their evolution, expression and function point to major differences among chordates. Here we focused on Hh genes in lampreys in order to characterize the evolution of Hh signalling at the emergence of vertebrates. Screening of a cosmid library of the river lamprey Lampetra fluviatilis and searching the preliminary genome assembly of the sea lamprey Petromyzon marinus indicate that lampreys have two Hh genes, named Hha and Hhb. Phylogenetic analyses suggest that Hha and Hhb are lamprey-specific paralogs closely related to Sonic/Indian Hh genes. Expression analysis indicates that Hha and Hhb are expressed in a Sonic Hh-like pattern. The two transcripts are expressed in largely overlapping but not identical domains in the lamprey embryonic brain, including a newly-described expression domain in the nasohypophyseal placode. Global alignments of genomic sequences and local alignment with known gnathostome regulatory motifs show that lamprey Hhs share conserved non-coding elements (CNE) with gnathostome Hhs albeit with sequences that have significantly diverged and dispersed. Functional assays using zebrafish embryos demonstrate gnathostome-like midline enhancer activity for CNEs contained in intron2. We conclude that lamprey Hh genes are gnathostome Shh-like in terms of expression and regulation. In addition, they show some lamprey-specific features, including duplication and structural (but not functional) changes in the intronic/regulatory sequences. PMID:20967201

  20. Notochord repression of endodermal Sonic hedgehog permits pancreas development

    PubMed Central

    Hebrok, Matthias; Kim, Seung K.; Melton, Douglas A.

    1998-01-01

    Notochord signals to the endoderm are required for development of the chick dorsal pancreas. Sonic hedgehog (SHH) is normally absent from pancreatic endoderm, and we provide evidence that notochord, in contrast to its effects on adjacent neuroectoderm where SHH expression is induced, represses SHH expression in adjacent nascent pancreatic endoderm. We identify activin-βB and FGF2 as notochord factors that can repress endodermal SHH and thereby permit expression of pancreas genes including Pdx1 and insulin. Endoderm treatment with antibodies that block hedgehog activity also results in pancreatic gene expression. Prevention of SHH expression in prepancreatic dorsal endoderm by intercellular signals, like activin and FGF, may be critical for permitting early steps of chick pancreatic development. PMID:9620856

  1. Equine cryptosporidial infection associated with Cryptosporidium hedgehog genotype in Algeria.

    PubMed

    Laatamna, Abd Elkarim; Wagnerová, Pavla; Sak, Bohumil; Květoňová, Dana; Aissi, Miriem; Rost, Michael; Kváč, Martin

    2013-10-18

    Faecal samples from two horse farms in Algeria keeping Arabian, Thoroughbred, and Barb horses were examined for the presence of Cryptosporidium in 2010-2011. A total of 138 faecal samples (16 from a farm keeping 50 animals and 122 from a farm with 267 horses) were screened for Cryptosporidium spp. infection using molecular tools. DNA was extracted from all samples. Nested PCR was performed to amplify fragments of the SSU rDNA and gp60 genes to determine the presence of Cryptosporidium species and genotypes. Sequence analyses of SSU and gp60 genes revealed four animals positive for the presence of subtype XIIIa A22R9 of the Cryptosporidium hedgehog genotype. The infections were not associated with diarrhoea. This study reports, for the first time, the occurrence of Cryptosporidium in Algeria and the first occurrence of the hedgehog genotype in horses. These findings support the potential role of infected horses in sylvatic-domestic transmission of Cryptosporidium. PMID:23731858

  2. WHEN AND WHY DO HEDGEHOGS AND FOXES DIFFER?

    PubMed Central

    Keil, Frank C.

    2011-01-01

    Philip E. Tetlock’s finding that “hedgehog” experts (those with one big theory) are worse predictors than “foxes” (those with multiple, less comprehensive theories) offers fertile ground for future research. Are experts as likely to exhibit hedgehog- or fox-like tendencies in areas that call for explanatory, diagnostic, and skill-based expertise—as they did when Tetlock called on experts to make predictions? Do particular domains of expertise curtail or encourage different styles of expertise? Can we trace these different styles to childhood? Finally, can we nudge hedgehogs to be more like foxes? Current research can only grope at the answers to these questions, but they are essential to gauging the health of expert political judgment. PMID:21698070

  3. Recurrent sebaceous carcinoma in an African hedgehog (Atelerix albiventris).

    PubMed

    Kim, Hyung-Jin; Kim, Yong-Baek; Park, Jun-Won; Oh, Won-Seok; Kim, Eun-Ok; Lim, Byoung-Yong; Kim, Dae-Yong

    2010-07-01

    A 1.5-year-old intact male African hedgehog (Atelerix albiventris) was presented with a firm, non-movable subcutaneous mass on ventral chest area. Microscopically, the tumor was un-encapsulated, invasive up to the muscle layer, and composed of highly pleomorphic polygonal cells arranged in variably-sized lobules. The neoplastic cells had abundant cytoplasm with vacuolation and a large pleomorphic nucleus with prominent nucleoli. Mitotic figures were frequently observed with atypical mitoses. Immunohistochemically, the neoplastic cells were strongly positive for cytokeratin, but negative for vimentin. Based on these findings, a diagnosis of sebaceous carcinoma was made. Three months after the surgery, a recurrent mass was found at the surgical site. On necropsy, the mass has penetrated the underlying intercostal musculature, without metastasis to distant organs. This is the first report of a sebaceous carcinoma in an African hedgehog. PMID:20215722

  4. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.

    PubMed

    Wu, Xu; Walker, John; Zhang, Jie; Ding, Sheng; Schultz, Peter G

    2004-09-01

    Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease. PMID:15380183

  5. Regulation of Hedgehog Signalling Inside and Outside the Cell

    PubMed Central

    Ramsbottom, Simon A.; Pownall, Mary E.

    2016-01-01

    The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction. PMID:27547735

  6. Hedgehog signalling in gut development, physiology and cancer

    PubMed Central

    Merchant, Juanita L

    2012-01-01

    The Hedgehog pathway is one of the most common signal transduction pathways used by mammalian cells. Most studies have focused on its role during development, primarily of the nervous system, skin, bone and pancreas. Due to the activation of this pathway during proliferation and neoplastic transformation, more recent studies have examined its role in adult tissues. Significant levels of sonic hedgehog are expressed in the gastric mucosa, which has served to direct analysis of its role during organogenesis, gastric acid secretion and neoplastic transformation. Therefore the goal of this review is to apply current knowledge of this pathway to further our understanding of gastrointestinal physiology and neoplasia, using the stomach as a prototype. PMID:22144577

  7. Point Defects in Nematic Gels: The Case for Hedgehogs

    NASA Astrophysics Data System (ADS)

    Dolbow, John; Fried, Eliot; Shen, Amy Q.

    2005-07-01

    We address the question of whether a nematic gel is capable of sustaining a radially-symmetric point defect (or, hedgehog). We consider the special case of a gel cross-linked in a state where the mesogens are randomly aligned, and study the behavior of a spherical specimen with boundary subjected to a uniform radial displacement. For simplicity, we allow only for distortions in which the chain conformation is uniaxial with constant chain anisotropy and, thus, is determined by a unit director field. Further, we use the particular free-energy density function arising from the neo-classical molecular-statistical description of nematic gels. We find that the potential energy of the specimen is a nonconvex function of the boundary displacement and chain anisotropy. In particular, whenever the displacement of the specimen boundary involves a relative radial expansion in excess of 0.35, which is reasonably mild for gel-like substances, the theory predicts an energetic preference for states involving a hedgehog at the center of the specimen. Under such conditions, states in which the chain anisotropy is either oblate or prolate have total free-energy less than that of an isotropic comparison state. However, the oblate alternative always provides the global minimum of the total free-energy. The Cauchy stress associated with an energetically-preferred hedgehog is found to vanish in a relatively large region surrounding the hedgehog. The radial component of Cauchy stress is tensile and exhibits a non-monotonic character with a peak value an order of magnitude less than what would be observed in a specimen consisting of a comparable isotropic gel. The hoop component of Cauchy stress is also non-monotonic, but, as opposed to being purely tensile, goes between a tensile maximum to a compressive minimum at the specimen boundary.

  8. Hedgehogs in higher dimensional gravity with curvature self-interactions

    NASA Astrophysics Data System (ADS)

    Giovannini, Massimo

    2001-04-01

    Static solutions of the higher dimensional Einstein-Hilbert gravity supplemented by quadratic curvature self-interactions are discussed in the presence of hedgehog configurations along the transverse dimensions. The quadratic part of the action is parametrized in terms of the (ghost-free) Euler-Gauss-Bonnet curvature invariant. Spherically symmetric profiles of the transverse metric admit exponentially decaying warp factors both for positive and negative bulk cosmological constants.

  9. Targeting the hedgehog pathway for gallbladder cancer therapy?

    PubMed

    Mittal, Balraj; Yadav, Saurabh

    2016-02-01

    Gallbladder carcinoma is a fatal malignancy of hepatobiliary tract that is generally diagnosed at advanced stages of cancer because of its asymptomatic nature. Advanced GBC tumors are unresectable with poor prognosis. Improvement in GBC patient care requires better understanding of the biological signaling pathways and application of newly discovered drugs for cancer therapy. Herein, we discuss the possibilities and challenges in targeting the hedgehog pathway in gallbladder cancer therapy based on recent developments in the area. PMID:26932426

  10. A review of hedgehog signaling in cranial bone development.

    PubMed

    Pan, Angel; Chang, Le; Nguyen, Alan; James, Aaron W

    2013-01-01

    During craniofacial development, the Hedgehog (HH) signaling pathway is essential for mesodermal tissue patterning and differentiation. The HH family consists of three protein ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH), of which two are expressed in the craniofacial complex (IHH and SHH). Dysregulations in HH signaling are well documented to result in a wide range of craniofacial abnormalities, including holoprosencephaly (HPE), hypotelorism, and cleft lip/palate. Furthermore, mutations in HH effectors, co-receptors, and ciliary proteins result in skeletal and craniofacial deformities. Cranial suture morphogenesis is a delicate developmental process that requires control of cell commitment, proliferation and differentiation. This review focuses on both what is known and what remains unknown regarding HH signaling in cranial suture morphogenesis and intramembranous ossification. As demonstrated from murine studies, expression of both SHH and IHH is critical to the formation and fusion of the cranial sutures and calvarial ossification. SHH expression has been observed in the cranial suture mesenchyme and its precise function is not fully defined, although some postulate SHH to delay cranial suture fusion. IHH expression is mainly found on the osteogenic fronts of the calvarial bones, and functions to induce cell proliferation and differentiation. Unfortunately, neonatal lethality of IHH deficient mice precludes a detailed examination of their postnatal calvarial phenotype. In summary, a number of basic questions are yet to be answered regarding domains of expression, developmental role, and functional overlap of HH morphogens in the calvaria. Nevertheless, SHH and IHH ligands are integral to cranial suture development and regulation of calvarial ossification. When HH signaling goes awry, the resultant suite of morphologic abnormalities highlights the important roles of HH signaling in cranial development. PMID:23565096

  11. A Hedgehog Survival Pathway in ‘Undead’ Lipotoxic Hepatocytes

    PubMed Central

    Kakisaka, Keisuke; Cazanave, Sophie C.; Werneburg, Nathan W.; Razumilava, Nataliya; Mertens, Joachim C.; Bronk, Steve F.; Gores, Gregory J.

    2012-01-01

    Background & Aims Ballooned hepatocytes in nonalcoholic steatohepatitis (NASH) generate sonic hedgehog (SHH). This observation is consistent with a cellular phenotype in which the cell death program has been initiated but cannot be executed. Our aim was to determine if ballooned hepatocytes have potentially disabled the cell death execution machinery, and if so, can their functional biology be modeled in vitro. Methods Immunohistochemistry was performed on human NASH specimens. In vitro studies were performed using Huh-7 cells with shRNA targeted knockdown of caspase 9 (shC9 cells) or primary hepatocytes from caspase 3−/− mice. Results Ballooned hepatocytes in NASH display diminished expression of the caspase 9. This phenotype was modeled using shC9 cells; these cells were resistant to lipoapoptosis by palmitate (PA) or lysophosphatidylcholine (LPC) despite lipid droplet formation. During lipid loading by either PA or LPC, shC9 cells activate JNK which via AP-1 induces SHH expression. An autocrine hedgehog survival signaling pathway was further delineated in both shC9 and caspase 3−/− cells during lipotoxic stress. Conclusion Ballooned hepatocytes in NASH downregulate caspase 9, a pivotal caspase executing the mitochondrial pathway of apoptosis. Hepatocytes engineered to reduce caspase 9 expression are resistant to lipoapoptosis, in part, due to a hedgehog autocrine survival signaling pathway. PMID:22641094

  12. Primary Cilia Integrate Hedgehog and Wnt Signaling during Tooth Development

    PubMed Central

    Liu, B.; Chen, S.; Cheng, D.; Jing, W.; Helms, J.A.

    2014-01-01

    Many ciliopathies have clinical features that include tooth malformations but how these defects come about is not clear. Here we show that genetic deletion of the motor protein Kif3a in dental mesenchyme results in an arrest in odontogenesis. Incisors are completely missing, and molars are enlarged in Wnt1Cre+Kif3afl/fl embryos. Although amelogenesis and dentinogenesis initiate in the molar tooth bud, both processes terminate prematurely. We demonstrate that loss of Kif3a in dental mesenchyme results in loss of Hedgehog signaling and gain of Wnt signaling in this same tissue. The defective dental mesenchyme then aberrantly signals to the dental epithelia, which prompts an up-regulation in the Hedgehog and Wnt responses in the epithelia and leads to multiple attempts at invagination and an expanded enamel organ. Thus, the primary cilium integrates Hedgehog and Wnt signaling between dental epithelia and mesenchyme, and this cilia-dependent integration is required for proper tooth development. PMID:24659776

  13. Topological Analysis of Hedgehog Acyltransferase, a Multipalmitoylated Transmembrane Protein*

    PubMed Central

    Konitsiotis, Antonio D.; Jovanović, Biljana; Ciepla, Paulina; Spitaler, Martin; Lanyon-Hogg, Thomas; Tate, Edward W.; Magee, Anthony I.

    2015-01-01

    Hedgehog proteins are secreted morphogens that play critical roles in development and disease. During maturation of the proteins through the secretory pathway, they are modified by the addition of N-terminal palmitic acid and C-terminal cholesterol moieties, both of which are critical for their correct function and localization. Hedgehog acyltransferase (HHAT) is the enzyme in the endoplasmic reticulum that palmitoylates Hedgehog proteins, is a member of a small subfamily of membrane-bound O-acyltransferase proteins that acylate secreted proteins, and is an important drug target in cancer. However, little is known about HHAT structure and mode of function. We show that HHAT is comprised of ten transmembrane domains and two reentrant loops with the critical His and Asp residues on opposite sides of the endoplasmic reticulum membrane. We further show that HHAT is palmitoylated on multiple cytosolic cysteines that maintain protein structure within the membrane. Finally, we provide evidence that mutation of the conserved His residue in the hypothesized catalytic domain results in a complete loss of HHAT palmitoylation, providing novel insights into how the protein may function in vivo. PMID:25505265

  14. Topological analysis of Hedgehog acyltransferase, a multipalmitoylated transmembrane protein.

    PubMed

    Konitsiotis, Antonio D; Jovanović, Biljana; Ciepla, Paulina; Spitaler, Martin; Lanyon-Hogg, Thomas; Tate, Edward W; Magee, Anthony I

    2015-02-01

    Hedgehog proteins are secreted morphogens that play critical roles in development and disease. During maturation of the proteins through the secretory pathway, they are modified by the addition of N-terminal palmitic acid and C-terminal cholesterol moieties, both of which are critical for their correct function and localization. Hedgehog acyltransferase (HHAT) is the enzyme in the endoplasmic reticulum that palmitoylates Hedgehog proteins, is a member of a small subfamily of membrane-bound O-acyltransferase proteins that acylate secreted proteins, and is an important drug target in cancer. However, little is known about HHAT structure and mode of function. We show that HHAT is comprised of ten transmembrane domains and two reentrant loops with the critical His and Asp residues on opposite sides of the endoplasmic reticulum membrane. We further show that HHAT is palmitoylated on multiple cytosolic cysteines that maintain protein structure within the membrane. Finally, we provide evidence that mutation of the conserved His residue in the hypothesized catalytic domain results in a complete loss of HHAT palmitoylation, providing novel insights into how the protein may function in vivo. PMID:25505265

  15. Detection of Canonical Hedgehog Signaling in Breast Cancer by 131-Iodine-Labeled Derivatives of the Sonic Hedgehog Protein

    PubMed Central

    Sims-Mourtada, Jennifer; Yang, David; Tworowska, Izabela; Larson, Richard; Smith, Daniel; Tsao, Ning; Opdenaker, Lynn; Mourtada, Firas; Woodward, Wendy

    2012-01-01

    Activation of hedgehog (HH) pathway signaling is observed in many tumors. Due to a feedback loop, the HH receptor Patched (PTCH-1) is overexpressed in tumors with activated HH signaling. Therefore, we sought to radiolabel the PTCH-1 ligand sonic (SHH) for detection of cancer cells with canonical HH activity. Receptor binding of 131I-SHH was increased in cell lines with high HH pathway activation. Our findings also show that PTCH-1 receptor expression is decreased upon treatment with HH signaling inhibitors, and receptor binding of 131I-SHH is significantly decreased following treatment with cyclopamine. In vivo imaging and biodistribution studies revealed significant accumulation of 131I-SHH within tumor tissue as compared to normal organs. Tumor-to-muscle ratios were approximately 8 : 1 at 5 hours, while tumor to blood and tumor to bone were 2 : 1 and 5 : 1, respectively. Significant uptake was also observed in liver and gastrointestinal tissue. These studies show that 131I-SHH is capable of in vivo detection of breast tumors with high HH signaling. We further demonstrate that the hedgehog receptor PTCH-1 is downregulated upon treatment with hedgehog inhibitors. Our data suggests that radiolabeled SHH derivatives may provide a method to determine response to SHH-targeted therapies. PMID:22811598

  16. Cadherin Cad99C is regulated by Hedgehog signaling in Drosophila.

    PubMed

    Schlichting, Karin; Demontis, Fabio; Dahmann, Christian

    2005-03-01

    The subdivision of the Drosophila wing imaginal disc into anterior and posterior compartments requires a transcriptional response to Hedgehog signaling. However, the genes regulated by Hedgehog signal transduction that mediate the segregation of anterior and posterior cells have not been identified. Here, we molecularly characterize the previously predicted gene cad99C and show that it is regulated by Hedgehog signaling. Cad99C encodes a transmembrane protein with a molecular weight of approximately 184 kDa that contains 11 cadherin repeats in its extracellular domain and a conserved type I PDZ-binding site at its C-terminus. The levels of cad99C RNA and protein are low throughout the wing imaginal disc. However, in the pouch region, these levels are elevated in a strip of anterior cells along the A/P boundary where the Hedgehog signal is transduced. Ectopic expression of Hedgehog, or the Hedgehog-regulated transcription factor Cubitus interruptus, induces high-level expression of Cad99C. Conversely, blocking Hedgehog signal transduction by either inactivating Smoothened or Cubitus interruptus reduces high-level Cad99C expression. Finally, by analyzing mutant clones of cells, we show that Cad99C is not essential for cell segregation at the A/P boundary. We conclude that cad99C is a novel Hedgehog-regulated gene encoding a member of the cadherin superfamily in Drosophila. PMID:15708564

  17. Surgical removal of a mammary adenocarcinoma and a granulosa cell tumor in an African pygmy hedgehog

    PubMed Central

    Wellehan, James F.X.; Southorn, Erin; Smith, Dale A.; Taylor, Michael

    2003-01-01

    A 3-year-old, female African pygmy hedgehog (Atelerix albiventris) was referred with a history of hematuria. Hyperglycemia and glucosuria were found at presentation. Mammary adenocarcinoma and a granulosa cell tumor were found and removed surgically. Glucosuria and hematuria resolved, and the hedgehog has done well for 10 mo postoperatively. PMID:12677695

  18. Surgical removal of a mammary adenocarcinoma and a granulosa cell tumor in an African pygmy hedgehog.

    PubMed

    Wellehan, James F X; Southorn, Erin; Smith, Dale A; Taylor, W Michael

    2003-03-01

    A 3-year-old, female African pygmy hedgehog (Atelerix albiventris) was referred with a history of hematuria. Hyperglycemia and glucosuria were found at presentation. Mammary adenocarcinoma and a granulosa cell tumor were found and removed surgically. Glucosuria and hematuria resolved, and the hedgehog has done well for 10 mo postoperatively. PMID:12677695

  19. Hedgehogs in Wilson loops and phase transition in SU(2) Yang Mills theory

    NASA Astrophysics Data System (ADS)

    Belavin, V. A.; Chernodub, M. N.; Kozlov, I. E.

    2006-08-01

    We suggest that the gauge-invariant hedgehog-like structures in the Wilson loops are physically interesting degrees of freedom in the Yang-Mills theory. The trajectories of these "hedgehog loops" are closed curves corresponding to center-valued (untraced) Wilson loops and are characterized by the center charge and winding number. We show numerically in the SU(2) Yang-Mills theory that the density of hedgehog structures in the thermal Wilson-Polyakov line is very sensitive to the finite-temperature phase transition. The (additively normalized) hedgehog line density behaves like an order parameter: The density is almost independent of the temperature in the confinement phase and changes substantially as the system enters the deconfinement phase. In particular, our results suggest that the (static) hedgehog lines may be relevant degrees of freedom around the deconfinement transition and thus affect evolution of the quark-gluon plasma in high-energy heavy-ion collisions.

  20. Infection with Crenosoma striatum lungworm in Long-eared Hedgehog (Hemiechinus auritus) in Kerman province southeast of Iran.

    PubMed

    Mirzaei, Mohammad

    2014-12-01

    Hedgehogs are distributed in different areas of Iran. Unfortunately, clinical and parasitological studies on parasites of hedgehogs are very few. Crenosoma striatum is a common lungworm in hedgehogs. C. striatum infection can cause weight loss, dry cough, bronchitis with ulcerous reactions based on secondary bacterial infections, pulmonary damage, thickening of the tracheal wall, and pulmonary emphysema up to cardiovascular failure. In this survey, six dead hedgehogs (Hemiechinus auritus) were investigated for lungworm infection. All the six hedgehogs had C. striatum infection in their lungs. PMID:25732884

  1. Reproductive characteristics of the african pygmy hedgehog, atelerix albiventris.

    PubMed

    Bedford, J M; Mock, O B; Nagdas, S K; Winfrey, V P; Olson, G E

    2000-09-01

    To obtain further perspective on reproduction and particularly gamete function among so-called primitive mammals presently grouped in the Order Insectivora, we have examined the African hedgehog, Atelerix albiventris, in light of unusual features reported in shrews and moles. Atelerix proves to share many but not all of the characteristics seen in these other insectivores. The penis of Atelerix has a 'snail-like' form, but lacks the surface spines common in insectivores and a number of other mammals. Hedgehog spermatozoa display an eccentric insertion of the tail on the sperm head, and they manifest the barbs on the perforatorium that, in shrews, probably effect the initial binding of the sperm head to the zona pellucida. As a possible correlate, the structural matrix of the hedgehog acrosome comprises only two main components, as judged by immunoblotting, rather than the complex of peptides seen in the matrix of some higher mammals. The Fallopian tube of Atelerix is relatively simple; it displays only minor differences in width and in the arborized epithelium between the isthmus and ampulla, and shows no evidence of the unusual sperm crypts that characterize the isthmus or ampulla, depending on the species, in shrews and moles. In common with other insectivores, Atelerix appears to be an induced ovulator, as judged by the ovulation of some 6-8 eggs by about 23 h after injection of hCG. The dense cumulus oophorus appeared to have little matrix, in keeping with the modest dimensions of the tubal ampulla and, while it was not quite as discrete as that of soricids, it did show the same insensitivity to 0.5% (w/v) ovine or bovine hyaluronidase. PMID:11006156

  2. Hedgehog signaling and radiation induced liver injury: a delicate balance

    PubMed Central

    Kabarriti, Rafi

    2016-01-01

    Radiation-induced liver disease (RILD) is a major limitation of radiation therapy (RT) for the treatment of liver cancer. Emerging data indicate that hedgehog (Hh) signaling plays a central role in liver fibrosis and regeneration after liver injury. Here, we review the potential role of Hh signaling in RILD and propose the temporary use of Hh inhibition during liver RT to radiosensitize HCC tumor cells and inhibit their progression, while blocking the initiation of the radiation-induced fibrotic response in the surrounding normal liver. PMID:26202634

  3. Hedgehogs and sugar gliders: respiratory anatomy, physiology, and disease.

    PubMed

    Johnson, Dan H

    2011-05-01

    This article discusses the respiratory anatomy, physiology, and disease of African pygmy hedgehogs (Atelerix albiventris) and sugar gliders (Petaurus breviceps), two species commonly seen in exotic animal practice. Where appropriate, information from closely related species is mentioned because cross-susceptibility is likely and because these additional species may also be encountered in practice. Other body systems and processes are discussed insofar as they relate to or affect respiratory function. Although some topics, such as special senses, hibernation, or vocalization, may seem out of place, in each case the information relates back to respiration in some important way. PMID:21601815

  4. Hedgehog Signaling and Steroidogenesis Annual Review of Physiology

    PubMed Central

    Finco, Isabella; LaPensee, Christopher R.; Krill, Kenneth T.; Hammer, Gary D.

    2016-01-01

    Since its discovery nearly 30 years ago, the Hedgehog (Hh) signaling pathway has been shown to be pivotal in many developmental and pathophysiological processes in several steroidogenic tissues, including the testis, ovary, adrenal cortex, and placenta. New evidence links the evolutionarily conserved Hh pathway to the steroidogenic organs, demonstrating how Hh signaling can influence their development and homeostasis and can act in concert with steroids to mediate physiological functions. In this review, we highlight the role of the components of the Hh signaling pathway in steroidogenesis of endocrine tissues. PMID:25668018

  5. Mechanism and evolution of cytosolic Hedgehog signal transduction

    PubMed Central

    Wilson, Christopher W.; Chuang, Pao-Tien

    2010-01-01

    Hedgehog (Hh) signaling is required for embryonic patterning and postnatal physiology in invertebrates and vertebrates. With the revelation that the primary cilium is crucial for mammalian Hh signaling, the prevailing view that Hh signal transduction mechanisms are conserved across species has been challenged. However, more recent progress on elucidating the function of core Hh pathway cytosolic regulators in Drosophila, zebrafish and mice has confirmed that the essential logic of Hh transduction is similar between species. Here, we review Hh signaling events at the membrane and in the cytosol, and focus on parallel and divergent functions of cytosolic Hh regulators in Drosophila and mammals. PMID:20530542

  6. Hedgehog signaling and radiation induced liver injury: a delicate balance.

    PubMed

    Kabarriti, Rafi; Guha, Chandan

    2014-07-01

    Radiation-induced liver disease (RILD) is a major limitation of radiation therapy (RT) for the treatment of liver cancer. Emerging data indicate that hedgehog (Hh) signaling plays a central role in liver fibrosis and regeneration after liver injury. Here, we review the potential role of Hh signaling in RILD and propose the temporary use of Hh inhibition during liver RT to radiosensitize HCC tumor cells and inhibit their progression, while blocking the initiation of the radiation-induced fibrotic response in the surrounding normal liver. PMID:26202634

  7. SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

    PubMed Central

    Popovic, Jelena; Schwirtlich, Marija; Rankovic, Branislava; Stevanovic, Milena

    2015-01-01

    Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation. PMID:26588701

  8. Suppressors of hedgehog signaling: Linking aberrant development of neural progenitors and tumorigenesis.

    PubMed

    Di Marcotullio, Lucia; Ferretti, Elisabetta; De Smaele, Enrico; Screpanti, Isabella; Gulino, Alberto

    2006-12-01

    Subversion of signals that physiologically suppress Hedgehog pathway results in aberrant neural progenitor development and medulloblastoma, a malignancy of the cerebellum. The Hedgehog antagonist RENKCTD11 maps to chromosome 17p13.2 and is involved in the withdrawal of the Hedgehog signaling at the granule cell progenitor transition from the outer to the inner external germinal layers, thus promoting growth arrest and differentiation. Deletion of chromosome 17p, the most frequent genetic lesion observed in this tumor, is responsible for the loss of function of RENKCTD11, resulting in upregulated Hedgehog signaling and medulloblastoma. Persistence of signals that limit Hedgehog activity is also associated with malignancy. Hedgehog signaling- induced downregulation of ErbB4 receptor expression is attenuated in medulloblastoma subsets in which the extent of Hedgehog pathway activity is limited, thus favoring the accumulation of ErbB4 with imbalanced alternative splice CYT-1 isoform over the CYT-2. This is responsible for both Neuregulin ligand-induced CYT-1-dependent prosurvival activity and loss of CYT-2-mediated growth arrest. PMID:17308352

  9. Feeding behavior and nutrition of the african pygmy hedgehog (Atelerix albiventris).

    PubMed

    Dierenfeld, Ellen S

    2009-05-01

    Despite their wide global distribution and popularity as pets, little is known concerning specific nutritional requirements of hedgehogs. They inhabit a wide variety of environments from desert to temperate forest, and they display flexible and opportunistic feeding behaviors. Natural diets include invertebrate and vertebrate prey, carrion, and plant material. Hedgehogs have enzymatic ability to digest chitin from insect exoskeletons as a dietary fiber source, but they do not seem to digest cellulose efficiently. Captive diets based on nutritionally balanced commercially available products containing moderate levels of protein (30%-50%, dry basis) and fat (10%-20%) are suitable for the omnivorous hedgehog. PMID:19341959

  10. Hedgehog signalling: how to get from Smo to Ci and Gli.

    PubMed

    Østerlund, Torben; Kogerman, Priit

    2006-04-01

    The secreted morphogens of the Hedgehog family have important roles in normal development as well as in associated pathologies, including cancer. The Hedgehog signalling pathway has been studied in Drosophila and is thought to be conserved in vertebrates. Hedgehog elicits a signalling response that activates Smoothened (Smo). There is evidence of differences between Drosophila and vertebrates concerning signalling downstream of Smo, as well as in Smo itself. Here, we discuss this evidence and its importance for investigations of the pathway and related biology, as well as for the development of drugs targeting components of the pathway for treatment of associated pathologies. PMID:16516476

  11. A new role for Hedgehogs in juxtacrine signaling.

    PubMed

    Pettigrew, Christopher A; Asp, Eva; Emerson, Charles P

    2014-02-01

    The Hedgehog pathway plays important roles in embryonic development, adult stem cell maintenance and tumorigenesis. In mammals these effects are mediated by Sonic, Desert and Indian Hedgehog (Shh, Dhh and Ihh). Shh undergoes autocatalytic cleavage and dual lipidation prior to secretion and forming a response gradient. Post-translational processing and secretion of Dhh and Ihh ligands has not previously been investigated. This study reports on the synthesis, processing, secretion and signaling activities of SHH, IHH and DHH preproteins expressed in cultured cells, providing unexpected evidence that DHH does not undergo substantial autoprocessing or secretion, and does not function in paracrine signaling. Rather, DHH functions as a juxtacrine signaling ligand to activate a cell contact-mediated HH signaling response, consistent with its localised signaling in vivo. Further, the LnCAP prostate cancer cell, when induced to express endogenous DHH and SHH, is active only in juxtacrine signaling. Domain swap studies reveal that the C-terminal domain of HH regulates its processing and secretion. These findings establish a new regulatory role for HHs in cell-mediated juxtacrine signaling in development and cancer. PMID:24342078

  12. Mast cells in the sheep, hedgehog and rat forebrain

    PubMed Central

    MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

    1999-01-01

    The study was designed to reveal the distribution of various mast cell types in the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical and immunocytochemical characteristics, mast cells were categorised as (1) connective tissue-type mast cells, staining metachromatically purple with the toluidine blue method, or pale red with the Alcian blue/safranin method, (2) mucosal-type or immature mast cells staining blue with the Alcian blue/safranin method and (3) serotonin immunopositive mast cells. All 3 types of brain mast cells in all species studied were located in both white and grey matter, often associated with intraparenchymal blood vessels. Their distribution pattern exhibited interspecies differences, while their number varied considerably not only between species but also between individuals of each species. A distributional left-right asymmetry, with more cells present on the left side, was observed in all species studied but it was most prominent in the sheep brain. In the sheep, mast cells were abundantly distributed in forebrain areas, while in the hedgehog and the rat forebrain, mast cells were less widely distributed and were relatively or substantially fewer in number respectively. A limited number of brain mast cells, in all 3 species, but primarily in the rat, were found to react both immunocytochemically to 5-HT antibody and histochemically with Alcian blue/safranin staining. PMID:10634696

  13. Rib osteoblastic osteosarcoma in an African hedgehog (Atelerix albiventris).

    PubMed

    Benoit-Biancamano, Marie-Odile; D'Anjou, Marc-André; Girard, Christiane; Langlois, Isabelle

    2006-07-01

    A 3-year-old African hedgehog (Atelerix albiventris) was presented to the Exotic Animal Clinic of the University of Montreal for evaluation of a mass growing on the right thoracic wall. The diagnostic workup, which included helical computed tomography, confirmed the presence of a large mass, originating from the right 7th rib, infiltrating the thoracic wall and cavity. The animal was euthanized due to the poor prognosis. At necropsy, a well-demarcated mass penetrated the thoracic wall and incorporated the 6th to 8th ribs. Cut sections of the tumor were white, glistening, firm, and gritty. Microscopically, it was composed of polyhedral to elongated cells with interspersed trabeculae of osteoid and large areas of coagulative necrosis. On the basis of histopathologic findings, a diagnosis of osteoblastic osteosarcoma was made. To the authors' knowledge, this is the first report of an osteoblastic osteosarcoma on the thoracic wall of an African hedgehog, as well as the first report of the use of helical computed tomography in that species. PMID:16921888

  14. Sonic hedgehog signaling in Basal cell nevus syndrome.

    PubMed

    Athar, Mohammad; Li, Changzhao; Kim, Arianna L; Spiegelman, Vladimir S; Bickers, David R

    2014-09-15

    The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein-coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012. PMID:25172843

  15. Sonic Hedgehog Signaling in the Lung. From Development to Disease

    PubMed Central

    Joyner, Alexandra L.; Loomis, Cynthia A.; Munger, John S.

    2015-01-01

    Over the past two decades, the secreted protein sonic hedgehog (SHH) has emerged as a critical morphogen during embryonic lung development, regulating the interaction between epithelial and mesenchymal cell populations in the airway and alveolar compartments. There is increasing evidence that the SHH pathway is active in adult lung diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, and lung cancer, which raises two questions: (1) What role does SHH signaling play in these diseases? and (2) Is it a primary driver of the disease or a response (perhaps beneficial) to the primary disturbance? In this review we aim to fill the gap between the well-studied period of embryonic lung development and the adult diseased lung by reviewing the hedgehog (HH) pathway during the postnatal period and in adult uninjured and injured lungs. We elucidate the similarities and differences in the epithelial–mesenchymal interplay during the fibrosis response to injury in lung compared with other organs and present a critical appraisal of tools and agents available to evaluate HH signaling. PMID:25068457

  16. Desert hedgehog is a mediator of demyelination in compression neuropathies.

    PubMed

    Jung, James; Frump, Derek; Su, Jared; Wang, Weiping; Mozaffar, Tahseen; Gupta, Ranjan

    2015-09-01

    The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination-induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh(-/-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies. PMID:25936873

  17. Involvement of the Sonic hedgehog gene in chick feather formation.

    PubMed

    Nohno, T; Kawakami, Y; Ohuchi, H; Fujiwara, A; Yoshioka, H; Noji, S

    1995-01-01

    To elucidate the molecular mechanisms of chick feather formation, we observed expression patterns of the Sonic hedgehog (Shh) gene, which is one of the vertebrate homologs of the Drosophila segment polarity gene, hedgehog, and encodes a signaling molecule functioning in limb pattern formation and motor neuron induction. We found that the Shh gene is also expressed in the apical region of the feather placodes and then in nine to eleven longitudinal stripes along feather filaments. The stripe was found to correspond to one of the outer marginal zones of each barb ridge, termed the zone of Shh expression. No significant expression signal was detected in the scale bud of developing legs. Thus, Shh is likely to function as an epithelial signaling molecule in epithelio-mesenchymal interaction during feather formation. Furthermore, since genes of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-4 (FGF-4) are coexpressed with Shh during feather formation as observed in limb morphogenesis, interactions among FGF-4, Shh and BMP-2 may be involved in formation of feather filaments and barbs in a similar fashion as elucidated in limb pattern formation. PMID:7818537

  18. The Role of Sonic Hedgehog Reemergence During Gastric Cancer

    PubMed Central

    Martin, Jason; Donnelly, Jessica M.; Houghton, JeanMarie

    2016-01-01

    Sonic Hedgehog (Shh) signaling has been extensively studied for its role in developmental biology and cancer biology. The association between Shh and cancer development in general is well established but the functional role of Shh in the development and progression of gastric cancer specifically is largely unknown. Bone marrow-derived stem cells, specifically mesenchymal stem cells (MSCs) infiltrate and engraft into the gastric mucosa in response to the chronic inflammatory environment of Helicobacter infection. In this review, MSC infiltration and changes in the cytokine and cellular profiles of later-stage chronic environments will be tied into their interactions with the Shh pathway. We will discuss how these changes shape tumorigenesis and tumor progression in the gastric mucosa. The current review focuses on the Shh signaling pathway and its role in the development of gastric cancer, specifically in response to Helicobacter pylori infection. We follow with an in-depth discussion of the regulation of the Hedgehog pathway during acute and chronic gastric inflammation with a focus on signaling within the MSC compartment. PMID:20437100

  19. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    PubMed

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  20. Tamoxifen Treatment of Breast Cancer Cells: Impact on Hedgehog/GLI1 Signaling.

    PubMed

    Villegas, Victoria E; Rondón-Lagos, Milena; Annaratone, Laura; Castellano, Isabella; Grismaldo, Adriana; Sapino, Anna; Zaphiropoulos, Peter G

    2016-01-01

    The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER- cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes. PMID:26927093

  1. Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.

    PubMed

    Hildebrand, Michael S; Griffin, Nicole G; Damiano, John A; Cops, Elisa J; Burgess, Rosemary; Ozturk, Ezgi; Jones, Nigel C; Leventer, Richard J; Freeman, Jeremy L; Harvey, A Simon; Sadleir, Lynette G; Scheffer, Ingrid E; Major, Heather; Darbro, Benjamin W; Allen, Andrew S; Goldstein, David B; Kerrigan, John F; Berkovic, Samuel F; Heinzen, Erin L

    2016-08-01

    Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease. PMID:27453577

  2. Diet controls Drosophila follicle stem cell proliferation via Hedgehog sequestration and release.

    PubMed

    Hartman, Tiffiney R; Strochlic, Todd I; Ji, Yingbiao; Zinshteyn, Daniel; O'Reilly, Alana M

    2013-05-27

    A healthy diet improves adult stem cell function and delays diseases such as cancer, heart disease, and neurodegeneration. Defining molecular mechanisms by which nutrients dictate stem cell behavior is a key step toward understanding the role of diet in tissue homeostasis. In this paper, we elucidate the mechanism by which dietary cholesterol controls epithelial follicle stem cell (FSC) proliferation in the fly ovary. In nutrient-restricted flies, the transmembrane protein Boi sequesters Hedgehog (Hh) ligand at the surface of Hh-producing cells within the ovary, limiting FSC proliferation. Upon feeding, dietary cholesterol stimulates S6 kinase-mediated phosphorylation of the Boi cytoplasmic domain, triggering Hh release and FSC proliferation. This mechanism enables a rapid, tissue-specific response to nutritional changes, tailoring stem cell divisions and egg production to environmental conditions sufficient for progeny survival. If conserved in other systems, this mechanism will likely have important implications for studies on molecular control of stem cell function, in which the benefits of low calorie and low cholesterol diets are beginning to emerge. PMID:23690177

  3. Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation.

    PubMed

    Malatesta, Martina; Steinhauer, Cornelia; Mohammad, Faizaan; Pandey, Deo P; Squatrito, Massimo; Helin, Kristian

    2013-10-15

    The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh-Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh-Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. PMID:23943798

  4. In Vivo RNAi Screen Reveals Neddylation Genes as Novel Regulators of Hedgehog Signaling

    PubMed Central

    Su, Ying; Liu, Min; Ospina, Jason K.; Yang, Shengyuan; Zhu, Alan Jian

    2011-01-01

    Hedgehog (Hh) signaling is highly conserved in all metazoan animals and plays critical roles in many developmental processes. Dysregulation of the Hh signaling cascade has been implicated in many diseases, including cancer. Although key components of the Hh pathway have been identified, significant gaps remain in our understanding of the regulation of individual Hh signaling molecules. Here, we report the identification of novel regulators of the Hh pathway, obtained from an in vivo RNA interference (RNAi) screen in Drosophila. By selectively targeting critical genes functioning in post-translational modification systems utilizing ubiquitin (Ub) and Ub-like proteins, we identify two novel genes (dUba3 and dUbc12) that negatively regulate Hh signaling activity. We provide in vivo and in vitro evidence illustrating that dUba3 and dUbc12 are essential components of the neddylation pathway; they function in an enzyme cascade to conjugate the ubiquitin-like NEDD8 modifier to Cullin proteins. Neddylation activates the Cullin-containing ubiquitin ligase complex, which in turn promotes the degradation of Cubitus interruptus (Ci), the downstream transcription factor of the Hh pathway. Our study reveals a conserved molecular mechanism of the neddylation pathway in Drosophila and sheds light on the complex post-translational regulations in Hh signaling. PMID:21931660

  5. Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling

    PubMed Central

    Tzelepi, Vassiliki; Karlou, Maria; Wen, Sijin; Hoang, Anh; Logothetis, Christopher; Troncoso, Patricia; Efstathiou, Eleni

    2016-01-01

    Aims The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial–mesenchymal interactions. The aim of this study was to elucidate the cell-type partitioned expression of the Hh pathway biomarkers in the non-neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer. Methods and results Expression of the Hh pathway components (Shh, Smo, Ptch, Gli1) in the microenvironment of non-neoplastic peripheral zone (n = 119), hormone-naive primary prostate carcinoma (n = 141) and castrate-resistant bone marrow metastases (n = 53) was analysed using immunohistochemistry in tissue microarrays and bone marrow sections. Results showed that epithelial Shh, Smo and Ptch expression was up-regulated, whereas stromal Smo, Ptch, and Gli1 expression was down-regulated in prostate carcinomas compared to non-neoplastic peripheral zone tissue. Ptch expression was modulated further in high-grade and high-stage primary tumours and in bone marrow metastases. Hh signalling correlated with ki67 and vascular endothelial growth factor (VEGF) but not with CD31 expression. Conclusion Our results highlight the importance of Hh-mediated epithelial–mesenchymal interactions in the non-neoplastic prostate and imply that shifting the balance from paracrine towards autocrine signalling is important in the pathogenesis and progression of prostate carcinoma. PMID:21707705

  6. Sonic hedgehog signalling in neurons of adult ventrolateral nucleus tractus solitarius.

    PubMed

    Pascual, Olivier; Traiffort, Elisabeth; Baker, Darren P; Galdes, Alphonse; Ruat, Martial; Champagnat, Jean

    2005-07-01

    The transmembrane receptor Patched (Ptc) mediates the action of the diffusing factor Sonic hedgehog (Shh), which is implicated in establishing morphogenetic gradients during embryonic development. Whereas alteration of Ptc function is associated with developmental abnormalities and brain tumors, its functional activity and roles in the adult brain have yet to be elucidated. Here we describe the complementary pattern of Shh and Ptc expression in the rat dorsal vagal motor nucleus and the ventrolateral nucleus tractus solitarius (vNTS), respectively. Those two interconnected structures regulate the cardiorespiratory function during hypoxia. Bath application of a subnanomolar concentration of aminoterminal Shh protein (ShhN) to a slice preparation of the vNTS induces a rapid decrease in neuronal firing followed by a bursting activity that propagates in the neuronal network. Intracellular current injections show that bursts result from an action on the neuronal membrane electro-responsiveness. Both inhibiting and bursting effects are blocked by the monoclonal Shh antibody 5E1 and may require the Ptc binding site of ShhN. Thus, ShhN acting on specific neuronal sites controls electrophysiological properties of differentiated neurons of the vNTS. We speculate on a retrocontrol of cardiorespiratory signals in the vNTS, by Shh generated in dorsal vagal motoneurons. PMID:16045492

  7. Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma.

    PubMed

    Hayden Gephart, Melanie G; Su, YouRong Sophie; Bandara, Samuel; Tsai, Feng-Chiao; Hong, Jennifer; Conley, Nicholas; Rayburn, Helen; Milenkovic, Ljiljana; Meyer, Tobias; Scott, Matthew P

    2013-11-01

    The Hedgehog (Hh) signaling pathway has been implicated in the most common childhood brain tumor, medulloblastoma (MB). Given the toxicity of post-surgical treatments for MB, continued need exists for new, targeted therapies. Based upon our finding that Neuropilin (Nrp) transmembrane proteins are required for Hh signal transduction, we investigated the role of Nrp in MB cells. Cultured cells derived from a mouse Ptch (+/-) ;LacZ MB (Med1-MB), effectively modeled the Hh pathway-related subcategory of human MBs in vitro. Med1-MB cells maintained constitutively active Hh target gene transcription, and consistently formed tumors within one month after injection into mouse cerebella. The proliferation rate of Med1-MBs in culture was dependent upon Nrp2, while reducing Nrp1 function had little effect. Knockdown of Nrp2 prior to cell implantation significantly increased mouse survival, compared to transfection with a non-targeting siRNA. Knocking down Nrp2 specifically in MB cells avoided any direct effect on tumor vascularization. Nrp2 should be further investigated as a potential target for adjuvant therapy in patients with MB. PMID:24026530

  8. A Screen for Modifiers of Hedgehog Signaling in Drosophila melanogaster Identifies swm and mts

    PubMed Central

    Casso, David J.; Liu, Songmei; Iwaki, D. David; Ogden, Stacey K.; Kornberg, Thomas B.

    2008-01-01

    Signaling by Hedgehog (Hh) proteins shapes most tissues and organs in both vertebrates and invertebrates, and its misregulation has been implicated in many human diseases. Although components of the signaling pathway have been identified, key aspects of the signaling mechanism and downstream targets remain to be elucidated. We performed an enhancer/suppressor screen in Drosophila to identify novel components of the pathway and identified 26 autosomal regions that modify a phenotypic readout of Hh signaling. Three of the regions include genes that contribute constituents to the pathway—patched, engrailed, and hh. One of the other regions includes the gene microtubule star (mts) that encodes a subunit of protein phosphatase 2A. We show that mts is necessary for full activation of Hh signaling. A second region includes the gene second mitotic wave missing (swm). swm is recessive lethal and is predicted to encode an evolutionarily conserved protein with RNA binding and Zn+ finger domains. Characterization of newly isolated alleles indicates that swm is a negative regulator of Hh signaling and is essential for cell polarity. PMID:18245841

  9. Tamoxifen Treatment of Breast Cancer Cells: Impact on Hedgehog/GLI1 Signaling

    PubMed Central

    Villegas, Victoria E.; Rondón-Lagos, Milena; Annaratone, Laura; Castellano, Isabella; Grismaldo, Adriana; Sapino, Anna; Zaphiropoulos, Peter G.

    2016-01-01

    The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER− cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes. PMID:26927093

  10. Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma.

    PubMed

    Blotta, Simona; Jakubikova, Jana; Calimeri, Teresa; Roccaro, Aldo M; Amodio, Nicola; Azab, Abdel Kareem; Foresta, Umberto; Mitsiades, Constantine S; Rossi, Marco; Todoerti, Katia; Molica, Stefano; Morabito, Fortunato; Neri, Antonino; Tagliaferri, Piersandro; Tassone, Pierfrancesco; Anderson, Kenneth C; Munshi, Nikhil C

    2012-12-13

    The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138(+) MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific down-regulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome. PMID:22821765

  11. Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma

    PubMed Central

    Blotta, Simona; Jakubikova, Jana; Calimeri, Teresa; Roccaro, Aldo M.; Amodio, Nicola; Azab, Abdel Kareem; Foresta, Umberto; Mitsiades, Constantine S.; Rossi, Marco; Todoerti, Katia; Molica, Stefano; Morabito, Fortunato; Neri, Antonino; Tagliaferri, Piersandro; Tassone, Pierfrancesco; Anderson, Kenneth C.

    2012-01-01

    The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138+ MM cells express Hh genes and confirmed Smoothened (Smo)–dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific down-regulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome. PMID:22821765

  12. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein

    SciTech Connect

    Lu, Na; Chen, Yan; Wang, Zhengmin; Chen, Guoling; Lin, Qin; Chen, Zheng-Yi; Li, Huawei

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer Shh activation in neonatal cochleae enhances sensory cell proliferation. Black-Right-Pointing-Pointer Proliferating supporting cells can transdifferentiate into hair cells. Black-Right-Pointing-Pointer Shh promotes proliferation by transiently modulating pRb activity. Black-Right-Pointing-Pointer Shh inhibits pRb by inhibiting transcription and increasing phosphorylation of pRb. -- Abstract: Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.

  13. Structural insights into human Kif7, a kinesin involved in Hedgehog signalling

    SciTech Connect

    Klejnot, Marta Kozielski, Frank

    2012-02-01

    The human Kif7 motor domain structure provides insights into a kinesin of medical significance. Kif7, a member of the kinesin 4 superfamily, is implicated in a variety of diseases including Joubert, hydrolethalus and acrocallosal syndromes. It is also involved in primary cilium formation and the Hedgehog signalling pathway and may play a role in cancer. Its activity is crucial for embryonic development. Kif7 and Kif27, a closely related kinesin in the same subfamily, are orthologues of the Drosophila melano@@gaster kinesin-like protein Costal-2 (Cos2). In vertebrates, they work together to fulfil the role of the single Cos2 gene in Drosophila. Here, the high-resolution structure of the human Kif7 motor domain is reported and is compared with that of conventional kinesin, the founding member of the kinesin superfamily. These data are a first step towards structural characterization of a kinesin-4 family member and of this interesting molecular motor of medical significance.

  14. Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis

    PubMed Central

    Hynes, Ann Marie; Giles, Rachel H.; Srivastava, Shalabh; Eley, Lorraine; Whitehead, Jennifer; Danilenko, Marina; Raman, Shreya; Slaats, Gisela G.; Colville, John G.; Ajzenberg, Henry; Kroes, Hester Y.; Thelwall, Peter E.; Simmons, Nicholas L.; Miles, Colin G.; Sayer, John A.

    2014-01-01

    Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically. PMID:24946806

  15. The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover

    PubMed Central

    Lu, Xingwu; Liu, Songmei; Kornberg, Thomas B.

    2006-01-01

    Patched (Ptc) is a membrane protein whose function in Hedgehog (Hh) signal transduction has been conserved among metazoans and whose malfunction has been implicated in human cancers. Genetic analysis has shown that Ptc negatively regulates Hh signal transduction, but its activity and structure are not known. We investigated the functional and structural properties of Drosophila Ptc and its C-terminal domain (CTD), 183 residues that are predicted to reside in the cytoplasm. Our results show that Ptc, as well as truncated Ptc deleted of its CTD, forms a stable trimer. This observation is consistent with the proposal that Ptc is structurally similar to trimeric transporters. The CTD itself trimerizes and is required for both Ptc internalization and turnover. Two mutant forms of the CTD, one that disrupts trimerization and the other that mutates the target sequence of the Nedd4 ubiquitin ligase, stabilize Ptc but do not prevent internalization and sequestration of Hh. Ptc deleted of its CTD is stable and localizes to the plasma membrane. These data show that degradation of Ptc is regulated at a step subsequent to endocytosis, although endocytosis is a likely prerequisite. We also show that the CTD of mouse Ptc regulates turnover. PMID:16980583

  16. Chromosome 17p deletion in human medulloblastoma: a missing checkpoint in the Hedgehog pathway.

    PubMed

    De Smaele, Enrico; Di Marcotullio, Lucia; Ferretti, Elisabetta; Screpanti, Isabella; Alesse, Edoardo; Gulino, Alberto

    2004-10-01

    Although deregulation of Hedgehog signalling is considered to play a crucial oncogenic role and commonly occurrs in medulloblastoma, genetic lesions in components of this pathway are observed in a minority of cases. The recent identification of a novel putative tumor suppressor (REN(KCTD11)) on chromosome 17p13.2, a region most frequently lost in human medulloblastoma, highlights the role of allelic deletion of the gene in this brain malignancy, leading to the loss of growth inhibitory activity via suppression of Gli-dependent activation of Hedgehog target genes. The presence on 17p13 of another tumor suppressor gene (p53) whose inactivation cooperates with Hedgehog pathway for medulloblastoma formation, suggests that 17p deletion unveils haploinsufficiency conditions leading to abrogation of either direct and indirect checkpoints of Hedgehog signalling in cancer. PMID:15467454

  17. Soft tissue sarcomas in the African hedgehog (Atelerix albiventris): microscopic and immunohistologic study of three cases.

    PubMed

    Ramos-Vara, J A

    2001-09-01

    Three soft tissue tumors from 2 female hedgehogs were examined microscopically and immunohistochemically. Two tumors involved haired skin and the third one was vaginal. Microscopically, the cutaneous tumors had features of malignant peripheral nerve sheath tumor (MPNST), whereas the vaginal tumor was classified only as a spindle cell sarcoma. Immunohistochemically, all 3 tumors were strongly positive for vimentin and strongly to moderately positive for CD10 and neuron-specific enolase but did not stain with antibody to S100 protein, an antigen typically present in human MPNST The cutaneous tumor from hedgehog no. 1 was examined ultrastructurally and the neoplastic cells resembled fibroblasts. Hedgehog no. 1 was euthanized at the time of the biopsy. The outcome of the other hedgehog was unknown. PMID:11580072

  18. Unilateral proptosis and orbital cellulitis in eight African hedgehogs (Atelerix albiventris).

    PubMed

    Wheler, C L; Grahn, B H; Pocknell, A M

    2001-06-01

    Eight African hedgehogs (Atelerix albiventris) were presented with unilateral proptosis. Six animals presented specifically for an ocular problem, whereas two had concurrent neurologic disease. Enucleation and light microscopic examination of tissues was performed in five animals, and euthanasia followed by complete postmortem examination was performed in three animals. Histopathologic findings in all hedgehogs included orbital cellulitis, panophthalmitis, and corneal ulceration, with perforation in seven of eight eyes. The etiology of the orbital cellulitis was not determined, but it appeared to precede proptosis. Orbits in hedgehogs are shallow and the palpebral fissures are large, which may predispose them to proptosis, similar to brachycephalic dogs. This clinical presentation was seen in 15% (8/54) of African hedgehogs presented to the Western College of Veterinary Medicine over a 2-yr period from January 1995 to December 1996 and warrants further investigation. PMID:12790427

  19. Spontaneous tumours in captive African hedgehogs (Atelerix albiventris): a retrospective study.

    PubMed

    Raymond, J T; Garner, M M

    2001-01-01

    Forty tumours were diagnosed in 35 (53%) of 66 captive African hedgehogs documented at Northwest ZooPath (NZP) between 1994 and 1999. Three hedgehogs had more than one type of tumour and the remaining 32 had a single type. Of the 35 hedgehogs with tumours, 14 were female, 11 were male, and 10 were of unknown gender; 21 were from zoological parks and 14 were privately owned. Twenty of the hedgehogs with tumours were adult (>1 year old) with a median age of 3.5 years (range 2-5.5 years); 15, of unreported age, were classified as adult. Thirty-four (85%) of the 40 tumours were classified as malignant and six (15%) as benign. The integumentary, haemolymphatic, digestive and endocrine systems were common sites for tumours. The most common tumours were mammary gland adenocarcinoma, lympho-sarcoma and oral squamous cell carcinoma. PMID:11222009

  20. Detection and molecular characterisation of Cryptosporidium parvum in British European hedgehogs (Erinaceus europaeus).

    PubMed

    Sangster, Lucy; Blake, Damer P; Robinson, Guy; Hopkins, Timothy C; Sa, Ricardo C C; Cunningham, Andrew A; Chalmers, Rachel M; Lawson, Becki

    2016-02-15

    Surveillance was conducted for the occurrence of protozoan parasites of the genus Cryptosporidium in European hedgehogs (Erinaceus europaeus) in Great Britain. In total, 108 voided faecal samples were collected from hedgehogs newly admitted to eight wildlife casualty treatment and rehabilitation centres. Terminal large intestinal (LI) contents from three hedgehog carcasses were also analysed. Information on host and location variables, including faecal appearance, body weight, and apparent health status, was compiled. Polymerase Chain Reaction (PCR) targeting the 18S ribosomal RNA gene, confirmed by sequencing, revealed an 8% (9/111) occurrence of Cryptosporidium parvum in faeces or LI contents, with no significant association between the host or location variables and infection. Archived small intestinal (SI) tissue from a hedgehog with histological evidence of cryptosporidiosis was also positive for C. parvum by PCR and sequence analysis of the 18S rRNA gene. No other Cryptosporidium species were detected. PCR and sequencing of the glycoprotein 60 gene identified three known zoonotic C. parvum subtypes not previously found in hedgehogs: IIdA17G1 (n=4), IIdA19G1 (n=1) and IIdA24G1 (n=1). These subtypes are also known to infect livestock. Another faecal sample contained C. parvum IIcA5G3j which has been found previously in hedgehogs, and for which there is one published report in a human, but is not known to affect livestock. The presence of zoonotic subtypes of C. parvum in British hedgehogs highlights a potential public health concern. Further research is needed to better understand the epidemiology and potential impacts of Cryptosporidium infection in hedgehogs. PMID:26827859

  1. Necropsy and histopathologic findings in 14 African hedgehogs (Atelerix albiventris): a retrospective study.

    PubMed

    Raymond, J T; White, M R

    1999-06-01

    From fiscal years 1992 through 1996, 14 African hedgehog (Atelerix albiventris) cases were submitted to the Animal Disease Diagnostic Laboratory at Purdue University. The most common diagnoses were splenic extramedullary hematopoiesis (91%), hepatic lipidosis (50%), renal disease (50%), and neoplastic disease (29%). Other less frequent necropsy findings were myocarditis (21%), colitis (14%), bacterial septicemia (14%), and pneumonia (14%). The data indicate that splenic extramedullary hematopoiesis, hepatic lipidosis, renal disease, and neoplasms are frequent postmortem findings in hedgehogs. PMID:10484145

  2. Use of permethrin as a miticide in the African hedgehog (Atelerix albiventris).

    PubMed

    Staley, E C; Staley, E E; Behr, M J

    1994-04-01

    The African hedgehog, Atelerix albiventris (also known as Erinaceous albiventris; 1,2) has recently undergone an increase in popularity as an exotic pet. This popularity (Beatrix Potter not withstanding) is due in part to the small size of the African hedgehog (adults are 4-6 in in length, weighing approximately 1 lb), its lack of hibernation or aestivation if reared under controlled light and temperature, and its general good nature and accommodation to handling. PMID:8197715

  3. Stability of the Melting Hedgehog in the Landau-de Gennes Theory of Nematic Liquid Crystals

    NASA Astrophysics Data System (ADS)

    Ignat, Radu; Nguyen, Luc; Slastikov, Valeriy; Zarnescu, Arghir

    2014-09-01

    We investigate stability properties of the radially symmetric solution corresponding to the vortex defect (the so called "melting hedgehog") in the framework of the Landau-de Gennes model of nematic liquid crystals. We prove local stability of the melting hedgehog under arbitrary Q-tensor valued perturbations in the temperature regime near the critical supercooling temperature. As a consequence of our method, we also rediscover the loss of stability of the vortex defect in the deep nematic regime.

  4. Stability of the Melting Hedgehog in the Landau-de Gennes Theory of Nematic Liquid Crystals

    NASA Astrophysics Data System (ADS)

    Ignat, Radu; Nguyen, Luc; Slastikov, Valeriy; Zarnescu, Arghir

    2015-02-01

    We investigate stability properties of the radially symmetric solution corresponding to the vortex defect (the so called "melting hedgehog") in the framework of the Landau-de Gennes model of nematic liquid crystals. We prove local stability of the melting hedgehog under arbitrary Q-tensor valued perturbations in the temperature regime near the critical supercooling temperature. As a consequence of our method, we also rediscover the loss of stability of the vortex defect in the deep nematic regime.

  5. Diagnosis and treatment of congestive heart failure secondary to dilated cardiomyopathy in a hedgehog.

    PubMed

    Delk, K W; Eshar, D; Garcia, E; Harkin, K

    2014-03-01

    A one-year-old African pygmy hedgehog (Atelerix albiventris) was evaluated for severe respiratory distress. Physical examination findings included marked dyspnoea, cyanosis and tachypnoea. Radiographic findings included an enlarged heart and pulmonary oedema, and dilated cardiomyopathy was confirmed via echocardiogram. The patient was treated for congestive heart failure because of dilated cardiomyopathy with furosemide, enalapril, pimobendan and l-carnitine. Within 24 hours of treatment, the pulmonary oedema and cyanosis had resolved. Following discharge, clinical improvement was noted by the owner and echocardiogram confirmed improved fractional shortening. Cardiomyopathy has been reported at post-mortem examination in hedgehogs, but there are no reports of ante-mortem diagnosis and treatment. Performing baseline cardiac assessment in hedgehogs is recommended, and treatment with l-carnitine and pimobendan may improve outcome, as carnitine deficiency is a possible cause of cardiomyopathy in hedgehogs. Successful emergency treatment of congestive heart failure in the hedgehog of this report may be effective for other hedgehogs presented with similar clinical signs. PMID:24372164

  6. Hedgehog inhibition causes complete loss of limb outgrowth and transformation of digit identity in Xenopus tropicalis.

    PubMed

    Stopper, Geffrey F; Richards-Hrdlicka, Kathryn L; Wagner, Günter P

    2016-03-01

    The study of the tetrapod limb has contributed greatly to our understanding of developmental pathways and how changes to these pathways affect the evolution of morphology. Most of our understanding of tetrapod limb development comes from research on amniotes, with far less known about mechanisms of limb development in amphibians. To better understand the mechanisms of limb development in anuran amphibians, we used cyclopamine to inhibit Hedgehog signaling at various stages of development in the western clawed frog, Xenopus tropicalis, and observed resulting morphologies. We also analyzed gene expression changes resulting from similar experiments in Xenopus laevis. Inhibition of Hedgehog signaling in X. tropicalis results in limb abnormalities including reduced digit number, missing skeletal elements, and complete absence of limbs. In addition, posterior digits assume an anterior identity by developing claws that are usually only found on anterior digits, confirming Sonic hedgehog's role in digit identity determination. Thus, Sonic hedgehog appears to play mechanistically separable roles in digit number specification and digit identity specification as in other studied tetrapods. The complete limb loss observed in response to reduced Hedgehog signaling in X. tropicalis, however, is striking, as this functional role for Hedgehog signaling has not been found in any other tetrapod. This changed mechanism may represent a substantial developmental constraint to digit number evolution in frogs. J. Exp. Zool. (Mol. Dev. Evol.) 9999B:XX-XX, 2016. © 2016 Wiley Periodicals, Inc. PMID:26918681

  7. REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma.

    PubMed

    Di Marcotullio, Lucia; Ferretti, Elisabetta; De Smaele, Enrico; Argenti, Beatrice; Mincione, Claudia; Zazzeroni, Francesca; Gallo, Rita; Masuelli, Laura; Napolitano, Maddalena; Maroder, Marella; Modesti, Andrea; Giangaspero, Felice; Screpanti, Isabella; Alesse, Edoardo; Gulino, Alberto

    2004-07-20

    Hedgehog signaling is suggested to be a major oncogenic pathway in medulloblastoma, which arises from aberrant development of cerebellar granule progenitors. Allelic loss of chromosome 17p has also been described as the most frequent genetic defect in this human neoplasia. This observation raises the question of a possible interplay between 17p deletion and the Hedgehog tumorigenic pathway. Here, we identify the human orthologue of mouse REN(KCTD11), previously reported to be expressed in differentiating and low proliferating neuroblasts. Human REN(KCTD11) maps to 17p13.2 and displays allelic deletion as well as significantly reduced expression in medulloblastoma. REN(KCTD11) inhibits medulloblastoma cell proliferation and colony formation in vitro and suppresses xenograft tumor growth in vivo. REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. Therefore, we identify REN(KCTD11) as a suppressor of Hedgehog signaling and suggest that its inactivation might lead to a deregulation of the tumor-promoting Hedgehog pathway in medulloblastoma. PMID:15249678

  8. Ticks of four-toed elephant shrews and Southern African hedgehogs.

    PubMed

    Horak, Ivan G; Welman, Shaun; Hallam, Stacey L; Lutermann, Heike; Mzilikazi, Nomakwezi

    2011-01-01

    Several studies on ticks infesting small mammals, including elephant shrews, have been conducted in South Africa; however, these studies have included only a single four-toed elephant shrew and no hedgehogs. This study thus aimed to identify and quantify the ixodid ticks infesting four-toed elephant shrews and Southern African hedgehogs. Four-toed elephant shrews (Petrodromus tetradactylus) were trapped in dense shrub undergrowth in a nature reserve in north-eastern KwaZulu-Natal. They were separately housed, first in cages and later in glass terraria fitted with wire-mesh bases to allow detached ticks to fall through for collection. Southern African hedgehogs (Atelerix frontalis) were hand caught on a farm in the eastern region of the Northern Cape Province and all visible ticks were collected by means of tweezers while the animals were anaesthetised. The ticks from each animal were preserved separately in 70% ethanol for later identification and counting. The immature stages of five ixodid tick species were collected from the elephant shrews, of which Rhipicephalus muehlensi was the most common. It has not been recorded previously on any species of elephant shrew. Three ixodid tick species were collected from the hedgehogs. Large numbers of adult Haemaphysalis colesbergensis, which has not been encountered previously on hedgehogs, were collected from these animals. Four-toed elephant shrews are good hosts of the larvae and nymphs of R. muehlensi, and Southern African hedgehogs are good hosts of adult H. colesbergensis. PMID:23327207

  9. Hedgehog signaling regulates dental papilla formation and tooth size during zebrafish odontogenesis

    PubMed Central

    Yu, Jeffrey C.; Fox, Zachary D.B.; Crimp, James L.; Littleford, Hana E.; Jowdry, Andrea L.; Jackman, William R.

    2015-01-01

    Background Intercellular communication by the hedgehog cell signaling pathway is necessary for tooth development throughout the vertebrates, but it remains unclear which specific developmental signals control cell behavior at different stages of odontogenesis. To address this issue, we have manipulated hedgehog activity during zebrafish tooth development and visualized the results using confocal microscopy. Results We first established that reporter lines for dlx2b, fli1, NF-κB, and prdm1a are markers for specific subsets of tooth germ tissues. We then blocked hedgehog signaling with cyclopamine and observed a reduction or elimination of the cranial neural crest derived dental papilla, which normally contains the cells that later give rise to dentin-producing odontoblasts. Upon further investigation we observed that the dental papilla begins to form and then regresses in the absence of hedgehog signaling, through a mechanism unrelated to cell proliferation or apoptosis. We also found evidence of an isometric reduction in tooth size that correlates with the time of earliest hedgehog inhibition. Conclusions We hypothesize that these results reveal a previously uncharacterized function of hedgehog signaling during tooth morphogenesis, regulating the number of cells in the dental papilla and thereby controlling tooth size. PMID:25645398

  10. Ticks and Fleas Infestation on East Hedgehogs (Erinaceus concolor) in Van Province, Eastern Region of Turkey

    PubMed Central

    Goz, Yaşar; Yilmaz, Ali Bilgin; Aydin, Abdulalim; Dicle, Yalçın

    2016-01-01

    Background: Ixodid ticks (Acari: İxodidae) and fleas (Siphonaptera) are the major vectors of pathogens threatening animals and human healths. The aim of our study was to detect the infestation rates of East Hedgehogs (Erinaceus concolor) with ticks and fleas in Van Province, eastern region of Turkey. Methods: We examined fleas and ticks infestation patterns in 21 hedgehogs, collected from three suburbs with the greater of number gardens. In order to estimate flea and tick infestation of hedgehogs, we immobilized the ectoparasites by treatment the body with a insecticide trichlorphon (Neguvon®-Bayer). Results: On the hedgehogs, 60 ixodid ticks and 125 fleas were detected. All of the ixodid ticks were Rhipicephalus turanicus and all of the fleas were Archaeopsylla erinacei. Infestation rate for ticks and fleas was detected 66.66 % and 100 %, respectively. Conclusion: We detected ticks (R. turanicus) and fleas (A. erinacei) in hedgehogs at fairly high rates. Since many ticks and fleas species may harbor on hedgehogs and transmit some tick-borne and flea-borne patogens, this results are the important in terms of veterinary and public health. PMID:27047971