Genetic evidence that Sil is required for the sonic hedgehog response pathway

The Sil gene encodes a cytosolic protein required for mouse embryonic midli ne and left/right axial development. Based on the phenotype of Sil mutant e mbryos, we hypothesized that Sil may be required for the activity of Sonic Hedgehog (Shh), a secreted signaling molecule also critically important for the development of the embryonic axes and found mutated in multiple types of cancer. Here we tested the genetic interaction between Sil and the Shh p athway by generating and analyzing embryos carrying mutations in both Sil a nd Patched (Ptch), a Shh receptor that normally inhibits the signaling path way in the absence of ligand and when mutated leads to constitutive activat ion of the pathway. We find that Sil(-/-) Ptch(-/-) embryos do not activate the Shh pathway and instead have a phenotype indistinguishable from Sil(-/ -) embryos, in which there is a loss of activity of Shh. These results prov ide genetic evidence that Sil is an essential component of the Shh response , acting downstream to Ptch. (C) 2001 Wiley-Liss, Inc.