Dev Cell

The Hedgehog (Hh) pathway depends on primary cilia\uc2\ua0in vertebrates, but the signaling machinery within cilia\uc2\ua0remains incompletely defined. We report the identification of a complex between two ciliary proteins, EFCAB7 and IQCE, which positively regulates the Hh\uc2\ua0pathway. The EFCAB7-IQCE module anchors the\uc2\ua0EVC-EVC2 complex in a signaling microdomain at\uc2\ua0the base of cilia. EVC and EVC2 genes are mutated in\uc2\ua0Ellis van Creveld and Weyers syndromes, characterized by impaired Hh signaling in skeletal, cardiac, and orofacial tissues. EFCAB7 binds to a C-terminal disordered region in EVC2 that is deleted in Weyers patients. EFCAB7 depletion mimics the Weyers cellular phenotype-the mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2. Evolutionary analysis suggests that emergence of these complexes might have been important for adaptation of an ancient organelle, the cilium, for an animal-specific signaling network.DP2 GM105448/GM/NIGMS NIH HHS/United StatesDP2GM105448/DP/NCCDPHP CDC HHS/United StatesIntramural NIH HHS/United States2015-03-10T00:00:00Z24582806PMC402704