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PubMed2006

Genomewide expression profiling in the zebrafish embryo identifies target genes regulated by Hedgehog signaling during vertebrate development.

Hedgehog proteins play critical roles in organizing the embryonic development of animals, largely through modulation of target gene expression. Little is currently known, however, about the kinds and numbers of genes whose expression is controlled, directly or indirectly, by Hedgehog activity. Using techniques to globally repress or activate Hedgehog signaling in zebrafish embryos followed by microarray-based expression profiling, we have discovered a cohort of genes whose expression responds significantly to loss or gain of Hedgehog function. We have confirmed the Hedgehog responsiveness of a representative set of these genes with whole-mount in situ hybridization as well as real time PCR. In addition, we show that the consensus Gli-binding motif is enriched within the putative regulatory elements of a sizeable proportion of genes that showed positive regulation in our assay, indicating that their expression is directly induced by Hedgehog. Finally, we provide evidence that the Hedgehog-dependent spatially restricted transcription of one such gene, nkx2.9, is indeed mediated by Gli1 through a single Gli recognition site located within an evolutionarily conserved enhancer fragment. Taken together, this study represents the first comprehensive survey of target genes regulated by the Hedgehog pathway during vertebrate development. Our data also demonstrate for the first time the functionality of the Gli-binding motif in the control of Hedgehog signaling-induced gene expression in the zebrafish embryo.

Animals↗
PubMed1997

Transmission cycles of Borrelia burgdorferi sensu lato involving Ixodes ricinus and/or I. hexagonus ticks and the European hedgehog, Erinaceus europaeus, in suburban and urban areas in Switzerland.

The European hedgehog, Erinaceus europaeus Linnaeus, 1758, is a common host of Ixodes ricinus L. and I. hexagonus Leach, vectors of the Lyme disease spirochaete, Borrelia burgdorferi sensu lato. To investigate whether hedgehogs are reservoirs for B. burgdorferi, hedgehogs were captured in a suburban area suitable for both tick species and in an urban area where I. ricinus is absent. The infection status of the hedgehogs was determined by xenodiagnosis using I. ricinus and I. hexagonus larvae. I. hexagonus and/or I. ricinus were found on all hedgehogs (n = 8) from the suburban area. In contrast, only I. hexagonus was infesting animals (n = 5) from the urban area. A total of 12/13 hedgehogs harboured B. burgdorferi infected ticks. Xenodiagnostic I. ricinus and I. hexagonus larvae that fed on hedgehogs became infected. The results clearly show that European hedgehogs are reservoir hosts of the Lyme disease spirochetes. DNA of B. burgdorferi sensu stricto, B. garinii and B. afzelii was detected in culture from ear biopsy and needle aspiration material and characterized by using a genospecies-specific PCR assay. One hedgehog presented a mixed infection of the skin with B. burgdorferi sensu stricto and B. garinii. This study also identifies an enzootic transmission cycle in an urban area involving E. europaeus and I. hexagonus. The close association of I. hexagonus with the burrows of its hosts mean that the risks of contact between I. hexagonus and humans may be low.

Animals↗
PubMed2003

The phylogenetic relationships of insectivores with special reference to the lesser hedgehog tenrec as inferred from the complete sequence of their mitochondrial genome.

The complete mitochondrial genome of a lesser hedgehog tenrec Echinops telfairi was determined in this study. It is an endemic African insectivore that is found specifically in Madagascar. The tenrec's back is covered with hedgehog-like spines. Unlike other spiny mammals, such as spiny mice, spiny rats, spiny dormice and porcupines, lesser hedgehog tenrecs look amazingly like true hedgehogs (Erinaceidae). However, they are distinguished morphologically from hedgehogs by the absence of a jugal bone. We determined the complete sequence of the mitochondrial genome of a lesser hedgehog tenrec and analyzed the results phylogenetically to determine the relationships between the tenrec and other insectivores (moles, shrews and hedgehogs), as well as the relationships between the tenrec and endemic African mammals, classified as Afrotheria, that have recently been shown by molecular analysis to be close relatives of the tenrec. Our data confirmed the afrotherian status of the tenrec, and no direct relation was recovered between the tenrec and the hedgehog. Comparing our data with those of others, we found that within-species variations in the mitochondrial DNA of lesser hedgehog tenrecs appear to be the largest recognized to date among mammals, apart from orangutans, which might be interesting from the view point of evolutionary history of tenrecs on Madagascar.

Animals↗
PubMed1999

Distribution of acetylcholinesterase and choline acetyltransferase in the main and accessory olfactory bulbs of the hedgehog (Erinaceus europaeus).

The distribution of cholinergic markers was studied in the main olfactory bulb (MOB) and accessory olfactory bulb (AOB) of the western European hedgehog (Erinaceus europaeus) by using choline acetyltransferase (ChAT) immunocytochemistry and acetylcholinesterase (AChE) histochemistry. A dense network of AChE-containing and ChAT-immunoreactive fibers was observed innervating all layers of the MOB except the olfactory nerve layer, where neither AChE- nor ChAT-labeled elements were found. The highest density of AChE- and ChAT-positive axons was found in the glomerular layer (GL)/external plexiform layer (EPL) boundary, and in the internal plexiform layer. This general distribution pattern of ChAT- and AChE-stained axons resembled the distribution pattern found in rodents. Nevertheless, some interspecies differences, such as the lack of atypical glomeruli in the hedgehog, were also found. In addition to fibers, a population of noncholinergic and presumably cholinoceptive AChE-active neurons was observed in the hedgehog. All mitral and tufted cells of the hedgehog MOB showed a dark AChE staining unlike previous observations in the mitral and tufted cells of rodents. As in other species previously reported, subpopulations of external tufted cells and short-axon cells were also AChE-active. Finally, a population of small AChE-containing cells was observed in the EPL of the hedgehog MOB. The size, shape, and location of these cells coincided with those of satellite and perinidal cells, two neuronal types described previously in the EPL of the hedgehog and not present in the rodent MOB. The AOB of the hedgehog showed a distribution of AChE- and ChAT-positive fibers similar to the rodent AOB. Nevertheless, a heterogeneous innervation of vomeronasal glomeruli by bundles of AChE- and ChAT-labeled axons found in the hedgehog has not been previously found in any other species. As in the MOB, all mitral cells in the AOB showed a strong AChE activity. These results demonstrate some similarities but also important differences between the distribution of ChAT and AChE in the MOB and AOB of rodents and this primitive mammalian. These variations may indicate a different organization of the cholinergic modulation of the olfactory information in the insectivores.

Acetylcholinesterase↗
PubMed1997

A role for Indian hedgehog in extraembryonic endoderm differentiation in F9 cells and the early mouse embryo.

Hedgehog genes in Drosophila and vertebrates control patterning of a number of different structures during embryogenesis. They code for secreted signaling proteins that are cleaved into an active aminopeptide and a carboxypeptide. The aminopeptide can mediate local and long range events and can act as a morphogen, inducing differentiation of distinct cell types in a concentration-dependent manner. We demonstrate here that the expression of Indian hedgehog mRNA and protein is upregulated dramatically as F9 cells differentiate in response to retinoic acid, into either parietal endoderm or embryoid bodies, containing an outer visceral endoderm layer. The ES cell line D3 forms embryoid bodies in suspension culture without addition of retinoic acid and also upregulates Indian hedgehog expression. RT-PCR analysis of blastocyst outgrowth cultures demonstrates that whereas little or no Indian hedgehog message is present in blastocysts, significant levels appear upon subsequent days of culture, coincident with the emergence of parietal endoderm cells. In situ hybridization analysis for Indian hedgehog mRNA expression demonstrates the presence of elevated levels of message in the outer visceral endoderm cells relative to the core cells in mature embryoid bodies and in the visceral endoderm of Day 6.5 embryos. Whole-mount in situ hybridization analysis of Day 7.5 and 8.5 embryos indicates that Indian hedgehog expression is highest in the visceral yolk sac at this stage. F9 cell lines expressing a full length Indian hedgehog cDNA express a number of characteristics of differentiated cells, in the absence of retinoic acid. Taken together, these data suggest that Indian hedgehog is involved in mediating differentiation of extraembryonic endoderm during early mouse embryogenesis.

Animals↗
PubMed2005

Cadherin Cad99C is regulated by Hedgehog signaling in Drosophila.

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

Amino Acid Sequence↗
PubMed2002

Effects of hedgehog proteins on tissue engineering of cartilage in vitro.

The effects of three derivatives of the N-terminal signaling domain of hedgehog proteins on cartilage engineered in vitro were investigated, with specific focus on the ability to increase tissue growth rate and concentrations of major extracellular matrix components, that is, glycosaminoglycans (GAG) and collagen, and on the effects on morphological appearance of the tissue. Bovine articular chondrocytes were cultured on biodegradable polyglycolic acid (PGA) scaffolds with or without the addition of dipalmitoylated sonic hedgehog (dp-shh), dipalmitoylated indian hedgehog (dp-ihh), or sonic hedgehog dimer (shh-dimer) to medium with either 1% or 10% fetal bovine serum (FBS). All three hedgehog proteins dose-dependently increased construct weights (by up to 1.95-fold, dp-shh at 1,000 ng/mL) and the fraction of GAG over 4 weeks (by up to 2.7-fold, dp-shh at 1,000 ng/mL), as compared to control constructs. Dp-shh and dp-ihh elicited similar responses; a 10-fold higher concentration of nonacylated shh-dimer was necessary to reach comparable results. Positive hedgehog effects were more pronounced in medium containing 1% FBS than in medium containing 10% FBS; however, at either FBS concentration, cartilaginous tissues grown in the presence of hedgehog proteins appeared morphologically more mature. Hedgehog derivatives thus appear as promising candidates to improve the development and composition of engineered cartilage.

Animals↗
PubMed2004

Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse.

Genetic analyses in Drosophila have demonstrated that a transmembrane protein Dispatched (Disp) is required for the release of lipid-modified Hedgehog (Hh) protein from Hh secreting cells. Analysis of Disp1 null mutant embryos has demonstrated that Disp1 plays a key role in hedgehog signaling in the early mouse embryo. Here we have used a hypomorphic allele in Disp1(Disp1(Delta)(2)), to extend our knowledge of Disp1 function in Hh-mediated patterning of the mammalian embryo. Through genetic combinations with null alleles of patched 1 (Ptch1), sonic hedgehog (Shh) and Indian hedgehog (Ihh), we demonstrate that Disp1 genetically interacts with Hh signaling components. As Disp1 activity is decreased we see a progressive increase in the severity of hedgehog-dependent phenotypes, which is further enhanced by reducing hedgehog ligand levels. Analysis of neural tube patterning demonstrates a progressive loss of ventral cell identities that most likely reflects decreased Shh signaling as Disp1 levels are attenuated. Conversely, increasing available Shh ligand by decreasing Ptch1 dosage leads to the restoration of ventral cell types in Disp1(Delta2/Delta2) mutants. Together, these studies suggest that Disp1 actively regulates the levels of hedgehog ligand that are available to the hedgehog target field. Further, they provide additional support for the dose-dependent action of Shh signaling in patterning the embryo. Finally, in-vitro studies on Disp1 null mutant fibroblasts indicate that Disp1 is not essential for membrane targeting or release of lipid-modified Shh ligand.

Amino Acid Sequence↗
PubMed1999

The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila.

The adult abdomen of Drosophila is a chain of anterior (A) and posterior (P) compartments. The engrailed gene is active in all P compartments and selects the P state. Hedgehog enters each A compartment across both its anterior and posterior edges; within A its concentration confers positional information. The A compartments are subdivided into an anterior and a posterior domain that each make different cell types in response to Hedgehog. We have studied the relationship between Hedgehog, engrailed and cell affinity. We made twin clones and measured the shape, size and displacement of the experimental clone, relative to its control twin. We varied the perceived level of Hedgehog in the experimental clone and find that, if this level is different from the surround, the clone fails to grow normally, rounds up and sometimes sorts out completely, becoming separated from the epithelium. Also, clones are displaced towards cells that are more like themselves: for example groups of cells in the middle of the A compartment that are persuaded to differentiate as if they were at the posterior limit of A, move posteriorly. Similarly, clones in the anterior domain of the A compartment that are forced to differentiate as if they were at the anterior limit of A, move anteriorly. Quantitation of these measures and the direction of displacement indicate that there is a U-shaped gradient of affinity in the A compartment that correlates with the U-shaped landscape of Hedgehog concentration. Since affinity changes are autonomous to the clone we believe that, normally, each cell's affinity is a direct response to Hedgehog. By removing engrailed in clones we show that A and P cells also differ in affinity from each other, in a manner that appears independent of Hedgehog. Within the P compartment we found some evidence for a U-shaped gradient of affinity, but this cannot be due to Hedgehog which does not act in the P compartment.

Abdomen↗
PubMed2006

Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation.

Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.

Animals↗
PubMed2006

WNT antagonist, SFRP1, is Hedgehog signaling target.

Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Hedgehog signaling in intestinal epithelium represses canonical WNT signaling to restrict expression of WNT target genes to stem or progenitor cells; however, the mechanism remains unclear. The Hedgehog signal is transduced to GLI family transcription factors though Patched receptor, Smoothened signal transducer, and other signaling components, such as KIF27, KIF7, STK36, SUFU, and DZIP1. Here, we searched for the GLI-binding site within the promoter region of genes encoding secreted-type WNT signal inhibitors, including SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1. The GLI-binding site was identified within the human SFRP1 promoter based on bioinformatics and human intelligence. The chimpanzee SFRP1 gene was identified within the NW_110515.1 genome sequence. The GLI-binding site of the human SFRP1 promoter was conserved in chimpanzee SFRP1, mouse Sfrp1, and rat Sfrp1 promoters. SFRP1 is the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. Expression domain analyses based on text mining revealed that Indian Hedgehog (IHH), SFRP1, and WNT6 are expressed in differentiated intestinal epithelial cells, mesenchymal cells, and stem/progenitor cells, respectively. Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effects of canonical WNT signaling. These facts indicate that SFRP1 is the Hedgehog target to confine canonical WNT signaling within stem or progenitor cells. Therefore, epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent WNT signal inhibition.

Animals↗
PubMed1996

Sonic hedgehog regulates patterning in early embryos.

Recently, a new family of genes, homologues of the Drosophila segment polarity gene hedgehog, has been cloned in vertebrates. One of them, Sonic hedgehog, is expressed in tissues that are known to be inductive centres for patterning early embryos, implicating Sonic hedgehog as an important signal in development. Functional experiments have demonstrated that Sonic hedgehog acts as a signalling molecule in patterning the anterior-posterior axis of the limb. By misexpression of Sonic hedgehog we show that Sonic hedgehog induces expression of Hoxd genes, known to be involved in patterning of the anterior-posterior axis of the limb, and Bmp-2, which might act as a secondary signal. We also demonstrate that Sonic hedgehog is not sufficient for these inductions. In fact, a signal from the mesoderm, Sonic hedgehog, and a signal from the ectoderm, Fgf-4, are required for the induction of Hoxd genes and Bmp-2.

Animals↗
PubMed2005

Dysregulation of hedgehog signalling predisposes to synovial chondromatosis.

Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.

Animals↗
PubMed1997

The role of sonic hedgehog in vertebrate development.

Members of the hedgehog family are important signalling molecules during embryonic development. One member, Sonic hedgehog, is expressed in embryonic structures such as the zone of polarizing activity in the posterior limb bud, the notochord, and the floor plate of the neural tube, where it plays a role in patterning of the embryo. Sonic hedgehog is synthesized as an inactive precursor which must be proteolytically cleaved and modified by the addition of a cholesterol moiety to become active as a signalling molecule. In this processing, the C-terminal region of Sonic hedgehog serves as both the endoprotease and a cholesterol transferase. The importance of cholesterol for Sonic hedgehog function may explain many of the profound developmental defects caused by perturbations of cholesterol metabolism. The receptor for Sonic hedgehog is Patched, a multi-pass transmembrane protein which forms a complex with Smoothened Mutations in Patched are associated with basal cell naevus syndrome, while mutations in Sonic hedgehog cause holoprosencephaly. Downstream targets of Sonic hedgehog signalling are transcription factors like Gli3, responsible for Greigs polycephalosyndactyly in humans and Hoxd13, responsible for polysyndactyly.

Animals↗
PubMed1999

Hedgehog hives.

BACKGROUND: Hedgehogs are increasingly popular pets in the United States and Europe. A number of infections may be acquired from these animals, and hedgehogs are possible hosts of parasites. However, to our knowledge there arc no previous reports of urticarial reactions to hedgehogs. OBSERVATIONS: We describe 3 patients who developed an acute, transient, urticarial reaction after contact with the extended spines of pet hedgehogs. One patient also developed a more prolonged reaction at the site of contact. Interestingly, all 3 patients had documented allergies to cats and/or dogs. The results of prick testing in 1 patient to an extract of hedgehog dander produced an immediate wheal-and-flare reaction. CONCLUSIONS: A variety of dermatologic disorders may be seen in handlers of hedgehogs. Due to the increasing popularity of these animals as pets, it is likely that these reactions will be noted more frequently by dermatologists. The presence of allergies to other pets may be predictive of hedgehog hives and further investigation of the cross reaction of various animal antigens may clarify this relationship.

Animals↗
PubMed1996

Sonic Hedgehog in feather morphogenesis: induction of mesenchymal condensation and association with cell death.

Sonic hedgehog is involved in vertebrate tissue interactions during development. During early feather development, Sonic hedgehog appears very early in epithelial placodes. During late feather development, Sonic hedgehog expression precedes the development of the marginal plates and is specifically localized in the marginal plate epithelium, which will later undergo cell death. By using retroviral vectors, exogenous Sonic hedgehog overexpression in developing feathers induced enlarged feather buds that have either lost their anterior-posterior polarity or exhibited reverse orientation. The enlarged dermal condensations may be mediated through broader TGF-beta 2 expression and reduced protein kinase C (PKC) expression. Reciprocal mesenchymal interaction is required for the induction and maintenance of Sonic hedgehog in the epithelial placodes. In scaleless mutant, Sonic hedgehog is absent in the apteric region and aberrantly expressed in the mesenchyme of the abnormal feather ridge. These findings suggest that Sonic hedgehog mediates key interactions between the epithelium and mesenchyme during feather morphogenesis.

Animals↗
PubMed2006

Hedgehog signaling in skeletal development.

Hedgehog signaling coordinates a variety of patterning processes during early embryonic development. Drosophila hedgehog and its vertebrate orthologs, Sonic hedgehog, Indian hedgehog, and Desert hedgehog, share a generally conserved signal transduction cascade. However, the particular mechanisms by which the lipid-modified molecules specify embryonic tissues differ substantially. Vertebrate skeletal patterning is one of the most intensively studied biological processes. During skeletogenesis, Sonic and Indian hedgehog provide positional information and initiate or maintain cellular differentiation programs regulating the formation of cartilage and bone. They either signal directly to adjacent cells or form tightly regulated gradients that act over long distances to pattern the axial and appendicular skeleton and regulate crucial steps during endochondral ossification. As a consequence, malfunction of the hedgehog signaling network can cause severe skeletal disorders and tumors.

Animals↗
PubMed1998

The effect of pertussis toxin on zebrafish development: a possible role for inhibitory G-proteins in hedgehog signaling.

Recent results have indicated that cAMP-dependent protein kinase (PKA) acts as a negative regulator of Hedgehog signaling in target cells of the vertebrate embryo. Consequently, suppression of PKA activity is sufficient to mimic the effect of receiving a Hedgehog signal. We have explored whether PKA-inhibiting Gi-proteins (GiPs) may also be involved in the regulation of Hedgehog signaling. Zebrafish embryos were injected with RNA encoding pertussis toxin (Ptx), a specific inhibitor of GiPs. These embryos developed phenotypic traits opposite to embryos expressing a dominant negative form of the PKA regulatory subunit (dnPKA), including a fusion of the eyes, a lack of ventral specification in the forebrain, and an expansion of the sclerotome at the expense of adaxial fates in the posterior somites. These effects can be partially rescued by coexpression of dnPKA, but not by coexpression of Indian Hedgehog, suggesting that GiPs act upstream of PKA and downstream of Hedgehogs. Other Hedgehog- and PKA-dependent processes, sclerotomal specification and adaxial specification in the first five somites, are not negatively affected by Ptx. Thus, GiPs may be involved in Hedgehog signaling in some, but not all target cells.

Animals↗