Editors' ChoiceMorphogens

New Mechanism Proposed for Hedgehog Signal

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Science's STKE  22 Aug 2006:
Vol. 2006, Issue 349, pp. tw282
DOI: 10.1126/stke.3492006tw282

The morphogen hedgehog activates an odd signaling pathway in which the receptor smoothened (Smo) is constitutively active and Hh functions to somehow relieve inhibition of Smo by the protein patched (Ptch1). Exactly how this works has been unclear, but hints include the fact that Ptch1 resembles proteins that function as pumps and another that contributes to trafficking of cholesterol molecules. To better understand how Ptch1 might communicate with Smo, Bijlsma et al. tested whether the two molecules even needed to be on the same cell. They cultured mouse fibroblasts expressing Ptch1 with similar cells expressing Smo and a transcriptional reporter for Smo-dependent gene expression and found that the Smo signal could be transferred in the medium between the cells. Because patients with a human disease known as Smith-Lemli-Opitz syndrome (SLOS) have altered sterol biosynthesis and phenotypes reminiscent of animals lacking Hh signaling, the authors tested for the presence of 3β-hydroxysteroids in the culture medium and found that their abundance was increased in medium from cells overexpressing Ptch1. Furthermore, a pharmacological inhibitor of 3β-hydroxysteroid synthesis disrupted Ptch1-dependent activation of a reporter gene in transfected cells. Fibroblasts from animals unable to produce 3β-hydroxysteroids did not produce the intercellular mediator that inhibited Smo. The authors suspected that the specific steroid involved might be 7-dehydrocholesterol or its metabolite vitamin D3. Indeed, addition of vitamin D3 to cells inhibited transcription of the reporter gene as effectively as did cyclopamine, a known inhibitor of Smo. The authors propose that Ptch1 may transport vitamin D3 and thus inhibit Smo function on the same or adjacent cells. This would endow Hh signals with the unusual property of being able to regulate signals on neighboring cells to those that actually encounter the morphogen.

M. F. Bijlsma, C. A. Spek, D. Zivkovic, S. van de Water, F. Rezaee, M. P. Peppelenbosch, Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 4, 1397-1410 (2006). [PubMed]

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