Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node

Genetic analyses in Drosophila have demonstrated that the multipass membran e protein Smoothened (Smo) is essential for all Hedgehog signaling. We show that Smo acts epistatic to Ptc1 to mediate Shh and Ihh signaling in the ea rly mouse embryo. Smo and Shh/Ihh compound mutants have identical phenotype s: embryos fail to turn, arresting at somite stages with a small, linear he art tube, an open gut and cyclopia. The absence of visible left/right (L/R) asymmetry led us to examine the pathways controlling L/R situs. We present evidence consistent with a model in which Hedgehog signaling within the no de is required for activation of Gdf1, and induction of left-side determina nts. Further, we demonstrate an absolute requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis.