Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals.The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors (GPCRs).Despite a conserved mechanism by which Hh activates Smo in Drosophild and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood.