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Sonic Hedgehog (sonic + hedgehog)
Terms modified by Sonic Hedgehog Selected AbstractsRecombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitroDEVELOPMENTAL DYNAMICS, Issue 10 2010K.L. Wells Abstract Hypohidrotic ectodermal dysplasia (HED) is characterized by defective ectodermal organ development. This includes the salivary glands (SGs), which have an important role in lubricating the oral cavity. In humans and mice, HED is caused by mutations in Ectodysplasin A (Eda) pathway genes. Various phenotypes of the mutant mouse EdaTa/Ta, which lacks the ligand Eda, can be rescued by maternal injection or in vitro culture supplementation with recombinant EDA. However, the response of the SGs to this treatment has not been investigated. Here, we show that the submandibular glands (SMGs) of EdaTa/Ta mice exhibit impaired branching morphogenesis, and that supplementation of EdaTa/Ta SMG explants with recombinant EDA rescues the defect. Supplementation of EdardlJ/dlJ SMGs with recombinant Sonic hedgehog (Shh) also rescues the defect, whereas treatment with recombinant Fgf8 does not. This work is the first to test the ability of putative Eda target molecules to rescue Eda pathway mutant SMGs. Developmental Dynamics 239:2674,2684, 2010. © 2010 Wiley-Liss, Inc. [source] Functional differentiation of a clone resembling embryonic cortical interneuron progenitorsDEVELOPMENTAL NEUROBIOLOGY, Issue 14 2008Hedong Li Abstract We have generated clones (L2.3 and RG3.6) of neural progenitors with radial glial properties from rat E14.5 cortex that differentiate into astrocytes, neurons, and oligodendrocytes. Here, we describe a different clone (L2.2) that gives rise exclusively to neurons, but not to glia. Neuronal differentiation of L2.2 cells was inhibited by bone morphogenic protein 2 (BMP2) and enhanced by Sonic Hedgehog (SHH) similar to cortical interneuron progenitors. Compared with L2.3, differentiating L2.2 cells expressed significantly higher levels of mRNAs for glutamate decarboxylases (GADs), DLX transcription factors, calretinin, calbindin, neuropeptide Y (NPY), and somatostatin. Increased levels of DLX-2, GADs, and calretinin proteins were confirmed upon differentiation. L2.2 cells differentiated into neurons that fired action potentials in vitro, and their electrophysiological differentiation was accelerated and more complete when cocultured with developing astroglial cells but not with conditioned medium from these cells. The combined results suggest that clone L2.2 resembles GABAergic interneuron progenitors in the developing forebrain. © 2008 Wiley Periodicals, Inc. Develop Neurobiol 2008 [source] Morphogens and cell survival during developmentDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2005Patrick Mehlen Abstract The notion of "morphogens" is an important one in developmental biology. By definition, a morphogen is a molecule that emanates from a specific set of cells that is present in a concentration gradient and that specifies the fate of each cell along this gradient. The strongest candidate morphogens are members of the transforming growth factor-, (TGF-,), Hedgehog (Hh), and Wnt families. While these morphogens have been extensively described as differentiation inducers, some reports also suggest their possible involvement in cell death and cell survival. It is frequently speculated that the cell death induction that is found associated with experimental removal of morphogens is the manifestation of abnormal differentiation signals. However, several recent reports have raised controversy about this death by default, suggesting that cell death regulation is an active process for shaping tissues and organs. In this review, we will present morphogens, with a specific emphasis on Sonic Hedgehog, a mammalian member of the Hh family, not as a positive regulators of cell differentiation but as key regulators of cell survival. © 2005 Wiley Periodicals, Inc. J Neurobiol 64: 357,366, 2005 [source] Targeted Expression of SHH Affects Chondrocyte Differentiation, Growth Plate Organization, and Sox9 Expression,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2004Sara Tavella Abstract The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation. Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates. Materials and Methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization. Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter. Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones. [source] Sonic Hedgehog signaling in the mammalian brainJOURNAL OF NEUROCHEMISTRY, Issue 3 2010Elisabeth Traiffort J. Neurochem. (2010) 113, 576,590. Abstract The discovery of a Sonic Hedgehog (Shh) signaling pathway in the mature vertebrate CNS has paved the way to the characterization of the functional roles of Shh signals in normal and diseased brain. Shh is proposed to participate in the establishment and maintenance of adult neurogenic niches and to regulate the proliferation of neuronal or glial precursors in several brain areas. Consistent with its role during brain development, misregulation of Shh signaling is associated with tumorigenesis while its recruitement in damaged neural tissue might be part of the regenerating process. This review focuses on the most recent data of the Hedgehog pathway in the adult brain and its relevance as a novel therapeutic approach for brain diseases including brain tumors. [source] A Sonic Hedgehog (SH) Fusion Protein Corrects Multifocal Defects In Experimental Diabetic NeuropathyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000Dr Tomlinson Diabetic neuropathy develops from defective interactions between nerve axons and other cells in the endoneurium; such interactions are influenced in development by hedgehog proteins. This study explored the possibility that this might be maintained in the adult and form a basis for therapy in diabetic neuropathies. Streptozotocin-diabetic rats were treated (final 5 weeks of 10 weeks diabetes) with a SH-IgG fusion protein (either 0.3mg/kg or 3.0mg/kg s.c. 3 times per week); control diabetic and non-diabetic rats received vehicle. Conduction velocity (MNCV, SNCV) data and sciatic nerve levels of nerve growth factor (NGF) and neuropeptide Y (NPY) are presented below. Diabetes caused significant (p < 0.05 by ANOVA with SNK tests) reductions in all variables and treatment with SH-IgG either attenuated or prevented (p < 0.05) these reductions. Since it is well-established that the conduction deficits are unrelated to neurotrophic deficits (NGF depletion) and that NPY depletion derives from a neurotrophic defect distinct from NGF, this treatment clearly acts at multiple components of the aetiology of diabetic neuropathy. [source] Cyclopia (synophthalmia) in Smith,Lemli,Opitz syndrome: First reported case and consideration of mechanism,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010David D. Weaver Abstract Here we present a 24-week fetus with Smith,Lemli,Opitz syndrome (SLOS), alobar holoprosencephaly (HPE) and cyclopia (synophthalmia). Following birth, we suspected SLOS in this fetus due to the additional findings of ambiguous genitalia and bilateral 2,3 toe syndactyly. The diagnosis of SLOS was confirmed by finding an elevated amniotic fluid 7-dehydrocholesterol level (9,890,ng/ml; normal range,=,3,9,ng/ml), and molecularly by detecting two different mutations in the DHCR7 gene, the gene causing SLOS. The first mutation was an IVS8-1G>T change and the second was a deletion of exons 3 and 4; this latter mutation has not been reported previously. The mother carries the deletion, while the father carries the splice-site mutation. Also of note, the father has an abnormally low total plasma cholesterol level (104,109,mg/dl). This is the most severe case of HPE described in any patient with SLOS. We postulate that the HPE in this case resulted from severe impairment of Sonic Hedgehog signaling secondary to abnormal cholesterol metabolism; however, the unique combination of mutations in the fetus functionally appears to be no different from other homozygous null mutations reported in DHCR7. Therefore, there must be other yet to be identified factors that contributed to the severity of HPE in SLOS. © 2010 Wiley-Liss, Inc. [source] Sonic and desert hedgehog signaling in human fetal prostate development,THE PROSTATE, Issue 6 2007Guodong Zhu Abstract Background Hedgehog signaling is thought to play an important role in rodent prostate organogenesis and morphogenesis. However, the role of this signaling pathway in human fetal prostate development has not been investigated. Methods Twenty-five human fetal prostates at various developmental stages (10,39 weeks) were included. Fifteen specimens were processed for H&E and immunohistochemical staining of the Hedgehog signaling components: Sonic Hedgehog (SHH), Desert Hedgehog (DHH), Patched-1(PTC1), Patched-2 (PTC2), Smoothened (SMO), GLI1, and proliferating cell nuclear antigen (PCNA). SHH, DHH, and GLI1 expression was also analyzed in ten snap-frozen specimens by Western blot. Results SHH, DHH, SMO, PTC1, GLI1, and PCNA expression, assessed by a semi-quantitative immunohistochemical method, was found mainly in the developing prostatic epithelial ducts, beginning at 10 weeks and peaking at 16 and 28 weeks with a dip occurring at 20 weeks, with the exception of PTC2. Conclusion Both SHH and DHH signaling components were detected during human fetal prostate development. Despite the high expression of PTC2 in the epithelium as well as the stroma in the early time of development, the expression of SHH, DHH, SMO, PTC1, and a SHH/DHH target transcription factor, GLI-1, were all largely restricted to epithelium in the developing prostate, suggesting that SHH/DHH signaling is primarily through an autocrine mechanism in human fetal prostate organogenesis. Prostate 67: 674,684, 2007. © 2007 Wiley-Liss, Inc. [source] Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxiaBIRTH DEFECTS RESEARCH, Issue 3 2003Maria Cristina Digilio BACKGROUND RSH/Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2,3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated. METHODS We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes. RESULTS Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis. CONCLUSIONS The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD ± common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations. Birth Defects Research (Part A) 67149,153, 2003. © 2003 Wiley-Liss, Inc. [source] Coordinated regulation of dorsal bone morphogenetic protein 4 and ventral Sonic hedgehog signaling specifies the dorso-ventral polarity in the optic vesicle and governs ocular morphogenesis through fibroblast growth factor 8 upregulationDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2010Takuma Kobayashi Dorsal and ventral specification in the early optic vesicle plays a crucial role in vertebrate ocular morphogenesis, and proper dorsal-ventral polarity in the optic vesicle ensures that distinct structures develop in separate domains within the eye primordium. The polarity is determined progressively during development by coordinated regulation of extraocular dorsal and ventral factors. In the present study, we cultured discrete portions of embryonic chick brains by preparing anterior cephalon, anterior dorsal cephalon and anterior ventral cephalon, and clearly demonstrate that bone morphogenetic protein 4 (BMP4) and Sonic hedgehog (Shh) constitute a dorsal-ventral signaling system together with fibroblast growth factor 8 (FGF8). BMP4 and Shh upregulate Tbx5 and Pax2, as reported previously, and at the same time Shh downregulates Tbx5, while BMP4 affects Pax2 expression to downregulate similarly. Shh induces Fgf8 expression in the ventral optic vesicle. This, in turn, determines the distinct boundary of the retinal pigmented epithelium and the neural retina by suppressing Mitf expression. The lens develops only when signals from both the dorsal and ventral regions come across together. Inverted deposition of Shh and BMP4 signals in organ-cultured optic vesicle completely re-organized ocular structures to be inverted. Based on these observations we propose a novel model in which the two signals govern the whole of ocular development when they encounter each other in the ocular morphogenic domain. [source] Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitroDEVELOPMENTAL DYNAMICS, Issue 10 2010K.L. Wells Abstract Hypohidrotic ectodermal dysplasia (HED) is characterized by defective ectodermal organ development. This includes the salivary glands (SGs), which have an important role in lubricating the oral cavity. In humans and mice, HED is caused by mutations in Ectodysplasin A (Eda) pathway genes. Various phenotypes of the mutant mouse EdaTa/Ta, which lacks the ligand Eda, can be rescued by maternal injection or in vitro culture supplementation with recombinant EDA. However, the response of the SGs to this treatment has not been investigated. Here, we show that the submandibular glands (SMGs) of EdaTa/Ta mice exhibit impaired branching morphogenesis, and that supplementation of EdaTa/Ta SMG explants with recombinant EDA rescues the defect. Supplementation of EdardlJ/dlJ SMGs with recombinant Sonic hedgehog (Shh) also rescues the defect, whereas treatment with recombinant Fgf8 does not. This work is the first to test the ability of putative Eda target molecules to rescue Eda pathway mutant SMGs. Developmental Dynamics 239:2674,2684, 2010. © 2010 Wiley-Liss, Inc. [source] Olfactory sensory axon growth and branching is influenced by sonic hedgehogDEVELOPMENTAL DYNAMICS, Issue 7 2009Qizhi Gong Abstract Olfactory sensory neuron (OSN) axons extend from the olfactory epithelium to the olfactory bulb without branching until they reach their target region, the glomerulus. In this report, we present evidence to support the involvement of sonic hedgehog in promoting rat olfactory sensory axons to branch and to enter into the glomerulus. Sonic hedgehog (Shh) protein is detected in the glomeruli of the olfactory bulb, whereas its transcript is expressed in the mitral and tufted cells, suggesting that Shh in the glomeruli is produced by mitral and tufted cells. In primary OSN cultures, Shh-N peptide promotes olfactory axon branching. When Shh function is neutralized in vivo by its antibody, growth of newly generated OSN axons into the glomeruli is vastly reduced. Developmental Dynamics 238:1768,1776, 2009. © 2009 Wiley-Liss, Inc. [source] Identification of candidate secreted factors involved in trigeminal placode inductionDEVELOPMENTAL DYNAMICS, Issue 10 2007Kathryn L. McCabe Abstract Cranial ectodermal placodes are critical for normal development of the peripheral nervous system of the head. However, many aspects of the molecular and tissue interactions involved in their induction have yet to be elucidated. The trigeminal placode is induced by an unidentified secreted factor(s) from the dorsal neural tube. To determine candidates that may be involved in this induction process, we have performed reverse transcriptase-polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization to screen for receptors expressed by uninduced presumptive trigeminal level ectoderm. We have found that receptors for fibroblast growth factors, insulin-like growth factors, platelet-derived growth factors, Sonic hedgehog, the transforming growth factor-beta superfamily, and Wnts all are expressed in patterns consistent with a role in trigeminal placode formation. This RT-PCR screen for candidate receptors expressed in presumptive trigeminal ectoderm is the first systematic screen to identify potential interactions underlying induction of the trigeminal placode and represents a critical step for understanding this complex process. Developmental Dynamics 236:2925,2935, 2007. © 2007 Wiley-Liss, Inc. [source] Studies on epidermal growth factor receptor signaling in vertebrate limb patterningDEVELOPMENTAL DYNAMICS, Issue 2 2005Minoru Omi Abstract The epidermal growth factor receptor (EGFR) regulates multiple patterning events in Drosophila limb development, but its role in vertebrate limb morphogenesis has received little attention. The EGFR and several of its ligands are expressed in developing vertebrate limbs in manners consistent with potential patterning roles. To gain insight into functions of EGFR signaling in vertebrate limb development, we expressed a constitutively active EGFR in developing chick limbs in ovo. Expression of activated EGFR causes pre- and postaxial polydactyly, including mirror-image,type digit duplication, likely due to induction of ectopic expression and/or modulation of genes involved in anterior,posterior (AP) patterning such as Sonic hedgehog (Shh), dHand, Patched (Ptc), Gli3, Hoxd13, Hoxd11, bone morphogenetic protein 2 (Bmp2), Gremlin, and FGF4. Activation of EGFR signaling dorsalizes the limb and alters expression of the dorsal,ventral (DV) patterning genes Wnt7a, Lmx, and En1. Ectopic and/or extended FGF8 expressing apical ectodermal ridges (AERs) are also seen. Interdigital regression is inhibited and the digits fail to separate, leading to syndactyly, likely due to antiapoptotic and pro-proliferative effects of activated EGFR signaling on limb mesoderm, and/or attenuation of interdigital Bmp4 expression. These findings suggest potential roles for EGFR signaling in AP and DV patterning, AER formation, and cell survival during limb morphogenesis. Developmental Dynamics 233:288,300, 2005. © 2005 Wiley-Liss, Inc. [source] Chick limbs with mouse teeth: An effective in vivo culture system for tooth germ development and analysisDEVELOPMENTAL DYNAMICS, Issue 1 2003Eiki Koyama Abstract Mouse tooth germ development is currently studied by three main approaches: in wild-type and mutant mouse lines, after transplantation of tooth germs to ectopic sites, and in organ culture. The in vivo approaches are the most physiological but do not provide accessibility to tooth germs for further experimental manipulation. Organ cultures, although readily accessible, do not sustain full tooth germ development and are appropriate for short-term analysis. Thus, we sought to establish a new approach that would combine experimental accessibility with sustained development. We implanted fragments of embryonic day 12 mouse embryo first branchial arch containing early bud stage tooth germs into the lateral mesenchyme of day 4,5 chick embryo wing buds in ovo. Eggs were reincubated, and implanted tissues were examined by histochemistry and in situ hybridization over time. The tooth germs underwent seemingly normal growth, differentiation, and morphogenesis. They reached the cap, bell, and crown stages in approximately 3, 6, and 10 days, respectively, mimicking in a striking manner native temporal patterns. To examine mechanisms regulating tooth germ development, we first implanted tooth germ fragments, microinjected them with neutralizing antibodies to the key signaling molecule Sonic hedgehog (Shh), and examined them over time. Tooth germ development was markedly delayed, as revealed by poor morphogenesis and lack of mature ameloblasts and odontoblasts displaying characteristic traits such as an elongated cell shape, nuclear relocalization, and amelogenin gene expression. These phenotypic changes began to be reversed upon further incubation. The data show that the limb bud represents an effective, experimentally accessible as well as economical system for growth and analysis of developing tooth germs. The inhibitory effects of Shh neutralizing antibody treatment are discussed in relation to roles of this signaling pathway proposed by this and other groups previously. © 2002 Wiley-Liss, Inc. [source] Expression of cell fate determinants and plastic changes after neurotoxic lesion of adult mice spinal cord by cholera toxin-B saporinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2010Rosario Gulino Abstract Recent studies have attempted to repair the damaged spinal cord (SC) by stimulating neurogenesis or neuroplasticity. Sonic hedgehog (Shh), Notch-1 and Numb are involved in the stem cell functioning. Additionally, Notch-1 has a role as modulator of synaptic plasticity. However, little is known about the role of these proteins in the adult SC after removal of motoneurons. In this study, we have injected cholera toxin-B saporin into the gastrocnemius muscle to induce a depletion of motoneurons within the lumbar SC of adult mice, and analysed the expression of choline acetyltransferase (ChAT), Synapsin-I, Shh, Notch-1 and Numb proteins. The functional outcome of the lesion was monitored by grid walk and rotarod tasks. The neurotoxin lesion determined a motoneuron depletion and a transient decrease of ChAT, Synapsin-I, Shh and Numb levels in the lumbar SC. ChAT was associated with Synapsin-I expression and motor performance at 1 week but not 1 month after lesion, suggesting that the recovery of locomotion could depend on synaptic plasticity, at least in an early phase. Shh and Notch-1 were associated with Synapsin-I levels, suggesting a role in modulating synaptic plasticity. Numb expression also appeared reduced after lesion and linked to motor performance. Moreover, unlike other lesion models, we observed glial reaction but no evidence of cell proliferation within the depleted SC. Given the mentioned roles of Shh, Notch-1 and Numb, we believe that an in vivo manipulation of their signalling after lesion could represent a suitable way to improve functional recovery by modulating synaptic plasticity and/or neurogenesis. [source] Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2005Sunayana B. Banerjee Abstract Electroconvulsive seizure (ECS) induces structural remodelling in the adult mammalian brain, including an increase in adult hippocampal neurogenesis. The molecular mechanisms that underlie this increase in the proliferation of adult hippocampal progenitors are at present not well understood. We hypothesized that ECS may recruit the Sonic hedgehog (Shh) pathway to mediate its effects on adult hippocampal neurogenesis, as Shh is known to enhance the proliferation of neuronal progenitors and is expressed in the adult basal forebrain, a region that sends robust projections to the hippocampus. Here we demonstrate that the ECS-induced increase in proliferation of adult hippocampal progenitors was completely blocked in animals treated with cyclopamine, a pharmacological inhibitor of Shh signalling. Our results suggest that both acute and chronic ECS enhance Shh signalling in the adult hippocampus, as we observed a robust upregulation of Patched (Ptc) mRNA, a component of the Shh receptor complex and a downstream transcriptional target of Shh signalling. This increase was rapid and restricted to the dentate gyrus, where the adult hippocampal progenitors reside. In addition, both acute and chronic ECS decreased Smoothened (Smo) mRNA, the other component of the Shh receptor complex, selectively within the dentate gyrus. However, ECS did not appear to influence Shh expression within the basal forebrain, the site from which it has been suggested to be anterogradely transported to the hippocampus. Together, our findings demonstrate that ECS regulates the Shh signalling cascade and indicate that the Shh pathway may be an important mechanism through which ECS enhances adult hippocampal neurogenesis. [source] Development of heterodont dentition in house shrew (Suncus murinus)EUROPEAN JOURNAL OF ORAL SCIENCES, Issue 6 2007Atsushi Yamanaka Mammalian heterodont dentition comprises incisors, canines, premolars, and molars. Although there has been intensive research, the patterning of these specific tooth types has not yet been elucidated. In order for the gene expression data to be linked with tooth type determination, it is first necessary to determine precisely the incisor-, canine-, premolar-, and molar-forming regions in the jaw primordia. To accomplish this, we studied dentition development in the house shrew (Suncus murinus), which has retained all the tooth types, using three-dimensional reconstructions from serial histological sections and the Sonic hedgehog (Shh) expression patterns. Before the appearance of morphological signs of odontogenesis, Shh expression localized to the presumptive tooth-forming regions, in which the mesial and distal expression domains corresponded to the incisor- and premolar-forming regions, respectively. The upper incisor region was found to extend across the boundary between the frontonasal and the maxillary processes. The canine-forming regions later appeared in the intermediate portions of the maxillary and the mandibular processes. The molar-forming regions later appeared distal to the initially demarcated tooth-forming regions by secondary extension of the distal ends. The demarcation visualized by the Shh expression pattern in the jaw primordia of the house shrew probably represents the basic developmental pattern of mammalian heterodont dentition. [source] Insight into the pathogenesis of sporadic basal cell carcinomaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 12 2004Zuzana Holíková Sporadic basal cell carcinoma (BCC) is the commonest human cancer. Although its aggressiveness is low and metastatic potential negligible, the increasing incidence of the tumor in the Western world drives attention to its pathogenesis. In 1996, germ-line mutations in the patched receptor of the Sonic hedgehog (Shh) signaling pathway were described in the Gorlin,Goltz syndrome in association with multiple nevoid BCCs. Later, the aberrant activation of the Shh was identified in sporadic BCCs as well. Recently, the role of other tumor suppressors and DNA repair gene mutations and their relationship with UV radiation-induced DNA damage have been elucidated. [source] Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2002Takahito Yuasa The roles of Sonic hedgehog (Shh) and Bone morphogenetic protein-2 (Bmp-2) in osteoblast differentiation were investigated using in vitro cell systems. Recombinant amino-terminal portion of SHH (rSHH-N) dose dependently stimulated ALP activity in C3H10T1/2 and MC3T3-E1 cells. rSHH-N induced expression of Osteocalcin mRNA in C3H10T1/2 cells. A soluble form of the receptor for type IA BMP receptor antagonized rSHH-N-induced ALP activity in C3H10T1/2 and MC3T3-E1 cells, indicating that BMPs are involved in SHH-induced osteoblast differentiation. Simultaneous supplement with rSHH-N and BMP-2 synergistically induced ALP activity and expression of Osteocalcin mRNA in C3H10T1/2 cells. Pretreatment with rSHH-N for 6 h enhanced the response to BMP-2 by increasing ALP activity in C3H10T1/2 and MC3T3-E1 cells. Stimulatory effects of rSHH-N and additive effects with rSHH-N and BMP-2 on ALP activity were also observed in mouse primary osteoblastic cells. Transplantation of BMP-2 (1 ,g) into muscle of mice induced formation of ectopic bone, whereas transplantation of r-SHH-N (1,5 ,g) failed to generate it. These results indicate that Shh plays important roles in osteoblast differentiation by cooperating with BMP. © 2002 Wiley-Liss, Inc. [source] Hedgehog in the human: A possible explanation for the VATER associationJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 2 2002D Arsic Abstract: Foregut malformations are relatively common anomalies, occurring in 1 in 2000,5000 live births. The adriamycin-induced rat model of the VATER association has provided a means of studying the morphogenesis of a variety of major congenital structural abnormalities similar to those seen in humans with VATER association. The secreted glycoprotein, Sonic hedgehog (Shh), may act as an endodermal signal that controls gut and lung patterning. Mice with targeted deletion of Shh have foregut defects that are consistent with those produced by administration of adriamycin. It is possible that mutations induced by adriamycin may result from the breakdown of the Shh signalling pathway. [source] Pathogenesis of medulloblastoma and current treatment outlookMEDICINAL RESEARCH REVIEWS, Issue 6 2007Jaroslaw Jozwiak Abstract Medulloblastoma is the most common malignant tumor of the cerebellum in children, with a tendency to metastasize via CSF pathway. Survival rate varies depending on several factors, but is rather favorable, with radiotherapy as the treatment of choice. Irradiation of the craniospinal axis results, however, in severe neuropsychological and psychosocial impairments pertaining to memory, attention, motor functioning, language, and visuospatial abilities. Precise mechanisms underlying the formation of medulloblastoma are still unclear, but implication of at least three signaling molecules is postulated: insulin-like growth factor-I, WNT, and Sonic hedgehog. Thanks to increasing knowledge on the cellular mechanisms contributing to tumor formation, it is possible to propose new therapies that could replace radiotherapy or allow decreasing irradiation doses. The current review presents recent developments in medulloblastoma pathophysiology research and proposed inhibitors that could constitute good candidates for further pharmacological research. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 6, 869,890, 2007 [source] Molecular Reproduction & Development: Volume 77, Issue 6, Cover imageMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 6 2010Article first published online: 21 APR 2010 This adrenal section shown was taken from a 1 year-old mouse lacking Sonic hedgehog (Shh) in the steroidogenic factor-positive adrenal cortical cells during fetal life. Lack of Shh did not affect formation of the cortex (magenta, positive for 3beta-HSD) and medulla (green, positive for tyrosine hydroxylase). However, the mutant adrenal cortex underwent hypoplasia and hypertrophy with age. The section was counterstained with the nuclear dye DAPI (blue). See the accompanying review by Huang and Yao in this issue. [source] Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010John Klingensmith Abstract Holoprosencephaly (HPE) is the most common malformation of the forebrain, resulting from a failure to completely septate the left and right hemispheres at the rostral end of the neural tube. Because of the tissue interactions that drive head development, these forebrain defects are typically accompanied by midline deficiencies of craniofacial structures. Early events in setting up tissue precursors of the head, as well as later interactions between these tissues, are critical for normal head formation. Defects in either process can result in HPE. Signaling by bone morphogenetic proteins (BMPs), a family of secreted cytokines, generally plays negative roles in early stages of head formation, and thus must be attenuated in multiple contexts to ensure proper forebrain and craniofacial development. Chordin and Noggin are endogenous, extracellular antagonists of BMP signaling that promote the normal organization of the forebrain and face. Mouse mutants with reduced levels of both factors display mutant phenotypes remarkably analogous to the range of malformations seen in human HPE sequence. Chordin and Noggin function in part by antagonizing the inhibitory effects of BMP signaling on the Sonic hedgehog and Nodal pathways, genetic lesions in each being associated with human HPE. Study of Chordin;Noggin mutant mice is helping us to understand the molecular, cellular, and genetic pathogenesis of HPE and associated malformations. © 2010 Wiley-Liss, Inc. [source] Analysis of Testosterone Effects on Sonic Hedgehog Signaling in Juvenile, Adolescent and Adult Sprague Dawley Rat PenisTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2010Christopher W. Bond MS ABSTRACT Introduction., Smooth muscle apoptosis is a major contributing factor to erectile dysfunction (ED) development in prostatectomy and diabetic patients and animal models. A critical regulator of penile smooth muscle and apoptosis is Sonic hedgehog (SHH). The SHH protein is decreased in ED models and SHH treatment of cavernous nerve (CN) injured rats prevents smooth muscle apoptosis. A close association between androgen deficiency and ED has been suggested in the literature, but few studies have examined the molecular effects on penile smooth muscle and on known signaling mechanisms that regulate morphology. Aim., Examine testosterone and SHH interaction in eugonadal adult, adolescent and juvenile rats by performing castration studies and treatment with supraphysiological testosterone. Methods., The eugonadal adult Sprague Dawley rats were either treated with testosterone for 7 or 14 days (N = 14) or were castrated for 4 or 7 days (N = 12). The juvenile rats were treated with testosterone for 8 days (N = 7). The adolescent rats were castrated and sacrificed at P88 (N = 8). The control rats had empty vehicle (N = 22) or sham surgery (N = 20). Main Outcome Measures., The active form of SHH protein and mRNA were quantified by semi-quantitative immunohistochemical analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results., Testosterone treatment did not alter SHH signaling in juvenile rats. Shh mRNA increased 3.2-fold and SHH protein increased 1.2-fold in rats castrated during puberty. In adult rats, castration decreased Shh mRNA 3.2-fold but did not alter SHH protein. Testosterone supplement in adult rats increased Shh mRNA 2.3-fold and decreased SHH protein 1.3-fold. Conclusions., SHH signaling is independent of testosterone in normal juvenile rats and is sensitive to testosterone during adolescence, while testosterone supplement in the adult adversely impacts SHH signaling in a very similar manner to that observed with CN injury. Bond CW, Angeloni NL, and Podlasek CA. Analysis of testosterone effects on sonic hedgehog signaling in juvenile, adolescent and adult Sprague Dawley rat penis. J Sex Med 2010;7:1116,1125. [source] Emerging mechanisms in morphogen-mediated axon guidanceBIOESSAYS, Issue 10 2009Cristina Sánchez-Camacho Abstract Early in animal development, gradients of secreted morphogenic molecules, such as Sonic hedgehog (Shh), Wnt and TGF,/Bmp family members, regulate cell proliferation and determine the fate and phenotype of the target cells by activating well-characterized signalling pathways, which ultimately control gene transcription. Shh, Wnt and TGF,/Bmp signalling also play an important and evolutionary conserved role in neural circuit assembly. They regulate neuronal polarization, axon and dendrite development and synaptogenesis, processes that require rapid and local changes in cytoskeletal organization and plasma membrane components. A key question then is whether morphogen signalling at the growth cone uses similar mechanisms and intracellular pathway components to those described for morphogen-mediated cell specification. This review discusses recent advances towards the understanding of this problem, showing how Shh, Wnt and TGF,/Bmp have adapted their ,classical' signalling pathways or adopted alternative and novel molecular mechanisms to influence different aspects of neuronal circuit formation. [source] Why cavefish are blindBIOESSAYS, Issue 3 2005Natasha M.M.-L. Some fish exist as eyed, surface-dwelling and eyeless, cave-dwelling forms. The developmental processes that cause eye degeneration in different populations of Astyanax cavefish are similar. Although small optic primordia start to form, apoptosis of lens cells triggers developmental arrest and degeneration of the eyes. Degeneration has been linked to reduced expression of the transcription factor Pax6 in the anterior embryonic midline and optic primordia. Recently, Yamamoto and colleagues1 reported that increased expression of the diffusible morphogen Sonic hedgehog (Shh) at the embryonic midline of cavefish reduces pax6 expression and increases expression of Shh-regulated genes, which might confer selective advantages for life in caves. BioEssays 27:235,238, 2005. © 2005 Wiley Periodicals, Inc. [source] Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cellsCANCER SCIENCE, Issue 6 2008Madoka Yamazaki Hedgehog signaling is important in the pathogenesis of pancreatic cancer. Several recent observations suggest the involvement of sonic hedgehog (SHH) in postnatal neovascularization. We identified a novel role for SHH in tumor-associated angiogenesis in pancreatic cancer. Immunohistochemical analysis revealed that patched homolog 1 (PTCH1), both a receptor for and transcriptional target of hedgehog signaling, was expressed in a small fraction of endothelial cells within pancreatic cancer, but not in normal pancreatic tissue. When endothelial progenitor cells (EPC) isolated from human peripheral blood were cultured with supernatant from SHH-transfected 293 cells or pancreatic cancer cells, mRNA levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and angiopoietin-1 were significantly increased, whereas no such induction was observed in human umbilical vein endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMVEC). HUVEC tube formation was stimulated when cocultured with EPC, and preconditioning EPC with supernatant from KP-1 N pancreatic cancer cells highly expressing SHH significantly enhanced the effect. The effect was partially attenuated by specific inhibition of SHH with cyclopamine or a neutralizing antibody. These findings suggest that tumor-derived SHH can induce angiogenesis, and this is mediated by its effects on EPC specifically. Targeting SHH would be a novel therapeutic approach that can inhibit not only proliferation of cancer cells but also EPC-mediated angiogenesis. (Cancer Sci 2008; 99: 1131,1138) [source] Essential roles of Gli3 and sonic hedgehog in pattern formation and developmental anomalies caused by their dysfunctionCONGENITAL ANOMALIES, Issue 3 2006Jun Motoyama ABSTRACT Pattern formation along the body axis directs the proportion of different types of cells required for functional tissue structures. The secreted protein sonic hedgehog (Shh) and zinc finger transcription factor Gli3 are key players in pattern formation during brain and limb development; the antagonistic action of Shh towards Gli3 may be crucial for pattern formation. Recent findings from Shh/Gli3 double homozygous mutants suggest that a balance of both activities is required for the production of the normal proportion of different cell types during organogenesis. This conclusion contrasts with the alternative hypothesis that a Shh gradient directs the specification of several different cell types. The observations reviewed here offer a new perspective on understanding the pathogenesis of human birth defects caused by mutations of the Shh and Gli3 genes. [source] Busulfan-induced central polydactyly, syndactyly and cleft hand or foot: A common mechanism of disruption leads to divergent phenotypesDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2007Takuji Naruse The prevalence of clinical phenotypes that exhibit combinations of central polydactyly, syndactyly, or cleft hand or foot is higher than would be expected for random independent mutations. We have previously demonstrated that maternal ingestion of a chemotherapeutic agent, busulfan, at embryonic day 11 (E11) induces these defects in various combinations in rat embryo limbs. In an effort to determine the mechanism by which busulfan disrupts digital development, we examined cell death by Nile Blue staining and TdT-mediated dUTP nick end labeling (TUNEL) assays; we also carried out whole mount in situ hybridization for fibroblast growth factor-8 (Fgf8), bone morphogenetic protein-4 (Bmp4), and sonic hedgehog (Shh) to examine developmental pathways linked to these defects. In busulfan-treated embryos, diffuse cell death was evident in both ectoderm and mesoderm, peaking at E13. The increased cell death leads to regression of Fgf8 in the apical ectodermal ridge (AER) and Bmp4 and Shh in the underlying mesoderm. The subsequent pattern of interdigital apoptosis and cartilage condensation was variably disrupted. These results suggest that busulfan manifests its teratogenic effects by inducing cell death of both ectoderm and mesoderm, with an associated reduction in tissue and a disruption in the generation of patterning molecules during critical periods of digit specification. [source] | ||||||||||||||||||||||||||||