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The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e\u2212\/\u2212 embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e\u2212\/\u2212 ciliopathy phenotypes and \u201cnormalizes\u201d Hedgehog signaling. INPP5E\u2019s phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulated at the transition zone (TZ) in Hedgehog-stimulated Inpp5e\u2212\/\u2212 cells, which was associated with reduced recruitment of TZ scaffolding proteins and reduced Smoothened levels at cilia. Expression of wild-type, but not 5-phosphatase-dead, INPP5E restored TZ molecular organization and Smoothened accumulation at cilia. Therefore, we identify INPP5E as an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains TZ function and Hedgehog-dependent embryonic development.<\/jats:p>","DOI":"10.1083\/jcb.201511055","type":"journal-article","created":{"date-parts":[[2017,1,5]],"date-time":"2017-01-05T17:38:33Z","timestamp":1483637913000},"page":"247-263","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":129,"title":["INPP5E regulates phosphoinositide-dependent cilia transition zone function"],"prefix":"10.1083","volume":"216","author":[{"given":"Jennifer M.","family":"Dyson","sequence":"first","affiliation":[{"name":"Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia 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