Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Hedgehogs”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed2005

Characterization of Rab23, a negative regulator of sonic hedgehog signaling.

The hedgehog signaling pathway is indispensable in embryogenesis, being responsible for the development of a wide array of vertebrate organs. Given its importance in embryogenesis, the precise regulation of hedgehog signaling is crucial. Aberrant activation of this pathway in postnatal life has been associated with a number of tumor types, reinforcing the role of developmental signaling pathways in tumorigenesis. The small GTPase Rab23 acts as a negative regulator of the hedgehog signaling pathway, most notably in the vertebrate neural system. By analogy with studies of other Rab proteins, analysis of the localization of wild-type and constitutively active and inactive forms of Rab23 provides the potential to shed light on the role of Rab23 at the cellular level. We previously produced expression constructs encoding these proteins for analysis in mammalian cell cultures at both the light and the electron microscopy level. This revealed that both wild-type and active Rab23 localizes to the plasma membrane and to endocytic vesicles (T. M. Evans et al. [2003] Traffic4, 869-884). We describe the methods used to design and make the Rab23 expression constructs, and to assess their localization relative to key hedgehog pathways and endocytic markers in both transiently and stably transfected cell cultures.

Amino Acid Sequence↗
PubMed2000

Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.

Ci/Gli zinc finger proteins mediate the transcriptional effects of Hedgehog protein signals. In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing. We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid2, producing a range of limb patterning malformations. The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation.

Animals↗
PubMed1997

The world according to hedgehog.

Members of the Hedgehog family of signaling molecules mediate many important short- and long-range patterning processes during invertebrate and vertebrate development. In the fly, a single hedgehog gene regulates segmental and imaginal disc patterning. In contrast, in vertebrates a hedgehog gene family is involved in the control of left-right asymmetry, polarity in the central nervous system (CNS), somites and limb, organogenesis, chondrogenesis and spermatogenesis. Here, we review recent experiments addressing the function of the various Hedgehog members during invertebrate and vertebrate development.

Animals↗
PubMed2001

The nodal pathway acts upstream of hedgehog signaling to specify ventral telencephalic identity.

The Nodal and Hedgehog signaling pathways influence dorsoventral patterning at all axial levels of the CNS, but it remains largely unclear how these pathways interact to mediate patterning. Here we show that, in zebrafish, Nodal signaling is required for induction of the homeobox genes nk2.1a in the ventral diencephalon and nk2.1b in the ventral telencephalon. Hedgehog signaling is also required for telencephalic nk2.1b expression but may not be essential to establish diencephalic nk2.1a expression. Furthermore, Shh does not restore ventral diencephalic development in embryos lacking Nodal activity. In contrast, Shh does restore telencephalic nk2.1b expression in the absence of Nodal activity, suggesting that Hedgehog signaling acts downstream of Nodal activity to pattern the ventral telencephalon. Thus, the Nodal pathway regulates ventral forebrain patterning through both Hedgehog signaling-dependent and -independent mechanisms.

Animals↗
PubMed1998

Role of sonic hedgehog in branchiomotor neuron induction in zebrafish.

The role of zebrafish hedgehog genes in branchiomotor neuron development was analyzed by examining mutations that affect the expression of the hedgehog genes and by overexpressing these genes in embryos. In cyclops mutants, reduction in sonic hedgehog (shh) expression, and elimination of tiggy-winkle hedgehog (twhh) expression, correlated with reductions in branchiomotor neuron populations. Furthermore, branchiomotor neurons were restored in cyclops mutants when shh or twhh was overexpressed. These results suggest that Shh and/or Twhh play an important role in the induction of branchiomotor neurons in vivo. In sonic-you (syu) mutants, where Shh activity was reduced or eliminated due to mutations in shh, branchiomotor neurons were reduced in number in a rhombomere-specific fashion, but never eliminated. Similarly, spinal motor neurons were reduced, but not eliminated, in syu mutants. These results demonstrate that Shh is not solely responsible for inducing branchiomotor and spinal motor neurons, and suggest that Shh and Twhh may function as partially redundant signals for motor neuron induction in zebrafish.

Animals↗
PubMed1995

Patterning activities of vertebrate hedgehog proteins in the developing eye and brain.

BACKGROUND: The hedgehog (hh) family of secreted signaling proteins is responsible for developmental patterning in a variety of systems, including the neural tube, limbs and somites. Within the neural tube, at the level of the spinal cord, products of the vertebrate gene sonic hedgehog (shh) are proposed to function as a ventral patterning influence, with the capability of inducing floor plate and motor neurons. RESULTS: We report the isolation of tiggy-winkle hedgehog (twhh), a novel member of the zebrafish hh gene family. Both twhh and shh are expressed in the ventral midline of the embryonic zebrafish neural tube and brain, but twhh expression becomes limited to the neural tube, whereas shh is also expressed in the notochord. Both genes are expressed in the developing brain, in domains that include a discrete region in the floor of the diencephalon, located between the sites of the future optic stalks. Using pax-2 and pax-6 as markers of proximo-distal fate within the developing eye, we found that ectopic expression of either hh gene promoted proximal fates and suppressed distal fates. In contrast, proximal fates were lost in cyclops mutant embryos, which lack twhh- and shh-expressing forebrain cells. Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. CONCLUSIONS: These findings suggest that secreted signals encoded by members of the hedgehog gene family, emanating from the ventral midline of the neural tube, not only play important roles in dorso-ventral patterning of the brain but also appear to constitute an early patterning activity along the proximo-distal axis of the developing eyes.

Amino Acid Sequence↗
PubMed2003

Hedgehog promotes primary osteoblast differentiation and increases PTHrP mRNA expression and iPTHrP secretion.

We used both clonal osteoblast-like cells and primary calvarial osteoblastic cells to examine the role of Hedgehog in osteoblast biology. Primary osteoblasts and several clonal osteoblast-like cell lines express Indian hedgehog (Ihh), and genes encoding both components of its receptor, patched (Ptc) and smoothened (Smo). Moreover, Ihh is relatively increased in phenotypically mature clonal cells and it increases by fivefold in primary osteoblasts as they mature in culture. Recombinant N-terminal Sonic Hedgehog (rSHH-N) upregulates Ptc and Gli-1 in osteoblasts, classical transcriptional targets. Furthermore; in response to rSHH-N, immunoreactive parathyroid hormone-related peptide (iPTHrP) secretion is transiently increased in medium conditioned by primary osteoblasts. Changes in PTHrP expression mirror those of iPTHrP, except in late cultures, when mRNA levels remain relatively elevated in response to rSHH-N. Gli-1, but not Ptc, becomes resistant to treatment with rSHH-N over a time course paralleling that of PTHrP, suggesting that mechanisms regulated by Gli-1 affect PTHrP. Last, rSHH-N increases formation of mineralized bone nodules and it accelerates expression of alkaline phosphatase, alkaline phosphatase activity, and mineralization. Taken together, these data suggest a functional role for Hedgehog protein in osteoblast recruitment and differentiation, which includes stimulation of PTHrP expression and secretion.

Animals↗
PubMed1995

The product of hedgehog autoproteolytic cleavage active in local and long-range signalling.

The secreted protein products of the hedgehog (hh) gene family are associated with local and long-range signalling activities that are responsible for developmental patterning in multiple systems, including Drosophila embryonic and larval tissues and vertebrate neural tube, limbs and somites. In a process that is critical for full biological activity, the hedgehog protein (Hh) undergoes autoproteolysis to generate two biochemically distinct products, an 18K amino-terminal fragment, N, and a 25K carboxy-terminal fragment, C (ref. 16); mutations that block autoproteolysis impair Hh function. We have identified the site of autoproteolytic cleavage and find that it is broadly conserved throughout the hedgehog family. Knowing the site of cleavage, we were able to test the function of the N and C cleavage products in Drosophila assays. We show here that the N product is the active species in both local and long-range signalling. Consistent with this, all twelve mapped hedgehog mutations either affected the structure of the N product directly or otherwise blocked the release of N from the Hh precursor as a result of deletion or alteration of sequences in the C domain.

Amino Acid Sequence↗
PubMed1995

Cytogenetic peculiarities in the Algerian hedgehog: silver stains not only NORs but also heterochromatic blocks.

Hedgehogs belong to one of the several mammalian taxa in which karyotype differences are based on variations in heterochromatin content. Furthermore, the number and location of nucleolar organizer regions (NORs) can also vary widely. In the present study these cytogenetic features were investigated in the Algerian hedgehog, Erinaceus (Aethechinus) algirus. The heterochromatin and NOR distribution patterns in the karyotype of this species are new among hedgehogs, whereas the euchromatic regions, including their G-band pattern, are similar to those reported by others. In addition, silver staining revealed a cytogenetic feature exclusive to the heterochromatic blocks of E. algirus: their silver staining with standard cytogenetic procedures. Because no similar phenomenon has been described previously in a mammalian species, several hypotheses about the significance and specificity of silver staining to NOR sites are discussed. Finally, the existence of different types of heterochromatin in the species analysed here, lead us to propose that what hedgehogs have inherited from their common ancestor is a mechanism which permits the accumulation of heterochromatin on specific chromosomes, rather than the heterochromatin itself.

Animals↗
PubMed1995

Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein.

Loss of substantia nigra dopaminergic neurons, which develop from the ventral region of the midbrain, is associated with Parkinson's disease. During embryogenesis, induction of these and other ventral neurons is influenced by interactions with the induction of mesoderm of the notochord and the floor plate, which lies at the ventral midline of the developing CNS. Sonic hedgehog encodes a secreted peptide, which is expressed in notochord and floor plate cells and can induce appropriate ventral cell types in the basal forebrain and spinal cord. Here we demonstrate that Sonic hedgehog is sufficient to induce dopaminergic and other neuronal phenotypes in chick mesencephalic explants in vitro. We find that Sonic hedgehog is a general ventralizing signal in the CNS, the specific response being determined by the receiving cells. These results suggest that Sonic hedgehog may have utility in the induction of clinically important cell types.

Animals↗
PubMed2006

Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development.

Sonic hedgehog has received an enormous amount of attention since its role as a morphogen that directs ventral patterning in the spinal cord was discovered a decade ago. Since that time, a bewildering array of information has been generated concerning both the components of the hedgehog signalling pathway and the remarkable number of contexts in which it functions. Nowhere is this more evident than in the nervous system, where hedgehog signalling has been implicated in events as disparate as axonal guidance and stem cell maintenance. Here we review our present knowledge of the hedgehog signalling pathway and speculate about areas in which further insights into this versatile pathway might be forthcoming.

Animals↗
PubMed2003

A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1.

BACKGROUND: Hedgehogs (Hhs) and their receptors are involved in organ development as well as in tumorigenesis observed in basal cell carcinoma. Among Hhs, Desert hedgehog secreted from Schwann cells mediates the formation of peripheral nerve sheaths. However, there has been no study on the role of Hhs and their receptors in tumorigenesis of neurofibromas in neurofibromatosis type 1 (NF1). OBJECTIVES: To clarify the expression and localization of Hhs and their receptors in neurofibromas of NF1 patients. METHODS: Expression of Hhs and their receptors was studied by immunohistochemistry using neurofibromas from NF1 patients and control normal skin samples. RESULTS: In neurofibromas, CD57-positive tumour cells with delicate elongated processes were positive for the receptor PTCH2. Perineurial cells of involved nerves within neurofibromas as well as those of normal cutaneous nerves expressed Indian hedgehog and Sonic hedgehog. Schwann cells of normal cutaneous nerves were positive for PTCH2. CONCLUSIONS: Our study suggests that a paracrine Hh signalling pathway may be involved in tumorigenesis of neurofibromas in NF1.

CD57 Antigens↗
PubMed1998

Regional distribution of Sonic Hedgehog, patched, and smoothened mRNA in the adult rat brain.

In vertebrates, Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh) genes encode a family of morphogen proteins that are implicated in a wide range of signaling activities, particularly during embryonic development. These secreted proteins are proposed to mediate their effects on target cells by interacting with their putative receptor, Patched (Ptc), and with a seven-pass transmembrane protein, Smoothened (Smo). However, the roles that these signaling molecules may play in adult tissues, particularly in brain, are not yet clearly defined. Therefore, we investigated the expression of these genes in adult rat tissues. Northern blot analysis revealed expression of Shh, Dhh, and Ihh genes in peripheral tissues, whereas Shh transcript was also identified in brain. It is interesting that northern blot analysis with probes derived from the mouse Ptc and Smo genes revealed the expression of a 7.9-kb and a 3.7-kb transcript, respectively, in all brain tissues examined. In situ hybridization experiments using specific digoxigenin-labeled riboprobes showed expression of Ptc and Smo transcripts in discrete brain areas. Shh-positive cells were observed in restricted regions of the brain. Within the cerebellum, Shh, Ptc, and Smo transcripts were colocalized in the Purkinje cell layer. These data suggest that, besides its roles in determining cell fate and patterning during embryogenesis, the hedgehog signaling pathway may have also important roles in the adult brain.

Age Factors↗
PubMed2001

Activation of expression of hedgehog target genes in basal cell carcinomas.

Mutations in hedgehog signaling pathway genes, especially PTC1 and SMO, are pivotal to the development of basal cell carcinomas. The study of basal cell carcinoma gene expression not only may elucidate mechanisms by which hedgehog signaling abnormalities produce aberrant tumor cell behavior but also can provide data on in vivo hedgehog target gene control in humans. We have found, in comparison with normal skin, that basal cell carcinomas have increased levels of mRNA for PTC1, GLI1, HIP, WNT2B, and WNT5a; decreased levels of mRNA for c-MYC, c-FOS, and WNT4; and unchanged levels of mRNA for PTC2, GLI2, WNT7B, and BMP2 and 4. These findings suggest that mutations in hedgehog signaling pathway genes may exert both cell autonomous and indirect effects and indicate that basal cell carcinoma tumor cells have a phenotype that at least in some aspects resembles that of epidermal stem cells.

Basal Cell Carcinoma↗
PubMed2006

Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer.

BACKGROUND & AIMS: Sonic hedgehog (SHH) and Indian hedgehog (IHH) have cell-specific actions in some organs. Only SHH has been shown to regulate parietal cell differentiation. This study examined whether SHH, 2 other ligands IHH and Desert hedgehog, and receptors or downstream targets are expressed in normal gastric epithelium or in intestinal and diffuse-type gastric cancers. The effects of a Hedgehog (Hh) inhibitor, cyclopamine, were assessed in primary gastric epithelium cultures and gastric cancer cell lines. METHODS: Reverse-transcription polymerase chain reaction and immunostaining compared expression and localization of Hh signaling molecules and phenotypic markers of pit, neck, and gland cells in situ and in cultured cells treated with cyclopamine. Bromodeoxyuridine staining assessed the effects of cyclopamine on proliferation. RESULTS: Hh signaling molecules were expressed differentially in pit, neck, and gland cells. IHH co-expressed with most downstream targets in the pit. IHH, SHH, Patched (PTCH), Smoothened (SMO), and downstream targets were expressed more frequently and highly in the diffuse as compared with intestinal type cancers. In diffuse cancers, IHH was expressed in cells with an epithelial phenotype and SHH in cells with a mesenchymal phenotype. Cyclopamine reduced the number of cells with a pit phenotype but not a gland phenotype in primary cultures. Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO. CONCLUSIONS: Expression of IHH and downstream targets correlates with pit cells. IHH and SMO may be useful biomarkers of diffuse cancers that may show growth inhibition with Hh antagonists such as cyclopamine.

Animals↗
PubMedDate not supplied

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

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.

Animals↗
PubMed2003

Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis.

In mammalian epidermis, the level of beta-catenin signaling regulates lineage selection by stem cell progeny. High levels of beta-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of beta-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks beta-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of beta-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH/Ptch). In DeltaNLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of DeltaNLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between beta-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.

Animals↗
PubMed1996

Evolutionary analyses of hedgehog and Hoxd-10 genes in fish species closely related to the zebrafish.

The study of development has relied primarily on the isolation of mutations in genes with specific functions in development and on the comparison of their expression patterns in normal and mutant phenotypes. Comparative evolutionary analyses can complement these approaches. Phylogenetic analyses of Sonic hedgehog (Shh) and Hoxd-10 genes from 18 cyprinid fish species closely related to the zebrafish provide novel insights into the functional constraints acting on Shh. Our results confirm and extend those gained from expression and crystalline structure analyses of this gene. Unexpectedly, exon 1 of Shh is found to be almost invariant even in third codon positions among these morphologically divergent species suggesting that this exon encodes for a functionally important domain of the hedgehog protein. This is surprising because the main functional domain of Shh had been thought to be that encoded by exon 2. Comparisons of Shh and Hoxd-10 gene sequences and of resulting gene trees document higher evolutionary constraints on the former than on the latter. This might be indicative of more general evolutionary patterns in networks of developmental regulatory genes interacting in a hierarchical fashion. The presence of four members of the hedgehog gene family in cyprinid fishes was documented and their homologies to known hedgehog genes in other vertebrates were established.

Amino Acid Sequence↗