Patched-dependent cell signalling is widespread in the animal kingdom, playing roles in developmental patterning, cell proliferation, and carcinogenesis. The first patched (ptc) gene was identified in Drosophila because of its role in establishing segment polarity. In humans, Ptc is a tumour-suppressor protein in basal cell carcinomas, and mutations in PTCH are implicated in Gorlin's syndrome. Biochemical evidence indicates that Ptc and the serpentine protein Smoothened (Smo) form a receptor complex for the morphogen Hedgehog (Hh). Current models suggest that Ptc inhibits Smo, and that Hh relieves this inhibition by binding to Ptc. In turn, Smo promotes the transcription of TGF- b and Wnt family members. In C. elegans , three genes encode proteins with strong sequence similarity to Drosophila and vertebrate PTC proteins. In addition, a number of other predicted C. elegans proteins comprise a subfamily of distant PTC relatives. Here it is reported that
ptc-1 and
ptc-3 are the C. elegans genes most closely related to the ptc genes so far identified in other phyla;
ptc-2 appears to be a pseudogene that arose through a recent duplication of
ptc-1 . Genomic and cDNA sequence analyses have been performed for both
ptc-1 and
ptc-3 . Similar to other Ptc proteins, the predicted PTC-1 and PTC-3 proteins each have 12 potential membrane spanning domains and a cholesterol sensing domain. PTC-1 and PTC-3 share approximately 33% identity with Ptc proteins from other phyla. Inactivation of
ptc-1 or -3 by RNAi reveals that each gene is essential for development:
ptc-1 is needed for cellularisation during gametogenesis, whereas
ptc-3 is required for late embryogenesis. To corroborate the
ptc-1(RNAi) and
ptc-3(RNAi) phenocopies, mutants have been obtained that delete regions of either
ptc-1 or
ptc-3 (thanks to B. Barstead and L. Liu). Each of the deletion mutants displays phenotypic properties similar to those observed by RNAi. Surprisingly, both Hh and Smo appear to be absent from the C. elegans genome. Therefore, these findings suggest that the control of ptc activity may have diverged during evolution, and further raise the possibility that PTC may have functions that are both Hh- and Smo-independent.