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At least 19 recordsLinked to original sources
PubMed1999

Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse.

Lingual taste buds form within taste papillae, which are specialized structures that develop in a characteristic spatial and temporal pattern. To investigate the signaling events responsible for patterning and morphogenesis of taste papillae, the authors examined the time course and distribution of expression of several related developmental signaling genes as well as the time course of innervation of taste papillae in mouse embryos from embryonic day 12 (E12) to E18. Lingual expression of the signaling molecule Sonic hedgehog (Shh), its receptor Patched (Ptc), and the Shh-activated transcription factor Gli1 were assayed by using in situ hybridization. Shh is expressed broadly in the lingual epithelium at E12 but becomes progressively restricted to developing circumvallate and fungiform papillary epithelia. Shh is expressed specifically within the central cells of the papillary epithelium starting at E13.5 and persisting through E18. Ptc and Gli1 expression follow a pattern similar to that of Shh. Compared with Shh, Ptc is expressed in larger regions surrounding the central papillary cells and also in the mesenchyme underlying Shh-expressing epithelium. Innervation of taste papillae was examined by using the panneuronal antibody to ubiquitin carboxyl terminal hydrolase (protein gene product 9.5). Nerves reach the basal lamina of developing taste papillae at E14 to densely innervate the papillary epithelium by E16. Thus, the pattern of Shh expression within developing taste papillae is established prior to innervation, ruling out neuronal induction of papillae. The results suggest that the Shh signaling pathway may be involved in: 1) establishing papillary boundaries in taste papilla morphogenesis, 2) papillary epithelial-mesenchymal interactions, and/or 3) specifying the location or development of taste buds within taste papillae.

Animals↗
PubMed1999

Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ.

We have used the mouse developing tooth germ as a model system to explore the transmission of Sonic hedgehog (Shh) signal in the induction of Patched (Ptc). In the early developing molar tooth germ, Shh is expressed in the dental epithelium, and the transcripts of Shh downstream target genes Ptc and Gli1 are expressed in dental epithelium as well as adjacent mesenchymal tissue. The homeobox gene Msx1 is also expressed in the dental mesenchyme of the molar tooth germ at this time. We show here that the expression of Ptc, but not Gli1, was downregulated in the dental mesenchyme of Msx1 mutants. In wild-type E11.0 molar tooth mesenchyme SHH-soaked beads induced the expression of Ptc and Gli1. However, in Msx1 mutant dental mesenchyme SHH-soaked beads were able to induce Gli1 but failed to induce Ptc expression, indicating a requirement for Msx1 in the induction of Ptc by SHH. Moreover, we show that another signaling molecule, BMP4, was able to induce Ptc expression in wild-type dental mesenchyme, but induced a distinct expression pattern of Ptc in the Msx1 mutant molar mesenchyme. We conclude that in the context of the tooth germ Msx1 is a component of the Shh signaling pathway that leads to Ptc induction. Our results also suggest that the precise pattern of Ptc expression in the prospective tooth-forming region is controlled and coordinated by at least two inductive signaling pathways.

Animals↗
PubMed1998

Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online.

Congential bilateral aplasia of vas deferens (CBAVD), a form of male sterility, has been suggested to represent a "genital" form of cystic fibrosis (CF), as mutations in the CFTR gene have been identified in most patients with this condition. Interestingly, the 5T allele in intron 8 appeared to be the most frequent mutation associated with CBAVD. However, the molecular basis of CBAVD is not completely understood. We have analysed the complete coding and flanking CFTR sequences by PCR-DGGE in 64 men with CBAVD from southern France with the aim to list any sequence alteration. Fourty-two of the 64 patients (65.6%) had mutations on both copies of the CFTR gene, including one patient with two mutations in the same copy (DF508 + A1067T). The 5T allele was present in 21/64 cases (33%). Six of the 28 different mutations identified in this study had never been described previously, and appeared to be specific to CBAVD (P111L, M244K, A1364V, G544V, 2896insAG,-33G->A).

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed1998

Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin.

The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.

Carcinoma, Squamous Cell↗
PubMed1999

Hedgehog signaling molecules in bone marrow cells at the initial stage of fracture repair.

Ihh is a secreted protein expressed in chondrocytes in cartilaginous soft callus and thought to be involved in regulation of chondrogenic differentiation in fracture repair processes. However, gene expression and function of Ihh and its signaling molecules, Ptc and Smo, at the initial stage of fracture repair remain unknown. In the present study, we showed by RT-PCR of mouse rib fractures that the upregulation of Ihh mRNA occurred within hours after fracture, immediately followed by that of Ptc mRNA, and that both Ihh and Ptc mRNAs exhibited the time course similar to those of OP and OC mRNAs at the initial stage of fracture repair. The transcript level of Smo mRNA gradually increased within hours after fracture and was continuously maintained throughout the subsequent fracture repair processes. By in situ hybridization analysis, the transcripts of Ptc and Smo genes localized in bone marrow of unfractured ribs, and those of Ihh, Ptc, and Smo were expressed in the vicinity of the fracture site at 8 h after fracture. Furthermore, in adherent bone marrow cells in culture, mrIhh-N upregulated the gene expression of TGF-beta(1) as well as OPGL, a potent stimulator of osteoclastogenesis and osteoclast activity. These observations suggest that Ihh may play roles in the initial stage of fracture repair via TGF-beta(1) and OPGL.

Animals↗
PubMed1999

Characterisation of a second patched gene in the zebrafish Danio rerio and the differential response of patched genes to Hedgehog signalling.

Hedgehog signalling has been implicated in a variety of processes in vertebrate development, and in each case, the activity of Hh proteins is thought to be mediated by their interaction with a large multipass transmembrane protein encoded by the patched (ptc) gene. In this study we present the full-length coding sequence and describe the wild-type expression pattern of a second ptc gene in zebrafish, Zf-ptc2. We find that at the sequence level Zf-ptc2 is more closely related than Zf-ptc1 to the ptc genes initially characterised in other vertebrate species. We also show that transcription of Zf-ptc2, like Zf-ptc1, is dependent upon Hh signalling and present evidence that it is activated in response to lower levels of Hh activity than is Zf-ptc1. In addition we find no evidence for any specificity in the regulatory interactions between the various Hh proteins and the two ptc genes in the zebrafish.

Amino Acid Sequence↗
PubMed1999

Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube.

Patched (Ptc) is a human tumor suppressor protein and a candidate receptor for Hedgehog (Hh) proteins, which regulate growth and patterning in embryos. Ptc represses expression of Hh target genes such as Gli1 and ptc1 itself. Localized secretion of Hh appears to induce transcription of target genes in specific patterns by binding to Ptc and preventing it from functioning in recipient cells. People who are heterozygous for PTC1 exhibit a range of developmental defects, suggesting that some genes are inappropriately expressed when there is not enough Ptc protein. To test the idea that a balance between Hh and Ptc activities is essential for normal development, we overexpressed Ptc in the neural tube. We find that excess Ptc is sufficient to inhibit expression of Gli1 and ptc1, suggesting that Sonic hedgehog (Shh) cannot signal effectively. This leads to partial dorsalization of the neural tube and a wide spectrum of neural defects, ranging from embryonic lethality to hydrocephaly.

Animals↗
PubMed1997

Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes.

The MSSE gene predisposes to the development of multiple invasive but self-healing skin tumours (multiple self-healing squamous epitheliomata, MSSE). MSSE (previously named ESS1) was mapped to chromosome 9q by linkage analysis; haplotype analysis in families then suggested a common founder mutation and indicated that the gene lies in the interval D9S1-D9S29 (9q22-q31). Squamous cell carcinomata also develop as one of the complications of xeroderma pigmentosum, and one of the xeroderma pigmentosum genes (XPA) maps within the MSSE interval. We have investigated the hypothesis that a novel dominant mutation in XPA is responsible for MSSE. We screened the entire coding region, 3' untranslated region (UTR) and 5'UTR of XPA for germline mutations in MSSE families by single-stranded conformation polymorphism analysis and by direct DNA sequencing. No mutations were detected but a novel intragenic polymorphism was identified in the 5'UTR of XPA, in both MSSE-affected and unrelated normal individuals. This XPA polymorphism and nine new polymorphic markers that map in the MSSE region were typed in eleven MSSE families; XPA was excluded as the MSSE gene and the most likely location of MSSE was reduced to the interval between D9S197 and (D9S287, D9S1809). The Patched (PTCH) gene, which is mutated in naevoid basal cell carcinoma syndrome (NBCCS or Gorlin syndrome) lies in this interval and all MSSE families have been shown to share a common haplotype at three novel intragenic PTCH polymorphisms. Although no mutation has been detected in MSSE families, PTCH has not been excluded as the MSSE gene.

Basal Cell Nevus Syndrome↗
PubMed1998

The effects of splice site mutations in patients with naevoid basal cell carcinoma syndrome.

We have previously identified the human homologue of the Drosophila patched gene and have described, in this gene, mutations that give rise to naevoid basal cell carcinoma syndrome (NBCCS). Here, we have analysed the effects of three splice site mutations within human PATCHED (PTCH) by the reverse transcription/polymerase chain reaction method in cultured patient lymphocyte cell lines. Two alterations, a point mutation in intron 7 and an insertion in intron 10, lead to premature truncation of the PATCHED protein. Another point mutation in intron 17 results in the skipping of exon 18 and the subsequent in-frame deletion of 46 amino acids. Additionally, in all lymphocyte and keratinocyte cell lines examined, exon 10 of PTCH is alternatively spliced leading to an in-frame deletion of 52 amino acids.

Alternative Splicing↗
PubMed1997

Hedgehog and patched gene expression in adult ocular tissues.

We analysed the expression of members of the hh gene family in adult ocular tissues of newt, frog and mouse by RT-PCR method. Shh displayed restricted expression in the neural retina that was conserved in each species analyzed. X-bhh, X-chh and mouse Ihh were detected in the iris and in the retinal pigment epithelium, while mouse Dhh was detected additionally in the neural retina and faintly in the cornea. We also found that two types of ptc genes, potential hh targets and receptors, were expressed in these tissues, suggesting the presence of active hh signalling there.

Amino Acid Sequence↗
PubMed1999

Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths.

We show that Schwann cell-derived Desert hedgehog (Dhh) signals the formation of the connective tissue sheath around peripheral nerves. mRNAs for dhh and its receptor patched (ptc) are expressed in Schwann cells and perineural mesenchyme, respectively. In dhh-/- mice, epineurial collagen is reduced, while the perineurium is thin and disorganized, has patchy basal lamina, and fails to express connexin 43. Perineurial tight junctions are abnormal and allow the passage of proteins and neutrophils. In nerve fibroblasts, Dhh upregulates ptc and hedgehog-interacting protein (hip). These experiments reveal a novel developmental signaling pathway between glia and mesenchymal connective tissue and demonstrate its molecular identity in peripheral nerve. They also show that Schwann cell-derived signals can act as important regulators of nerve development.

Animals↗
PubMed1997

Expression of the mouse Gli and Ptc genes is adjacent to embryonic sources of hedgehog signals suggesting a conservation of pathways between flies and mice.

The three mouse Gli genes are putative transcription factors which are the homologs of cubitus interruptus (ci) in Drosophila. Along with the gene patched (Ptc), ci has been implicated in the hedgehog (Hh) signal transduction pathway. To assess the role of Gli in embryogenesis, we compared its expression with that of Ptc and Hh family members in mouse. We found that Gli and Ptc are expressed in similar domains in diverse regions of the developing mouse embryo and these regions are adjacent to Hh signals. We also show that Gli is expressed ectopically along with Ptc and Shh in Strong's luxoid mutant mice. These results are consistent with conservation of the Hh signal transduction pathway in mice with Gli potentially mediating Hh signaling in multiple regions of the developing embryo.

Animals↗
PubMed1998

Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis.

In Drosophila, patched encodes a negative regulator of Hedgehog signaling. Biochemical experiments have demonstrated that vertebrate patched homologues might function as a Sonic hedgehog (Shh) receptor. In mice, two patched homologues, Ptch and Ptch2, have been identified. Sequence comparison have suggested that they might possess distinct properties in Shh signaling. In the developing tooth, hair and whisker, Shh and Ptch2 are co-expressed in the epithelium while Ptch is strongly expressed in the mesenchymal cells. We report here the chromosomal localization of Ptch2 and further analysis of Ptch2 expression. Throughout mouse development, the level of Ptch2 expression is significantly lower than that of Ptch. In early mouse embryos, Ptch and Ptch2 were found to be co-expressed in regions adjacent to Shh-expressing cells in the developing CNS. Similar to other epidermal structures, Shh and Ptch2 also show overlapping expression in the developing nasal gland and eyelids. Thus, during mouse development, Ptch2 is expressed in both Shh-producing and -nonproducing cells.

Animals↗
PubMed1999

The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for H133Y SHH, PTCH and SMO mutations.

The patched/hedgehog/smoothened signalling pathway has been implicated in the development of sporadic tumours associated with the naevoid basal cell carcinoma (Gorlin) syndrome (NBCCS). Mutations in sporadic basal cell carcinomas (BCCs) of the skin and medulloblastomas have been found in genes encoding all three proteins of the pathway. A substantial proportion of breast carcinomas has recently been suggested to contain missense mutations in the human patched (PTCH) and sonic hedgehog (SHH) homologues. However, an independent study showed that the implicated mutation in SHH (H133Y) was absent in a large number of BCCs, medulloblastomas, breast, ovary and colorectal tumours. We searched for the H133Y SHH mutation in 84 primary breast carcinomas, but did not detect this change in any sample. In addition, a subset of 45 primary breast tumours was analysed for mutations in the PTCH coding region and 48 samples in previously implicated exons of human smoothened, but no mutations were found. Although our results do not exclude the presence of clonal alterations of these genes in a small proportion of breast carcinomas, these data do not support the existence of frequent mutations in genes encoding major protein partners of this signalling pathway. The absence of nucleotide changes in PTCH may point to another linked gene in the chromosome region 9q22-q23, previously suggested to contain a breast cancer susceptibility gene.

Basal Cell Nevus Syndrome↗
PubMed1999

Sonic hedgehog signaling by the patched-smoothened receptor complex.

BACKGROUND: The Hedgehog (Hh) family of secreted proteins is involved in a number of developmental processes as well as in cancer. Genetic and biochemical data suggest that the Sonic hedgehog (Shh) receptor is composed of at least two proteins: the tumor suppressor protein Patched (Ptc) and the seven-transmembrane protein Smoothened (Smo). RESULTS: Using a biochemical assay for activation of the transcription factor Gli, a downstream component of the Hh pathway, we show here that Smo functions as the signaling component of the Shh receptor, and that this activity can be blocked by Ptc. The inhibition of Smo by Ptc can be relieved by the addition of Shh. Furthermore, oncogenic forms of Smo are insensitive to Ptc repression in this assay. Mapping of the Smo domains required for binding to Ptc and for signaling revealed that the Smo-Ptc interaction involves mainly the amino terminus of Smo, and that the third intracellular loop and the seventh transmembrane domain are required for signaling. CONCLUSIONS: These data demonstrate that Smo is the signaling component of a multicomponent Hh receptor complex and that Ptc is a ligand-regulated inhibitor of Smo. Different domains of Smo are involved in Ptc binding and activation of a Gli reporter construct. The latter requires the third intracellular loop and the seventh transmembrane domain of Smo, regions often involved in coupling to G proteins. No changes in the levels of cyclic AMP or calcium associated with such pathways could be detected following receptor activation, however.

Amino Acid Sequence↗
PubMed1999

The molecular pathways of ultraviolet-induced carcinogenesis.

Cancer development requires the accumulation of numerous genetic changes which are usually believed to occur through the presence of unrepaired DNA lesions. Exogenous or endogenous DNA-damaging agents can lead to mutations in the absence of efficient error-free repair, via replication of DNA damage. Several DNA repair pathways are present in living cells and well-conserved from bacteria to human cells. The nucleotide excision repair (NER), the most versatile of these DNA repair systems, recognizes and eliminates a wide variety of DNA lesions and particularly those induced by ultraviolet (UV) light. The phenotypic consequences of a NER defect in humans are apparent in rare but dramatic diseases characterized by hypersensitivity to UV and a striking clinical and genetic heterogeneity. The xeroderma pigmentosum (XP) syndrome is a human disorder inherited as an autosomal recessive trait. Persistence of unrepaired DNA damage produced by exposure to UV light is associated, in the XP syndrome, with an extremely high level of skin tumors in sun-exposed sites. Several key genes are mutagenized by UV-light and are responsible for skin cancer development. Mutations are found on ras oncogenes, p53 and PTCH tumour suppressor genes in skin cancers from DNA repair proficient as well as XP patients. The typical signature of UV-induced mutations found on these genes allows one to conclude that the uvB part of sunlight is responsible for the initiation of the carcinogenesis process.

DNA Damage↗
PubMed1999

Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals.

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The syndrome is characterised by numerous basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, palmar and/or plantar pits, skeletal abnormalities and intracranial calcifications. In this paper, the clinical features of 37 Italian patients are reviewed. Jaw cysts and calcification of falx cerebri were the most frequently observed anomalies, followed by BCCs and palmar/plantar pits. Similar to the case of African Americans, the relatively low frequency of BCCs in the Italian population is probably due to protective skin pigmentation. A future search based on mutation screening might establish a possible genotype phenotype correlation in Italian patients.

Adolescent↗
PubMed1999

Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein.

The Hedgehog signalling pathway is essential for the development of diverse tissues during embryogenesis. Signalling is activated by binding of Hedgehog protein to the multipass membrane protein Patched (Ptc). We have now identified a novel component in the vertebrate signalling pathway, which we name Hip (for Hedgehog-interacting protein) because of its ability to bind Hedgehog proteins. Hip encodes a membrane glycoprotein that binds to all three mammalian Hedgehog proteins with an affinity comparable to that of Ptc-1. Hip-expressing cells are located next to cells that express each Hedgehog gene. Hip expression is induced by ectopic Hedgehog signalling and is lost in Hedgehog mutants. Thus, Hip, like Ptc-1, is a general transcriptional target of Hedgehog signalling. Overexpression of Hip in cartilage, where Indian hedgehog (Ihh) controls growth, leads to a shortened skeleton that resembles that seen when Ihh function is lost (B. St-Jacques, M. Hammerschmidt & A.P.M., in preparation). Our findings support a model in which Hip attenuates Hedgehog signalling as a result of binding to Hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any Hedgehog signal.

Amino Acid Sequence↗