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PubMed1995

Restrictions to floor plate induction by hedgehog and winged-helix genes in the neural tube of frog embryos.

Intercellular signaling molecules of the vertebrate hedgehog family and transcription factors of the winged-helix family have been implicated in floor plate development. We have examined the consequences of misexpressing the vertebrate hedgehog gene vhh-1 (sonic hedgehog, shh) and the winged-helix gene HNF-3 beta in the neural plate and neural tube of frog embryos. Misexpression of either of these genes induces floor plate differentiation at ectopic locations. However, ectopic floor plate induction in response to both vhh-1 and HNF-3 beta was temporally and spatially restricted. At neural plate stages, ectopic floor plate differentiation was not detected. After neural tube closure, ectopic floor plate differentiation was detected but was restricted predominantly to the dorsal region of the neural tube. The ability of winged-helix and vertebrate hedgehog genes to induce floor plate differentiation in vivo may, therefore, be constrained by additional signals that specify the time and position of floor plate differentiation.

Animals↗
PubMed1981

Oxytocin- and vasopressin-immunoreactive nerve fibers in the pineal gland of the hedgehog, Erinaceus europaeus L.

Oxytocin- and vasopressin-immunoreactive nerve fibers, apparently originating from a dorsal subunit of the paraventricular nucleus, were demonstrated in the pineal gland of the hedgehog. The majority of these fibers (pinealopetal projections) is intimately related to the capillaries of the pineal organ, whereas only a few elements are scattered throughout the pineal parenchyma. The number of peptidergic elements observed in the central portion of the pineal organ exceeds that of fibers located at the periphery. In relation to the functional state of the animals, the amount of immunoreactive material in these pinealopetal nerve fibers exhibits conspicuous variations. In hibernating hedgehogs (group 1), these nerve fibers were considerably richer in oxytocin than in non-hibernating or arousing winter animals (group 2 and 3). In contrast, only weak immunoreactivity for vasopressin was found in intrapineal nerve fibers of hibernating hedgehogs (group 1), whereas the fibers of arousing or non-hibernating hedgehogs (group 2 and 3) contained slightly larger amounts of vasopressin. In the pineal organ of animals sacrificed during the summer period (group 4), no immunoreactivity for both neuropeptides was found. The functional significance of the connection between the hypothalamic paraventricular nucleus and the pineal organ is discussed with special reference to the vascular terminals of the pinealopetal peptidergic nerve fibers.

Animals↗
PubMed1998

Hedgehog's escape from Pandora's box.

The Hedgehog family of secreted glycoproteins proteins plays multifarious roles during vertebrate embryogenesis. In both the Drosophila and vertebrate embryo correct deployment of Hedgehog-like proteins is critical for the generation of pattern in many tissues and organs. New evidence now reveals that genes involved in hedgehog signalling are mutated in a number of common human genetic disorders, including skin cancer and craniofacial defects. The understanding of how cells generate, receive and transduce the Hedgehog signal during development has led to the establishment of molecular paradigms for the pathogenesis of these diseases. These studies clearly illustrate that knowledge of the normal role of a gene during development is critical for generating an understanding of the disease state in which it is mutated.

Abnormalities, Multiple↗
PubMed1996

Spatial and temporal distribution of Indian hedgehog mRNA in the embryonic mouse mandible.

Hedgehog genes are involved in pattern formation during embryonic development. A recent report showed that Sonic hedgehog is expressed in the mouse mandible in the presumptive incisor region. In the present study, Indian hedgehog (Ihh) transcripts were present from gestational day 9 to 14 in the mouse mandible (reverse transcription/polymerase chain reaction analysis). Ihh mRNA was present in the dental lamina in both incisor and molar regions and in the developing whiskers (in-situ hybridization). Ihh may be involved in the site-specific proliferation of mandibular epithelium during the formation of the dental lamina. This is consistent with the observation that endogenous synthesis of retinoic acid is necessary for the initiation of odontogenesis and that retinoic acid induces hedgehog expression.

Animals↗
PubMed1982

Hippocampal mossy fibers in the regio superior of the European hedgehog.

The hippocampal mossy fiber zone of the European hedgehog has been studied at the light and electron microscopic levels. In contrast to the organization of this zone in other mammals, the mossy fiber zone of the hedgehog is not confined to the region of Ammon's horn that is characterized by large pyramidal cells (i.e. regio inferior) but extends into the region that contains small pyramidal cells (i.e. regio superior). The terminals, throughout the relatively extensive mossy fiber zone of the hedgehog, have the large multivesicular, multicontact morphology that characterizes the mossy fiber terminals observed in other species and can be demonstrated to be the axon terminals of granule cells located in the fascia dentata. In view of the primitive organization of the forebrain of the European hedgehog, which is believed to be representative of that of the first mammals, the boundaries of the mossy fiber zone of these animals suggest that the mossy fibers extended over a larger part of Ammon's horn during the first phases of mammalian evolution and became restricted to the regio inferior during the early stages of mammalian evolution.

Animals↗
PubMed1983

Pancreatic A cell response to arginine in the hibernating hedgehog (Erinaceus europaeus).

Pancreatic A cell response to arginine was measured in hedgehogs during the periods of lethargy and arousal and then during activity. Spontaneous plasma glucagon concentrations were lower during lethargy than during activity, and they increased during arousal. Arginine administration induced a slight, but significant delayed increase in plasma glucagon concentration in the lethargic hedgehog (body temperature: 6 degrees). During arousal, in vitro glucagon secretion was temperature dependent suggesting that body rewarming might, in itself, be an important stimulating factor of the A cells. In the presence of arginine, the glucagon output of the pancreas of lethargic hedgehogs was high at low temperatures. It decreased to a nadir at 19 degrees and increased up to 37 degrees. However, the basal or arginine-stimulated glucagon secretion of animals in lethargy was higher than that of animals in activity. These characteristics suggested the presence of a particular pool of cold-adapted enzymes in the A cells of lethargic hedgehogs.

Animals↗
PubMed1987

Purification and characterization of alpha 2-, alpha 2-beta- and beta-macroglobulin inhibitors in the hedgehog, Erinaceus europaeus: beta-macroglobulin identified as the plasma antihemorrhagic factor.

Three macroglobulin inhibitors were purified from hedgehog (Erinaceus europaeus) plasma by sequential chromatography on Cibacron Blue Sepharose, Sephacryl S-200 and preparative agarose gel electrophoresis. Each macroglobulin was characterized for proteinase inhibiting activity, molecular weight by polyacrylamide gel electrophoresis (PAGE), subunit size by sodium dodecyl sulfate (SDS)-PAGE, immunological cross-reactivity to other macroglobulins and antihemorrhagic activity against European viper (Vipera berus) venom. Hedgehog alpha 2-macroglobulin is a tetramer (Mr 800,000) composed of identical monomers (Mr 200,000) that inhibits all proteinases tested and is the homologue of human alpha 2-macroglobulin, rat alpha 2-acute phase globulin, dog alpha 1-macroglobulin and swine alpha 2-macroglobulin fast. Hedgehog alpha 2-beta-macroglobulin is a dimer (Mr 450-550,000) composed of identical monomers (Mr 200,000) that inhibits all proteinases tested and appears to be structurally similar to other animal 'half-molecule' macroglobulins. Hedgehog beta-macroglobulin (Mr 700,000) gave subunits of 34,000 and 39,000 after SDS-PAGE and showed cross-reactivity with swine alpha 2-macroglobulin slow. It inhibits all proteinases tested and is the only macroglobulin with antihemorrhagic activity against V. berus venom. This antihemorrhagic activity may be due to beta-macroglobulin's different structure as compared to other macroglobulins, which may make it less susceptible to inactivation by venom proteinases.

Animals↗
PubMed1992

Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog.

The segment polarity genes engrailed and wingless are expressed in neighboring stripes of cells on opposite sides of the Drosophila parasegment boundary. Each gene is mutually required for maintenance of the other's expression; continued expression of both also requires several other segment polarity genes. We show here that one such gene, hedgehog, encodes a protein targeted to the secretory pathway and is expressed coincidently with engrailed in embryos and in imaginal discs; maintenance of the hedgehog expression pattern is itself dependent upon other segment polarity genes including engrailed and wingless. Expression of hedgehog thus functions in, and is sensitive to, positional signaling. These properties are consistent with the non-cell autonomous requirement for hedgehog in cuticular patterning and in maintenance of wingless expression.

Amino Acid Sequence↗
PubMed1994

Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud.

Proper limb growth and patterning requires signals from the zone of polarizing activity in the posterior mesoderm and from the overlying apical ectodermal ridge (AER). Sonic hedgehog and Fgf-4, respectively, have recently been identified as candidates for these signals. We have dissected the roles of these secreted proteins in early limb development by ectopically regulating their activities in a number of surgical contexts. Our results indicate that Sonic hedgehog initiates expression of secondary signaling molecules, including Bmp-2 in the mesoderm and Fgf-4 in the ectoderm. The mesoderm requires ectodermally derived competence factors, which include Fgf-4, to activate target gene expression in response to Sonic hedgehog. The expression of Sonic hedgehog and Fgf-4 is coordinately regulated by a positive feedback loop operating between the posterior mesoderm and the overlying AER. Taken together, these data provide a basis for understanding the integration of growth and patterning in the developing limb.

Animals↗
PubMed2004

Participation of Polycomb group gene extra sex combs in hedgehog signaling pathway.

Polycomb group (PcG) genes are required for stable inheritance of epigenetic states across cell divisions, a phenomenon termed cellular memory. PcG proteins form multimeric nuclear complex which modifies the chromatin structure of target site. Drosophila PcG gene extra sex combs (esc) and its vertebrate orthologs constitute a member of ESC-E(Z) complex, which possesses histone methyltransferase activity. Here we report isolation and characterization of medaka esc homolog, termed oleed. Hypomorphic knock-down of oleed using morpholino antisense oligonucleotides resulted in the fusion of eyes, termed cyclopia. Prechordal plate formation was not substantially impaired, but expression of hedgehog target genes was dependent on oleed, suggesting some link with hedgehog signaling. In support of this implication, histone methylation, which requires the activity of esc gene product, is increased in hedgehog stimulated mouse NIH-3T3 cells. Our data argue for the novel role of esc in hedgehog signaling and provide fundamental insight into the epigenetic mechanisms in general.

Amino Acid Sequence↗
PubMed2006

Perlecan signaling: helping hedgehog stimulate prostate cancer growth.

Perlecan, an extracellular matrix proteoglycan, regulates signaling by a variety of growth factors through protein-protein and protein-carbohydrate interactions. Recent evidence demonstrates that Perlecan modulates sonic hedgehog signaling during both development and neoplasia, in particular in prostate cancer. Perlecan directly binds to sonic hedgehog and is required for its signaling. Increased sonic hedgehog signaling due to Perlecan in aggressive and metastatic prostate cancer cells can be attributed to increased Perlecan expression or changes in Perlecan glycan structure. Additional co-localization studies suggest that other tumor types may also have a Perlecan-modulated hedgehog signaling pathway. Inhibitors of Perlecan function at either the protein or glycan level would be ideal drug candidates for anti-cancer therapies.

Animals↗
PubMed2004

Sonic hedgehog signaling in basal cell carcinomas.

The development of basal cell carcinoma, the commonest human cancer in fair skinned populations, is clearly associated with constitutive activation of sonic hedgehog signaling. Insight into the genesis of BCC came from the identification of germline mutations of the tumor suppressor gene, PATCHED, a key regulatory component of hedgehog signaling in the nevoid basal cell carcinoma syndrome. Analysis of sporadic basal cell carcinomas and those from repair deficient xeroderma pigmentosum patients has revealed mutational inactivation of PATCHED and gain of function mutations of the proto-oncogenes, SMOOTHENED and SONIC HEDGEHOG associated with solar UV exposure. The molecular mechanisms involved in alterations of the hedgehog signaling pathway that lead to the formation of basal cell carcinomas are being unraveled and has already allowed the investigation of future therapeutic strategies for treating these skin cancers.

Animals↗
PubMed2006

Activation of the hedgehog pathway in a subset of lung cancers.

Activation of the hedgehog pathway is reported in lung cancer, but its frequency remains unknown. We examine activation of this pathway in lung cancers by in situ hybridization and immunohistochemstry, and find that less than 10% of the tumors have elevated hedgehog target gene expression. We further identify a cell line NCI-H209 and two primary tumors with no detectable Su(Fu), a negative regulator of the pathway. Ectopic expression of Su(Fu) in NCI-H209 cells down-regulates hedgehog target gene expression and leads to inhibition of cell proliferation. These data indicate that activation of the hedgehog pathway is activated through Shh over-expression or Su(Fu) inactivation in only a subset of lung cancers.

Adenocarcinoma↗
PubMed2006

New "hogs" in Hedgehog transport and signal reception.

A recent paper in Cell (Yao et al., 2006) and two papers in Developmental Cell (Tenzen et al., 2006; Zhang et al., 2006) identify a new receptor component for Hedgehog, a key morphogen in embryonic development. Many other proteins that bind to Hedgehog in the extracellular matrix or on the cell surface have been identified. In light of these recent discoveries, we discuss how these factors control the stability, transport, reception, and availability of Hedgehog in modulating Hedgehog-mediated responses.

Animals↗
PubMed2005

Homeotic proboscipedia function modulates hedgehog-mediated organizer activity to pattern adult Drosophila mouthparts.

Drosophila proboscipedia (pb; HoxA2/B2 homolog) mutants develop distal legs in place of their adult labial mouthparts. Here we examine how pb homeotic function distinguishes the developmental programs of labium and leg. We find that the labial-to-leg transformation in pb mutants occurs progressively over a 2-day period in mid-development, as viewed with identity markers such as dachshund (dac). This transformation requires hedgehog activity, and involves a morphogenetic reorganization of the labial imaginal disc. Our results implicate pb function in modulating global axial organization. Pb protein acts in at least two ways. First, Pb cell autonomously regulates the expression of target genes such as dac. Second, Pb acts in opposition to the organizing action of hedgehog. This latter action is cell-autonomous, but has a nonautonomous effect on labial structure, via the negative regulation of wingless/dWnt and decapentaplegic/TGF-beta. This opposition of Pb to hedgehog target expression appears to occur at the level of the conserved transcription factor cubitus interruptus/Gli that mediates hedgehog signaling activity. These results extend selector function to primary steps of tissue patterning, and lead us to suggest the notion of a homeotic organizer.

Animals↗
PubMed2006

Functional compensation in Hedgehog signaling during mouse prostate development.

Studies of hedgehog signaling in prostate development using anti-Shh antibodies, chemical inhibitors of hedgehog signaling and Shh(-/-) mutant mice have yielded conflicting data regarding the requirements of hedgehog signaling for normal ductal budding and glandular morphogenesis. We used transgenic mouse models in combination with chemical inhibitors and renal grafting to clarify the role of Hh signaling in prostate development. These studies showed that genetic loss of Shh is accompanied by an up-regulation of Indian Hedgehog (Ihh) and maintenance of Hh pathway activity. We found that while neither Gli1 nor Gli3 are required for normal prostate ductal budding, the urogenital sinus (UGS) of the Gli2(-/-) mutant mouse displays aberrant ductal budding in utero. When grown as a subcapsular graft, the Gli2(-/-) UGS exhibited prostatic differentiation but also displayed areas of focal epithelial hyperplasia. Functional redundancy between the three Gli transcription factors appears to mitigate the effect of Gli2 LOF as evidenced by residual Hh pathway activity in the E14 Gli2(-/-) UGS that could be inhibited by cyclopamine treatment. Together, these studies reveal a surprising degree of functional redundancy operating both at the level of the ligand and at the level of transcriptional regulation that effectively mitigates phenotypes associated with Hh-signaling perturbations.

Animals↗
PubMed1990

Mechanical restitution at different temperatures in papillary muscles from rabbit, rat, and hedgehog.

Mechanical restitution curves, i.e., peak isometric force as a function of the duration of the preceding test interval, were investigated in papillary muscles from rabbit, rat, and hedgehog. Peak force of rabbit papillary muscle increased with prolongation of the test interval from about 0.3 s to about 1.0 s and for longer intervals peak force declined (called type I mechanical restitution). On the other hand, in rat and hedgehog, papillary muscles' force reached a maximum value at intervals of 30-120 s (called type II mechanical restitution). When temperature was decreased from 35 to 15 degrees C, maximum force of type I mechanical restitution shifted from 1.0 to 10 s, whereas maximum force of type II restitution did not change significantly. Type II mechanical restitution consisted of two different phases, designated phase A and phase B, respectively. As temperature was decreased from 35 to 0 degree C in the hedgehog preparation, the two phases became even more separated. At 35 degrees C, the rising part of mechanical restitution in the rabbit muscle could not be distinguished from phase A of the hedgehog preparation and was also very similar to phase A of the rat muscle. Phase A is thus present in both type I and type II mechanical restitution, but phase B is a special feature of type II mechanical restitution. Phase A and phase B might be a manifestation of activator calcium originating from two different sources, e.g., the sarcoplasmic reticulum and the sarcolemma.

Animals↗
PubMed2003

Developmental roles and clinical significance of hedgehog signaling.

Cell signaling plays a key role in the development of all multicellular organisms. Numerous studies have established the importance of Hedgehog signaling in a wide variety of regulatory functions during the development of vertebrate and invertebrate organisms. Several reviews have discussed the signaling components in this pathway, their various interactions, and some of the general principles that govern Hedgehog signaling mechanisms. This review focuses on the developing systems themselves, providing a comprehensive survey of the role of Hedgehog signaling in each of these. We also discuss the increasing significance of Hedgehog signaling in the clinical setting.

Animals↗