What vitamins can do for hedgehog
Vitamin D3 contributes to silencing the hedgehog signaling pathway in the absence of ligand.
The hedgehog (HH) pathway ranks high in the league of important developmental pathways, yet the mechanics of HH signalling are still sketchy. Now, a study that pulls together evidence from genetic mutants, cell culture experiments and human disease phenotypes has concluded that vitamin D3 (or its precursor) is what keeps the pathway silenced in the absence of the HH ligand, and that it does so non-cell-autonomously.
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The HH pathway is highly conserved and also highly unusual: for example, there are two receptors involved, Patched1 (PTCH1) and Smoothened (SMO). These two transmembrane proteins have different functions, with PTCH1 inhibiting SMO constitutively; binding of HH to PTCH1 relieves this inhibition and allows the transcription of downstream genes, including glioma associated (Gli). What precisely goes on between PTCH1 and SMO was the focus of the current study, which made use of a culture of mouse fibroblasts in which activation of the HH pathway was monitored by a Gli-reporter gene.
The first question to be asked by Maarten Bijlsma and colleagues was about the cell autonomy of the effect of PTCH1 on SMO. They show that HH signalling in cells that were constitutively activated by SMO was silenced if PTCH1-overexpressing cells were also present. This and other evidence indicated that the effect of PTCH1 is non-cell-autonomous and that it involves an intermediary molecule. Because the inhibiting effect was not visible when a PTCH1-exposed but serum-free medium was used, the authors then suggested that the inhibitory intermediary must be transported by a lipoprotein (which is absent from serum-free media). But what could the intermediary be?
A clue came from humans who suffer from decreased HH signalling — these individuals have high levels of a hydroxysteroid, 7-dehydrocholesterol (7-DHC). This molecule was indeed shown to inhibit SMO, and the effect was also seen in vivo by exposing zebrafish embryos to the 7-DHC derivative vitamin D3. The fact that PTCH1 looks like a pump means that the pieces of the puzzle can be put into place. PTCH1 normally pumps out vitamin D3 (or its precursor) from the cell, which then inhibits SMO in cells nearby. When HH comes along and binds to PTCH1, the pump shuts down, and SMO is free to activate the intracellular HH pathway.
This neat story has ramifications beyond the understanding of animal development. By acting non-cell-autonomously, PTCH1 could exert a tumour-suppressor function on surrounding PTCH1-inactivated (that is, HH-pathway hyperactive) cells, and so manipulating the expression of wild-type PTCH1 could represent a fruitful avenue for cancer therapy.
Tanita Casci
References
- Bijlsma, M. F. et al. Repression of Smoothened by Patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 4, e232 (2006) | Article | PubMed |
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