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Dev Cell. 2015 Aug 10;34(3):338-50. doi: 10.1016/j.devcel.2015.06.016. Epub 2015 Jul 16.

Modulation of Ciliary Phosphoinositide Content Regulates Trafficking and Sonic Hedgehog Signaling Output.

Author information

1
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: echavez@ulb.ac.be.
2
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
3
IRIBHM, Université Libre de Bruxelles, Brussels 1070, Belgium.
4
Laboratory of Functional Genetics, GIGA Research Centre, and WELBIO, Université de Liège, Liège 4000, Belgium.
5
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: sschiffm@ulb.ac.be.

Abstract

Ciliary transport is required for ciliogenesis, signal transduction, and trafficking of receptors to the primary cilium. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) have been associated with ciliary dysfunction; however, its role in regulating ciliary phosphoinositides is unknown. Here we report that in neural stem cells, phosphatidylinositol 4-phosphate (PI4P) is found in high levels in cilia whereas phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is not detectable. Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted. This is accompanied by recruitment of the PI(4,5)P2-interacting protein TULP3 to the ciliary membrane, along with Gpr161. This results in an increased production of cAMP and a repression of the Shh transcription gene Gli1. Our results reveal the link between ciliary regulation of phosphoinositides by INPP5E and Shh regulation via ciliary trafficking of TULP3/Gpr161 and also provide mechanistic insight into ciliary alterations found in Joubert and MORM syndromes resulting from INPP5E mutations.

PMID:
26190144
DOI:
10.1016/j.devcel.2015.06.016
[Indexed for MEDLINE]
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