Uncoupling Intraflagellar Transport and Primary Cilia Formation Demonstrates Deep Integration of IFT in Hedgehog Signaling

Abstract

Abstract The vertebrate hedgehog pathway is organized in primary cilia and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling. Determining if IFT drives the movement of hedgehog components is difficult due to the requirement of IFT for building cilia. Unlike most IFT proteins, IFT27 is dispensable for cilia formation but affects hedgehog signaling similar to other IFTs allowing us to examine its role in the dynamics of signaling. Activating signaling at points along the pathway in Ift27 mutant cells showed that IFT is extensively involved in the pathway. Similar analysis of Bbs mutant cells showed that BBS proteins participate at many levels of signaling but are not needed to concentrate Gli transcription factors at the ciliary tip. Our analysis showed that smoothened delivery to cilia does not require IFT27, but the role of other IFTs is not known. Using a rapamycin-induced dimerization system to stop IFT after ciliary assembly was complete we show that smoothened delivery to cilia is IFT independent. Abbreviations MEFs mouse embryonic fibroblasts SAG smoothen agonist IFT intraflagellar transport FKBP FK506 Binding Protein 12 FRB FKBP12-rapamycin binding

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