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PubMed2004

Regulatory analysis of the mouse Fgf3 gene: control of embryonic expression patterns and dependence upon sonic hedgehog (Shh) signalling.

Fgf3 displays a dynamic and complex expression pattern during mouse embryogenesis. To address the molecular mechanisms underlying Fgf3 expression, we used a transgenic approach to assay genomic regions from the mouse Fgf3 gene for regulatory activity. We identified an enhancer that mediates major components of embryonic expression, governing expression in the midbrain, hindbrain, surface ectoderm, dorsal roots and dorsal root ganglia (DRG), proximal sensory ganglia, and the developing central nervous system (CNS). Deletional analysis of the enhancer further delimited this regulatory activity to a 5.7-kb fragment. We have also revealed sonic hedgehog (Shh) -dependent and Shh-independent aspects of Fgf3 expression through breeding the Fgf3 reporter transgene into Shh mutants. In the absence of Shh signalling, Fgf3 reporter expression is lost in the ventral CNS, DRG, and superior cervical nerves, whereas activation of reporter expression in cranial ganglion cells is Shh independent. Moreover, detailed re-examination of the Shh phenotype revealed that Shh signalling is required for the correct development/maturation of the DRG.

Animals↗

PubMed2004

Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung.

Sonic hedgehog (Shh) was conditionally deleted in respiratory epithelial cells of the embryonic lung in vivo. Deletion of Shh before embryonic day (E) 13.5 resulted in respiratory failure at birth. While lobulation was not perturbed, the lungs were hypoplastic, with reduced branching of peripheral lung tubules, evident from E13.5. Smooth muscle and endothelial cells were absent or reduced, the latter in relationship to the loss of peripheral lung parenchyma. Tracheal-bronchial ring abnormalities occurred when Shh was deleted between E8.5 and E12.5. Deletion of Shh later in gestation (after E13.5) caused mild abrogation of peripheral branching morphogenesis but did not disrupt tracheal-bronchial development. Defects in branching morphogenesis and vascularization seen in Shh null mutant (Shh(-/-)) mice were substantially corrected when SHH was ectopically expressed in the respiratory epithelium; however, peripheral expression of SHH failed to correct cartilage abnormalities in the trachea and bronchi, indicating a spatial requirement for SHH expression near sites of cartilage formation. Expression of SHH by the respiratory epithelium plays an important role in the patterning of tracheal-bronchial mesenchyme required for formation of cartilage rings in conducting airways. SHH regulates branching morphogenesis and influences differentiation of the peripheral lung mesenchyme required for formation of bronchial and vascular smooth muscle.

Animals↗

PubMed2004

Recapitulation of the parathyroid hormone-related peptide-Indian hedgehog pathway in the regenerating deer antler.

Parathyroid hormone (PTH)-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR) play an essential role in controlling growth plate development. The aim of the present study was to use the deer antler as a model to determine whether PTHrP and PPR may also have a function in regulating cartilage and bone regeneration in an adult mammal. Antlers are the only mammalian appendages that are able to undergo repeated cycles of regeneration, and their growth from a blastema involves a modified endochondral process. Immunohistochemistry was used to establish sites of localization of PTHrP and PPR in antlers at different stages of development. The pattern of Indian Hedgehog (IHH) and transforming growth factor-beta1 (TGF beta1) distribution was also investigated, because PTHrP expression in the developing limb is regulated by IHH and during embryonic growth plate formation TGF beta1 acts upstream of PTHrP to regulate the rate of chondrocyte differentiation. In the antler blastema (<10 days of development), PTHrP, PPR, and TGF beta1 were localized in epidermis, dermis, regenerating epithelium, and in mesenchymal cells but IHH expression was not detected. In the rapidly growing antler (weeks 4-8 of development), PTHrP, PPR, and TGF beta1 were localized in skin, perichondrium, undifferentiated mesenchyme, recently differentiated chondrocytes, and in perivascular cells in cartilage but not in fully differentiated hyperytrophic chondrocytes. IHH was restricted to recently differentiated chondrocytes and to perivascular cells in cartilage. In mineralized cartilage and bone, PTHrP, PPR, IHH, and TGF beta1 were immunolocalized in perivascular cells and differentiated osteoblasts. PTHrP and PPR were also present in the periosteum. TGF beta1 in vitro stimulated PTHrP synthesis by cells from blastema, perichondrium, and cartilage. The findings of this study suggest that molecules which regulate embryonic skeletal development and postnatal epiphyseal growth may also control blastema formation, chondrogenesis, and bone formation in the regenerating deer antler. This finding is further evidence that developmental signaling pathways are recapitulated during adult mammalian bone regeneration.

Animals↗

PubMed2005

Expression of the mouse Fgf15 gene is directly initiated by Sonic hedgehog signaling in the diencephalon and midbrain.

Sonic hedgehog (Shh) is a secreted molecule that is thought to regulate tissue growth and patterning in vertebrate embryos. Although it has been reported that Gli transcription factors mediate Shh signaling to the nucleus, little is known about developmental target genes of Gli. In the previous genetic study, we showed that Shh is required for Fgf15 expression in the diencephalon and midbrain. Here, we examined whether Fgf15 is a direct target of Shh signaling through Gli. Shh was expressed in the midline cells and Fgf15 in the medial region of the diencephalon/midbrain by the seven-somite stage. The Fgf15 expression domain coincided with that of Gli1 and overlapped with that of Gli2 at this stage. Fgf15 expression in the diencephalon/midbrain was greatly reduced in the seven-somite Shh mutant embryos. Transgenic analysis showed that the 3.6-kb 5'-flanking region of the Fgf15 gene is sufficient for induction of Fgf15 in the medial/ventral diencephalon/midbrain. Luciferase assay showed that the 3.6-kb Fgf15 enhancer/promoter was activated by Gli2. A Gli-binding site was located 1 kb upstream of the transcription start site and was required for expression in the medial/ventral diencephalon/midbrain in transgenic embryos and for activation in luciferase assay. These findings indicate that Fgf15 is directly regulated by Shh signaling through Gli proteins.

Amino Acid Motifs↗

PubMed2005

Distinct tissue-specificity of three zebrafish ext1 genes encoding proteoglycan modifying enzymes and their relationship to somitic Sonic hedgehog signaling.

Proteins of the EXT (Exostosin) 1 family are known for their role in human disease. Mutations in EXT1 cause hereditary multiple exostoses (HME), benign outgrowths of the bones, and therefore were classed as tumor suppressors. More recently, their role during embryonic development of Drosophila and mouse was addressed, revealing important functions of EXT1 genes in major signaling pathways. Here, we report the isolation of three zebrafish members of the EXT1 family, which we named ext1a, ext1b, and ext1c, respectively. They are expressed in restricted temporal and spatial domains during development. Both ext1a and ext1b are provided maternally and expressed during gastrulation: ext1a in the neurectoderm and ext1b in the embryonic midline and in the involuting mesendoderm of the germ ring. During somitogenesis stages, transcripts of all three ext genes can be found in the somitic mesoderm. Furthermore, ext1a is expressed in the dorsal neural tube. These expression domains become more pronounced at 24 hr postfertilization (hpf). At 48 hpf, ext1 genes are present in the brain, while somitic expression ceases. Zebrafish have three members of the EXT1 family, in contrast to only one EXT1 gene in mammals or Xenopus, consistent with the occurrence of partial genome duplications in the teleost lineage. Our expression analysis reveals that the three ext genes have distinct expression patterns, reflecting functional divergence after duplication. In addition, expression of ext1a and ext1c responds to elevated and reduced levels of Sonic hedgehog (shh) signaling in the somites, whereas expression of ext1b does not. This suggests a differential relationship between the shh pathway and individual ext gene function in zebrafish.

Amino Acid Sequence↗

PubMed2005

Single base pair change in the long-range Sonic hedgehog limb-specific enhancer is a genetic basis for preaxial polydactyly.

In most instances of preaxial polydactyly (PPD), Sonic Hedgehog (Shh), an essential limb patterning signal, is ectopically expressed in an anterior region of the developing limb in addition to the normal posterior domain. It is thought that this anterior Shh expression leads directly to the development of the extra digits. Recent reports have identified a conserved limb-specific Shh enhancer approximately 1 megabase upstream of the Shh transcription initiation site, and individual base pair changes within this region are associated with PPD. We report here that a single base pair change within this enhancer is sufficient to drive beta-galactosidase expression in both anterior and posterior limb domains, similar to Shh expression in animal PPD models, whereas a wild-type construct is expressed only in the posterior limb, similar to Shh expression in normal embryos. These findings provide the first direct evidence that a single base pair change within the limb-specific Shh enhancer acts as a genetic basis for PPD.

Animals↗

PubMed2005

Sonic hedgehog regulates proliferation of the retinal ciliary marginal zone in posthatch chicks.

The ciliary marginal zone (CMZ) has long been known to be a source of postembryonic neuronal production in the retinas of fish and amphibians, and more recently, birds. However, there is little known about the factors that are required for the maintenance of this neural stem cell zone. The cells of the CMZ respond to mitogens such as endothelial growth factor, insulin-like growth factor-1, and insulin, factors that are also mitogenic for embryonic retinal progenitors, suggesting that the continued expression of embryonic mitogenic factors might be required to maintain the postembryonic proliferative potential of the CMZ. To test this hypothesis, we examined the expression and functional role of a critical embryonic retinal progenitor mitogen, Sonic hedgehog (Shh) in the regulation of proliferation of the cells of the CMZ. We have found that Shh is concentrated at the retinal margin of postembryonic chicks. Moreover, we report that intraocular injection of Shh stimulates proliferation of the CMZ cells, whereas cyclopamine, an inhibitor of the Shh pathway, inhibits CMZ proliferation. We conclude that Shh signaling is an important factor in the maintenance of postembryonic retinal neurogenesis.

Animals↗

PubMed2006

Hedgehog signalling controls zebrafish neural keel morphogenesis via its level-dependent effects on neurogenesis.

We investigated the role of hedgehog (Hh) signalling on zebrafish neurulation, focusing on the intimate relationship between neurogenesis and morphogenesis during the neural keel stage. Through the analyses of Hh loss- and gain-of-function phenotypes, we found that Hh signalling controls the neural keel morphogenesis. To investigate underlying mechanisms, we examined cellular elongation polarity in the neural keel of Hh loss- and gain-of-function phenotypes and compared this with the deficient phenotype of a planar cell polarity (PCP) molecule, Trilobite/Strabismus. We found that Hh signalling controls cell elongation polarity of the neuroepithelium at least in part by means of PCP pathway; however, its effects are not strong enough per se to affect keel morphogenesis; instead Hh signalling mainly controls keel morphogenesis by means of affecting both medial and lateral neurogenesis. We devised a method for precise evaluation of neurogenesis in loss- and gain-of-Hh phenotypes that compensates for its delay caused by disturbed morphogenesis. We present a model that Hh signalling exerts level-dependent and binary-opposite effects on medial neurogenesis, whose modification to explain lateral neurogenesis reveals regional differences of underlying mechanisms between the two proneural domains. Such differences seem to be created in part by regional effector signalling; the effects of high Hh-signalling on medial neurogenesis can be reversed in accordance to medial Tri/Stbm level, in a polarity independent manner.

Animals↗

PubMed2006

The hedgehog-related gene qua-1 is required for molting in Caenorhabditis elegans.

The Caenorhabditis elegans genome encodes ten proteins that share similarity with Hedgehog through the C-terminal Hint/Hog domain. While most genes are members of larger gene families, qua-1 is a single copy gene. Here we show that orthologs of qua-1 exist in many nematodes, including Brugia malayi, which shared a common ancestor with C. elegans about 300 million years ago. The QUA-1 proteins contain an N-terminal domain, the Qua domain, that is highly conserved, but whose molecular function is not known. We have studied the expression pattern of qua-1 in C. elegans using a qua-1::GFP transcriptional fusion. qua-1 is mainly expressed in hyp1 to hyp11 hypodermal cells, but not in seam cells. It is also expressed in intestinal and rectal cells, sensilla support cells, and the P cell lineage in L1. The expression of qua-1::GFP undergoes cyclical changes during development in phase with the molting cycle. It accumulates prior to molting and disappears between molts. Disruption of the qua-1 gene function through an internal deletion that causes a frame shift with premature stop in the middle of the gene results in strong lethality. The animals arrest in the early larval stages due to defects in molting. Electron microscopy reveals double cuticles due to defective ecdysis, but no obvious defects are seen in the hypodermis. Qua domain-only::GFP and full-length QUA-1::GFP fusion constructs are secreted and associated with the overlying cuticle, but only QUA-1::GFP rescues the mutant phenotype. Our results suggest that both the Hint/Hog domain and Qua domain are critically required for the function of QUA-1.

Amino Acid Sequence↗

PubMed2006

Expression of hedgehog signalling components in adult mouse testis.

Hedgehog (Hh) signalling is known to regulate many aspects of normal development as well as being upregulated in various cancers. Signalling is mediated by the Gli family of zinc finger transcription factors. Based on observations that deletion of one of the three Hh genes, Dhh, leads to male infertility, we hypothesized that regulated expression of Hh signalling components would be a feature of adult spermatogenesis. We used in situ hybridization to characterise Gli gene expression in juvenile and adult mouse testes. In the first wave of spermatogenesis, mRNAs encoding all three Glis are detected in spermatogonia and Sertoli cells. In adult mouse testes, these transcripts are observed in spermatogonia and spermatocytes, with reduced signal intensity in round spermatids. The mRNAs encoding key effectors of Hh signalling, Ptc2, Smo, and Fu, are also most apparent in spermatogonia, spermatocytes, and to a lower extent in round spermatids. In contrast, mRNA encoding SuFu, a negative regulator of Hh signalling, was most predominant in round spermatids and the protein is evident in round and elongating spermatids, suggesting that SuFu protein may switch off Hh signalling in haploid germ cells. Overall, the coordinated expression pattern of these genes in adult mouse testis indicates a role for Hh signalling in spermatogenesis.

Animals↗

PubMed2007

Temporomandibular joint formation and condyle growth require Indian hedgehog signaling.

The temporomandibular joint (TMJ) is essential for jaw function, but the mechanisms regulating its development remain poorly understood. Because Indian hedgehog (Ihh) regulates trunk and limb skeletogenesis, we studied its possible roles in TMJ development. In wild-type mouse embryos, Ihh expression was already strong in condylar cartilage by embryonic day (E) 15.5, and expression of Ihh receptors and effector genes (Gli1, Gli2, Gli3, and PTHrP) indicated that Ihh range of action normally reached apical condylar tissue layers, including polymorphic chondroprogenitor layer and articular disc primordia. In Ihh(-/-) embryos, TMJ development was severely compromised. Condylar cartilage growth, polymorphic cell proliferation, and PTHrP expression were all inhibited, and growth plate organization and chondrocyte gene expression patterns were abnormal. These severe defects were partially corrected in double Ihh(-/-)/Gli3(-/-) mutants, signifying that Ihh action is normally modulated and delimited by Gli3 and Gli3(R) in particular. Both single and double mutants, however, failed to form an articular disc primordium, normally appreciable as an independent condensation between condylar apex and neighboring developing temporal bone in wild-type. This failure persisted at later stages, leading to complete absence of a normal functional disc and lubricin-expressing joint cavities. In summary, Ihh is very important for TMJ development, where it appears to regulate growth and elongation events, condylar cartilage phenotype, and chondroprogenitor cell function. Absence of articular disc and joint cavities in single and double mutants points to irreplaceable Ihh roles in formation of those critical TMJ components.

Animals↗

PubMed2001

Genetic evidence that Sil is required for the Sonic Hedgehog response pathway.

The Sil gene encodes a cytosolic protein required for mouse embryonic midline and left/right axial development. Based on the phenotype of Sil mutant embryos, we hypothesized that Sil may be required for the activity of Sonic Hedgehog (Shh), a secreted signaling molecule also critically important for the development of the embryonic axes and found mutated in multiple types of cancer. Here we tested the genetic interaction between Sil and the Shh pathway by generating and analyzing embryos carrying mutations in both Sil and Patched (Ptch), a Shh receptor that normally inhibits the signaling pathway in the absence of ligand and when mutated leads to constitutive activation of the pathway. We find that Sil(-/-) Ptch(-/-) embryos do not activate the Shh pathway and instead have a phenotype indistinguishable from Sil(-/-) embryos, in which there is a loss of activity of Shh. These results provide genetic evidence that Sil is an essential component of the Shh response, acting downstream to Ptch.

Animals↗

PubMed2002

Extracellular and intracellular regulation of oligodendrocyte development: roles of Sonic hedgehog and expression of E proteins.

Recent advances in understanding oligodendrocyte development have revealed the importance of both extra- and intracellular molecules in regulating the induction, survival, and proliferation of early oligodendrocyte progenitors. The signaling molecule Sonic hedgehog (Shh) is critical for normal development of oligodendrocytes, although the precise influences of Shh on cells of the oligodendrocyte lineage are unclear. The present study shows that Shh increased the number of oligodendrocyte precursors in both pure cultures of oligodendrocyte precursors and mixed cultures from embryonic rat spinal cord. In pure precursor cultures Shh increased cell survival. In mixed cultures, Shh increased both the survival and proliferation of oligodendrocyte precursors in a concentration dependent manner. One intracellular consequence of exposure to Shh is the activation of transcription factors in oligodendrocyte lineage cells, which are critical for oligodendrocyte development, helix-loop-helix (HLH) transcription factors, Olig1 and 2. In many cases, HLH proteins such as Olig1 and Olig2 heterodimerize with other HLH proteins, such as members of the E subfamily, which are critical regulators of cell proliferation and differentiation. Immature (A2B5(+)) and more mature (O4(+)) rat oligodendrocyte precursors in dissociated cell culture expressed Olig1 as well as E proteins, HEB and E2A. Similarly, cells bearing the morphology of oligodendrocyte precursors expressed both Olig1 and HEB or E2A. We propose that E2A and/or HEB, possibly in combination with Olig1 and 2, are critical components of oligodendrogenesis and may regulate cell survival, proliferation, and fate decisions in the oligodendrocyte lineage.

Animals↗

PubMed2001

SCIP/Oct-6, Krox-20, and desert hedgehog mRNA expression during CNS remyelination by transplanted olfactory ensheathing cells.

Olfactory ensheathing cells (OECs), although having a separate developmental origin to Schwann cells, are able to generate myelin sheaths following transplantation into areas of CNS demyelination that are remarkably similar to those made by Schwann cells. The transcriptional control of Schwann cell myelination has been well documented, in particular the role of SCIP/Oct-6 and Krox-20. It is not known, however, whether these transcription factors are also expressed when OECs assume a myelinating phenotype. In this study, we addressed this question by using a transplantation approach to generate myelinating OECs and then examined the expression of SCIP/Oct-6 and Krox-20 mRNA by in situ hybridization using oligonucleotide probes. We also examined the expression of desert hedgehog (Dhh), a Schwann cell-derived signaling molecule that is responsible for regulating the development of the connective tissue elements in peripheral nerve, which bear similarities to the morphologies adopted by nonmyelinating transplanted cells. Our results indicate that both Krox-20 and Dhh mRNA are strongly expressed by transplanted OECs, with SCIP mRNA present at much lower levels. The expression of Krox-20 relative to the expression of P0 mRNA by the transplanted OECs is consistent with its playing a similar role in OEC myelination to that in Schwann cell myelination, while the expression of Dhh suggests a possible mechanism for the diverse morphologies that cells adopt following OEC transplantation into the damaged CNS. Taken together, our results provide further evidence for the close similarity of OECs and Schwann cells and suggest that, despite their separate origins, the manner in which they generate a peripheral-type myelin sheath involves similar regulatory mechanisms.

Animals↗

PubMed2004

Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment.

Hedgehog (Hh) signalling controls many aspects of development. It also regulates cell growth and differentiation in adult tissues and is activated in a number of human malignancies. Hh and Wnt signalling frequently act together in controlling cell growth and tissue morphogenesis. Despite the fact that the majority of colorectal tumours have a constitutively activated canonical Wnt pathway, few previous studies have investigated the expression of Hh signalling components in colorectal tumours. We describe here epithelial cell lines derived from both nonmalignant colorectal adenomas and colorectal adenocarcinomas that express both Sonic and Indian Hh. Interestingly, these cells also express the Hh receptor Patched and the downstream signalling components Smoothened and Gli1, suggesting autocrine Hh signalling in these cells. To test whether autocrine Hh signalling contributes to cell survival, we treated colorectal tumour cells with cyclopamine, a known inhibitor of Hh signalling. Cyclopamine treatment induced apoptosis in both adenoma- and carcinoma-derived cell lines, which could be partially rescued by further stimulation of Hh signalling. These data suggest that autocrine Hh signalling can increase aberrant cell survival in colorectal tumour cells and may be a novel target for colon cancer therapy using drugs such as cyclopamine.

Adenoma↗

PubMed2005

Indian hedgehog: its roles and regulation in endochondral bone development.

Normal endochondral bone development requires the coordination of chondrocyte proliferation and differentiation. Indian hedgehog (Ihh) is a morphogen produced by chondrocytes in the early stage of terminal differentiation and plays several key roles in this process. Ihh regulates growth of adjacent proliferative chondrocytes and can also regulate the rate of differentiation of chondrocytes indirectly through its stimulation of parathyroid hormone-related protein (PTHrP). In this review, we focus on recent studies that have identified new functions of Ihh and how Ihh itself is being regulated.

Angiogenesis Inducing Agents↗

PubMed2002

Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2.

The roles of Sonic hedgehog (Shh) and Bone morphogenetic protein-2 (Bmp-2) in osteoblast differentiation were investigated using in vitro cell systems. Recombinant amino-terminal portion of SHH (rSHH-N) dose dependently stimulated ALP activity in C3H10T1/2 and MC3T3-E1 cells. rSHH-N induced expression of Osteocalcin mRNA in C3H10T1/2 cells. A soluble form of the receptor for type IA BMP receptor antagonized rSHH-N-induced ALP activity in C3H10T1/2 and MC3T3-E1 cells, indicating that BMPs are involved in SHH-induced osteoblast differentiation. Simultaneous supplement with rSHH-N and BMP-2 synergistically induced ALP activity and expression of Osteocalcin mRNA in C3H10T1/2 cells. Pretreatment with rSHH-N for 6 h enhanced the response to BMP-2 by increasing ALP activity in C3H10T1/2 and MC3T3-E1 cells. Stimulatory effects of rSHH-N and additive effects with rSHH-N and BMP-2 on ALP activity were also observed in mouse primary osteoblastic cells. Transplantation of BMP-2 (1 microg) into muscle of mice induced formation of ectopic bone, whereas transplantation of r-SHH-N (1-5 microg) failed to generate it. These results indicate that Shh plays important roles in osteoblast differentiation by cooperating with BMP.

Alkaline Phosphatase↗

PubMed2005

Regulation of Indian hedgehog mRNA levels in chondrocytic cells by ERK1/2 and p38 mitogen-activated protein kinases.

Indian hedgehog (Ihh) is produced by growth plate pre-hypertrophic chondrocytes, and is an important regulator of endochondral ossification. However, little is known about the regulation of Ihh in chondrocytes. We have examined the role of integrins and mitogen-activated protein (MAP) kinases in Ihh mRNA regulation in CFK-2 chondrocytic cells. Cells incubated with the beta1-integrin blocking antibody had decreased Ihh mRNA levels, which was accompanied by decreases of activated extracellular signal-regulated kinases (ERK1/2) and activated p38 MAPK. Ihh mRNA levels were also inhibited by U0126, a specific MEK1/2 inhibitor, or SB203580, a specific p38 MAPK inhibitor. Cells transfected with constitutively active MEK1 or MKK3 had increased Ihh mRNA levels, which were diminished by dominant-negative MEK1, p38alpha or p38beta. Stimulation of the PTH1R with 10(-8) M rPTH (1-34) resulted in dephosphorylation of ERK1/2 that was evident within 15 min and sustained for 1 h, as well as transient dephosphorylation of p38 MAPK that was maximal after 25 min. PTH stimulation decreased Ihh mRNA levels, and this effect was blocked by transfecting the cells with constitutively active MEK1 but not by MKK3. These studies demonstrated that activation of ERK1/2 or p38 MAPK increased Ihh mRNA levels. Stimulation of the PTH1R or blocking of beta1-integrin resulted in inhibition of ERK1/2 and p38 MAPK and decreased levels of Ihh mRNA. Our data demonstrate the central role of MAPK in the regulation of Ihh in CFK-2 cells.

Animals↗