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Developmental biology

Testing times for Hedgehog

Nature Reviews Genetics volume 5, pages 718–719 (2004)Cite this article

The first paper investigated how Hh concentration is sensed by the cell. The Hh signalling pathway is unlike most others in that its receptor, Patched (Ptc), is active when not bound to its ligand, as in this state it blocks signalling from the transmembrane protein Smoothened (Smo). Binding of Hh to Ptc relieves this repression and leads to the expression of Smo-target genes. In this deceptively simple interaction, one would assume that ligand-bound Ptc would essentially be equivalent to having no Ptc at all — and that the cell's measure of ambient Hh would be governed simply by the amount of Ptc that remains unliganded. But is this intuitive model true?

Casali and Struhl entertained the alternative hypothesis that the ability of a cell to sense the concentration of Hh depends on the ratio of bound to unbound Ptc; that is, that the Hh–Ptc unit might titrate the inhibitory effect of unbound Ptc on Smo. To distinguish between the two hypotheses, the authors expressed a form of Ptc (PtcΔloop2) that cannot bind Hh and so constitutively represses Smo at three distinct expression levels in the fly wing. They then asked: is the minimum level of PtcΔloop2 necessary to shut down Smo the same, regardless of endogenous Ptc–Hh levels (in which case the traditional model is correct), or does it depend on the presence and amount of the ligand-bound receptor? Their new model was vindicated when they saw that low levels of PtcΔloop2 expression is sufficient to block the pathway in ptc−/− cells, but has little or no effect on normal Hh signalling in otherwise wild-type cells. Instead, high levels of PtcΔloop2 expression was necessary to block Smo activity in the presence of liganded Ptc, indicating some form of titration. Although the model relies on assumptions that remain to be investigated, it seems that Hh-bound Ptc is not the same as having no Ptc at all and that Hh transduction depends on the ratio of bound to unbound Ptc rather than the absolute amount of unbound Ptc.

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ORIGINAL RESEARCH PAPERS

  1. Casali, A. & Struhl, G. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature 431, 76–80 (2004)

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  2. Ahn, S. & Joyner, A. L. Dynamic changes in the response of cells to positive Hedgehog signaling during mouse limb patterning. Cell 118, 505–516 (2004)

    Article  CAS  Google Scholar 

  3. Harfe, B. D., Scherz, P. J. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004)

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Authors
  1. Tanita Casci
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Casci, T. Testing times for Hedgehog. Nat Rev Genet 5, 718–719 (2004). https://doi.org/10.1038/nrg1466

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  • DOI: https://doi.org/10.1038/nrg1466

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