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PubMed1994

Acquisition of Borrelia burgdorferi by Ixodes ricinus ticks fed on the European hedgehog, Erinaceus europaeus L.

A hedgehog, Erinaceus europaeus, was found to be heavily infested with larval and nymphal Ixodes ricinus in a forest park in Co. Galway, Ireland. A large proportion of the ticks that engorged and detached were infected with the spirochaete, Borrelia burgdorferi, the causative agent of human Lyme borreliosis. The identity of these spirochaetes was confirmed by immunofluorescent assay with B. burgdorferi-specific monoclonal antibody and by polymerase chain reaction test and they were transmitted from the hedgehog to laboratory-reared ticks and from the ticks obtained from the hedgehog to gerbils (Meriones unguiculatus). The high infection rate of the larvae that fed on the hedgehog in comparison with unfed larvae from the same habitat was interpreted as strong evidence that this host species is reservoir competent. Since hedgehogs can evidently feed adult ticks as well as many immature stages, they may well have an important role in the ecology of Lyme borreliosis in some habitats.

Animals↗
PubMed2000

Hedgehog signalling in cancer.

Hedgehog signalling is a key regulator of embryonic development controlling proliferation and/or cell fate determination. With identification of the Hedgehog receptor PTCH1 as a tumour suppressor gene that underlies the human nevoid basal cell carcinoma syndrome (NBCCS), the Hedgehog signalling pathway was firmly linked to cancer. It now appears that constitutive activation of Hedgehog signalling, by inactivating mutations in PTCH1 or activating mutations in the coreceptor SMOH, is required and possibly sufficient for basal cell carcinoma development and also contributes to the formation of a variety of other tumour types, including medulloblastoma and rhabdomyosarcoma. Several lines of evidence, including transgenic mice experiments, suggest that the critical cellular effect is stimulation of proliferation mediated by the transcriptional effector GLI1. Additional components of the signal transduction machinery as well as essential target genes remain to be identified, and involvement of the Hedgehog signalling pathway in other tumour types and/or hereditary cancer predisposition syndromes is to be expected.

Animals↗
PubMed1990

Effects of low temperature on contraction in papillary muscles from rabbit, rat, and hedgehog.

During hibernation the body temperature may fall to only a few degrees above 0 degree C. The heart of the hedgehog continues to function whereas the hearts of nonhibernating mammals stop beating. The present study was performed to investigate and compare the mechanical responses to hypothermia in rabbits, rats, and hedgehogs. Isometric force was recorded from papillary muscles mounted in an organ bath and effects of hypothermia on the mechanical restitution curve were also compared. A reduction of bath temperature from 35 degrees C caused an increase in peak developed force. Maximum force was seen at 20 degrees C in the rabbit, 15 degrees C in the rat, and 10 degrees C in the hedgehog preparations. In all the species there was a similar prolongation of time to peak force and of time from peak to half-relaxation as temperature was lowered. An increase in resting force and after-contractions were recorded in the rabbit and rat muscles at temperatures below 15 and 10 degrees C, respectively. The rabbit and rat preparations became inexcitable at temperatures below 10 and 5 degrees C, respectively. The hedgehog papillary muscle, on the other hand, still contracted at 0 degree C and did not show increased resting force nor after-contractions. The results are consistent with the hypothesis that there is a calcium overload in cardiac cells from rabbit and rat at low temperatures but there is no calcium overload in the hedgehog muscle during hypothermia.

Animals↗
PubMed1987

Further studies of plasma protease inhibitors in the hedgehog, Erinaceus europaeus; collagenase, papain and plasmin inhibitors.

Hedgehog plasma was separated by gel filtration on Sephacryl S-200, the fractions resolved by electrophoresis and the electrophoretograms characterized for collagenase, papain and plasmin inhibiting activities with the high mol. wt substrate casein. The three inhibitors previously identified as alpha 2-, alpha 2-beta- and beta-macroglobulins were found to inhibit all three proteases. These were the only collagenase inhibitors found in plasma. Hedgehog alpha 2-chymotrypsin inhibitor and beta-protease inhibitor were both found to also inhibit papain. Three new inhibitors specific for papain (gamma-, alpha 2- and alpha 1-cysteine protease inhibitors) and one for plasmin (alpha 2-antiplasmin) were also found, bringing the number of protease inhibitors in hedgehog plasma to 14. Immunological cross-reactivity as studied by immunoelectrophoresis showed homology between hedgehog alpha 2-macroglobulin and rat murinoglobulin I and between hedgehog alpha 2-antithrombin and rat antithrombin III.

Animals↗
PubMed2006

GSK3beta positively regulates Hedgehog signaling through Sufu in mammalian cells.

Hedgehog signaling plays important roles in embryonic patterning of multicellular organisms. This pathway is ultimately transmitted by the zinc-finger transcriptional factor Gli, of which activity is suppressed by Sufu, a negative regulator of this signaling. To clarify this regulation to more detail, we screened for Sufu-binding proteins. We identified GSK3beta as a specific binding partner of Sufu by mass spectrometric analysis. GSK3beta bound to Sufu both in vitro and in vivo. Down-regulation of GSK3beta expression by RNAi in Hedgehog-responsive cells attenuated Hedgehog signaling, suggesting that GSK3beta functions as a positive regulator of Hedgehog signaling. In addition, an in vitro kinase assay showed that GSK3beta phosphorylates Sufu and phosphorylation-mimicking mutant of Sufu showed significantly decreased ability to bind Gli1 and could not suppress the Gli-mediated expression of a reporter gene efficiently. These results strongly suggest that GSK3beta phosphorylates Sufu to positively regulate Hedgehog signaling in mammalian cells.

Animals↗
PubMed2003

Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells.

The involvement of hedgehog signaling in the initiation of osteoblastic differentiation in the bone collar during endochondral bone formation has been well established. The stages at which hedgehog acts during osteoblast differentiation as well as its molecular mechanism of action are less well understood. To address these questions, we have made use of the preosteoblastic cell line KS483. First, a systematic survey of mRNA expression of osteoblastic differentiation showed expression of Ihh and signaling intermediates at all stages. Interestingly, expression of Ihh, Gli1 and Ptc1 peaked during the maturation phase. Addition of recombinant human sonic hedgehog (rShh) potently increased osteoblastic differentiation of KS483 cells dose-dependently as assayed by a modest increase in alkaline phosphatase (ALP) activity, a strong increase in matrix mineralization, and increased mRNA expression of established osteoblast marker genes. These effects were blocked by the hedgehog antagonist cyclopamine, which by itself was ineffective. Addition of rShh during early stages was sufficient, while addition to mature osteoblasts had no effect. Furthermore, hedgehog signaling could be completely blocked by the BMP antagonists, soluble truncated BMPR-IA and noggin. In contrast, the BMP-induced differentiation of KS483 cells could only be partly inhibited by high doses of cyclopamine. These data demonstrate that Hh-induced osteoblastic differentiation requires functional BMP signaling. In KS483 cells, Hh and BMP synergistically induced alkaline phosphatase activity only when suboptimal concentrations of BMP were used. This synergy did not occur at the level of immediate early BMP response, but at the level of Hh response as determined by transient transfection studies using either a BMP reporter or a Gli reporter construct. In addition, rShh inhibited adipogenesis of KS483 cells cultured under adipogenic culture conditions, suggesting that Hh is involved in directing differentiation of KS483 cells toward osteoblasts at the expense of adipogenesis. Using in situ hybridization, we demonstrated, for the first time, Ihh mRNA expression in vivo in osteoblasts and lining cells in the humerus of developing human skeleton. Our in vitro and in vivo data indicate a stimulatory role for osteoblast-expressed Ihh in bone formation in a positive feedback loop. It may recruit progenitor cells in the osteoblastic lineage at the expense of adipocytes and it may stimulate maturation of early osteoblasts.

Adipocytes↗
PubMed2005

Non-destructive pollution exposure assessment in the European hedgehog (Erinaceus europaeus): II. Hair and spines as indicators of endogenous metal and As concentrations.

The role of hair and spines of the European hedgehog as non-destructive monitoring tools of metal (Ag, Al, Cd, Co, Cr, Cu, Fe, Ni, Pb, Zn) and As pollution in terrestrial ecosystems was investigated. Our results showed that mean pollution levels of a random sample of hedgehogs in Flanders are low to moderate. Yet, individual hedgehogs may be at risk for metal toxicity. Tissue distribution analyses (hair, spines, liver, kidney, muscle and fat tissue) indicated that metals and As may reach considerable concentrations in external tissues, such as hair and spines. Positive relationships were observed between concentrations in hair and those in liver, kidney and muscle for Al, Co, Cr, Cu, and Pb (0.43 < r < 0.85). Spine concentrations were positively related to liver, kidney and muscle concentrations for Cd, Co, Cr, Cu and Pb (0.37 < r < 0.62). Hair Ag, As, Fe and Zn and spine Ag, Al, As and Fe were related to metal concentrations in one or two of the investigated internal tissues (0.31 < r < 0.45). The regression models presented here may be used to predict metal and As concentrations in internal tissues of hedgehogs when concentrations in hair or spines are available. The present study demonstrated the possibility of using hair and spines for non-destructive monitoring of metal and As pollution in hedgehogs.

Adipose Tissue↗
PubMed2006

Independent roles of Drosophila Moesin in imaginal disc morphogenesis and hedgehog signalling.

The three ERM proteins (Ezrin, Radixin and Moesin) form a conserved family required in many developmental processes involving regulation of the cytoskeleton. In general, the molecular function of ERM proteins is to link specific membrane proteins to the actin cytoskeleton. In Drosophila, loss of moesin (moe) activity causes incorrect localisation of maternal determinants during oogenesis, failures in rhabdomere differentiation in the eye and alterations of epithelial integrity in the wing imaginal disc. Some aspects of Drosophila Moe are related to the activity of the small GTPase RhoA, because the reduction of RhoA activity corrects many phenotypes of moe mutant embryos and imaginal discs. We have analysed the phenotype of moesin loss-of-function alleles in the wing disc and adult wing, and studied the effects of reduced Moesin activity on signalling mediated by the Notch, Decapentaplegic, Wingless and Hedgehog pathways. We found that reductions in Moesin levels in the wing disc cause the formation of wing-tissue vesicles and large thickenings of the vein L3, corresponding to breakdowns of epithelial continuity in the wing base and modifications of Hedgehog signalling in the wing blade, respectively. We did not observe any effect on signalling pathways other than Hedgehog, indicating that the moe defects in epithelial integrity have not generalised effects on cell signalling. The effects of moe mutants on Hedgehog signalling depend on the correct gene-dose of rhoA, suggesting that the requirements for Moesin in disc morphogenesis and Hh signalling in the wing disc are mediated by its regulation of RhoA activity. The mechanism linking Moesin activity with RhoA function and Hedgehog signalling remains to be elucidated.

Animals↗
PubMed2006

Critical time window of hedgehog-dependent angiogenesis in murine yolk sac.

Hedgehog family was reported to be involved in murine yolk sac angiogenesis. However, it has not been clarified whether impaired angiogenesis under hedgehog signaling blockade is attributable to true defect in angiogenic process or just a sequel of earlier vasculogenic abnormalities. In the present study, we examined the effects of stage-specific inhibition of hedgehog cascade on vascular morphogenesis by applying cyclopamine or jervine to culture media of whole embryo culture system from embryonic days 8.0 until 9.5. Whole-mount immunostaining revealed that cyclopamine or jervine treatment in a narrow time window impaired angiogenic remodeling such as ramification into large and small branches and pericyte recruitment, although vasculogenesis was grossly normal. Molecular analyses suggest that indian hedgehog in the yolk sac endoderm regulates the induction of VEGF, Flk-1 and Notch-1. Our results indicate that hedgehog signaling is indispensable for mouse yolk sac angiogenesis, even when vasculogenesis is not perturbed.

Angiopoietin-1↗
PubMed1996

Physiological response of the European hedgehog to predator and nonpredator odour.

A respiratory chamber was used to investigate physiological responses of hedgehogs to predator and nonpredator odour cues, introduced by passing air through different faecal suspensions. Five recently caught hedgehogs showed a significant increase in oxygen consumption (29% +/- 18% at 95% c.i.) when treated with badger (predator) faecal suspension, and 10 hedgehogs held in captivity for ca. 2 years showed no significant response. The responses of recently caught hedgehogs to odour from badger (predator) and roe deer (non-predator) faecal suspensions were then investigated, over a range of concentrations spanning 3 orders of magnitude. Five hedgehogs were tested with badger odour; of these, 3 were also tested with roe deer odour. The mean rise in oxygen consumption was significantly greater in response to badger than to roe deer faecal suspension, but there was no significant variation in strength of response over the range of concentrations tested, and increased oxygen consumption was not associated with any increase in levels of visible activity. The responses are interpreted as an increase in arousal in response to a potential predatory threat. Lack of response in the captive-held animals raises questions about the welfare of such animals following release. Energy costs and foraging inefficiency associated with arousal may be significant factors of foraging decisions involving predation risk, but more naturalistic measurements would be required for any quantitative analysis.

Animals↗
PubMed2003

Hedgehog signaling in pancreas development.

Hedgehog proteins are secreted molecules that bind to their cell surface receptors to elicit concentration dependent responses essential for numerous tissue patterning and cell differentiation events during embryogenesis. However, during early stages of pancreas organogenesis, hedgehog signaling has been shown to inhibit tissue morphogenesis and cell differentiation. By contrast, recent cell culture studies indicate that an active hedgehog pathway might be required for maintenance of adult endocrine cell functions. This review describes our current understanding of the requirement of hedgehog signaling during pancreas morphogenesis and cell differentiation and discusses how individual hedgehog genes might act at various stages to ensure proper pancreas development and organ function.

Animals↗
PubMed1999

The hedgehog signalling pathway and its role in basal cell carcinoma.

The hedgehog signalling pathway plays a vital role in Drosophila embryonic patterning and development. Hedgehog is a secreted protein, unrelated to classical growth factors, which seems to form concentration gradients across those tissues involved in pattern formation. Cloning of vertebrate homologues of hedgehog and other genes has illustrated the remarkable conservation of function of this pathway throughout evolution. The human homologue of patched, a receptor for the hedgehog protein, was cloned as the gene responsible for naevoid basal cell carcinoma syndrome (NBCCS/'Gorlin Syndrome'), an autosomal dominant condition in which patients suffer from multiple basal cell carcinomas and a wide spectrum of developmental abnormalities. Its role as a tumour suppressor gene in both NBCCS and sporadic basal cell carcinoma led to the suggestion that mutation or inactivation of human patched may be an essential step in development of basal cell carcinomas and other skin tumours. This review describes our current understanding of hedgehog signalling in Drosophila and vertebrates and its relation to the development of human basal cell carcinoma and other skin tumours, together with a discussion of future avenues of research into this critical and intriguing pathway.

Animals↗
PubMed1996

Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish.

The notochord plays a central role in vertebrate development, acting as a signalling source that patterns the neural tube and somites. In in vitro assays, the secreted protein Sonic hedgehog mimics the inducing effects of notochord on both presomitic mesoderm and neural plate explants of amniote embryos, suggesting that both patterning activities of the notochord may be mediated by this protein in vivo. In zebrafish, however, mutants with disrupted notochord development lack a specific muscle cell type, the muscle pioneers, although they retain the ability to induce neural differentiation, raising the possibility that neural tube and somite patterning may be mediated by distinct signals. Here we describe a new member of the hedgehog family, echidna hedgehog, that is expressed exclusively in the notochord and has the ability to rescue the differentiation of muscle pioneer cells in mutants with no notochord. Moreover, we show that a combination of ectopic echidna hedgehog and sonic hedgehog expression induces supernumary muscle pioneers in wild-type embryos, suggesting that both signals act sequentially to pattern the developing somites.

Amino Acid Sequence↗
PubMed1996

smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.

Members of the Hedgehog family of secreted proteins control a number of important inductive interactions in the development of both vertebrates and Drosophila, but little is known about the ways in which their signalling activities are transduced. In Drosophila, hedgehog is one of the segment-polarity genes, mutations of which disrupt the pattern and polarity of individual embryonic segments and their adult derivatives; several of these genes have been implicated in transduction of the hedgehog signal. Here we show that the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs. Sequence analysis of the smoothened transcription unit reveals a single open reading frame encoding a protein with seven putative transmembrane domains. This structure is typical of G-protein-coupled receptors, suggesting that the Smoothened protein may act as a receptor for the Hedgehog ligand.

Alleles↗
PubMed2003

Hedgehog signalling in the mouse requires intraflagellar transport proteins.

Intraflagellar transport (IFT) proteins were first identified as essential factors for the growth and maintenance of flagella in the single-celled alga Chlamydomonas reinhardtii. In a screen for embryonic patterning mutations induced by ethylnitrosourea, here we identify two mouse mutants, wimple (wim) and flexo (fxo), that lack ventral neural cell types and show other phenotypes characteristic of defects in Sonic hedgehog signalling. Both mutations disrupt IFT proteins: the wim mutation is an allele of the previously uncharacterized mouse homologue of IFT172; and fxo is a new hypomorphic allele of polaris, the mouse homologue of IFT88. Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling. Our data show that IFT machinery has an essential and vertebrate-specific role in Hedgehog signal transduction.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination.

The developmental protein Numb is a major determinant of binary cell fates. It is also required for the differentiation of cerebellar granule cell progenitors (GCPs) at a stage of development responsive to the morphogenic glycoprotein Hedehog. Hedgehog signalling is crucial for the physiological maintenance and self-renewal of neural stem cells and its deregulation is responsible for their progression towards tumorigenesis. The mechanisms that inhibit this pathway during the differentiation stage are poorly understood. Here, we identify Numb as a Hedgehog-pathway inhibitor that is downregulated in early GCPs and GCP-derived cancer cells. We demonstrate that the Hedgehog transcription factor Gli1 is targeted by Numb for Itch-dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation. This novel Numb-dependent regulatory loop may limit the extent and duration of Hedgehog signalling during neural-progenitor differentiation, and its subversion may be a relevant event in brain tumorigenesis.

Animals↗
PubMedDate not supplied

Expression of sonic hedgehog gene in regenerating newt limbs.

Urodele amphibians such as the newt can regenerate their limbs even as adults. We have focused on the expression of sonic hedgehog, a gene that plays an important role in pattern formation during limb development, in regenerating limbs. Our in situ hybridization experiments showed that the sonic hedgehog gene was expressed in mesenchymal cells of the posterior region of regenerating limb blastemas, strongly suggesting the presence of a zone of polarizing activity (ZPA) in blastemas. Experiments with axially reversed grafts of blastemas further supported this suggestion. Axial reversal of blastemas leads to the regeneration of supernumerary limbs. The sonic hedgehog gene, which was used as a posterior marker, was expressed not only in the original region (new anterior side) of the graft, but also ectopically in the other region (new posterior side) of the same graft. The formation of supernumerary limbs was closely related to the duplication of sonic hedgehog expression on axially reversed grafts of blastemas. This duplication of sonic hedgehog expression could represent the presence of two ZPAs in axially reversed grafts. Thus, we suggest that the limb-regeneration blastema employs a ZPA as the signaling center for anterior-posterior patterning, as is the case in the developing limb bud.

Amputation, Surgical↗
PubMed2005

The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease.

The hedgehog signalling pathway is critical to normal mammalian gastrointestinal development. Through epithelial-mesenchymal interactions, hedgehog signalling ensures appropriate axial patterning of the embryonic gut. Congenital abnormalities, including malrotations, anorectal malformations, and tracheoesophageal fistula are associated with germ-line mutations/deletion of genes encoding hedgehog signalling components in man and present in genetically engineered animal models. In adults, there is evidence that the pathway plays a role in maintaining stem cell populations in the stomach and directing epithelial cell differentiation in the intestine. Recent data implicate hedgehog signalling in the formation and maintenance of a number of malignancies, including those of the upper gastrointestinal (GI) tract and pancreas, in which abrogation of the pathway offers a novel therapeutic approach in animal models. Most recently, evidence in vitro indicates that there is a recapitulation of embryonic hedgehog signalling in acute epithelial injury and chronic inflammation, a finding with key implications for inflammatory disorders of the intestine, such as inflammatory bowel diseases. This pathway may provide an important link between chronic inflammation and cancer. We summarize the available evidence demonstrating that this developmental pathway has continuing roles in adult homeostasis and is dysregulated in malignancy and inflammation of the gastrointestinal tract.

Animals↗