INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse

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Abstract

The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing1,2,3. Here, we report that mice deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor α (PDGFRα) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction.

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Figure 1: Phenotypic characterization of Inpp5eΔ/Δ mice.
Figure 2: Primary cilium alterations and Inpp5e localization.
Figure 3: Role of Inpp5e in primary cilium stability.
Figure 4: Studies of human INPP5E.

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Acknowledgements

We thank C. Erneux, C. Moreau, F. Fontaine and L. Cuvelier for discussions and technical help, S.J. Elledge for the recombineering reagents, A. de Kerchove d'Exaerde for help with the design of the oligonucleotide probes, A. Nagy for the R1 ES cells, A.P. McMahon for the CAGG-Cre-ERTM mice and E. Golemis for hTERT-RPE1 cells. This work was supported by the Fonds de la Recherche Scientifique-FNRS (FRS-FNRS; to S.G. and S.S.), the Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA; to M.J., M.B. and E.P.), the Fonds de la Recherche Scientifique Médicale (FRSM; to S.S. and S.N.S.), the Fondation Rose et Jean Hoguet (to E.P.), Action de Recherches Concertée de la Communauté Française de Belgique (to S.N.S., S.S. and M.B.), The Queen Elisabeth Medical Fundation (to S.N.S.), the Fonds David et Alice Van Buuren (to M.J.), the Royal Society and Cancer Research UK (to F.G.), the American Heart Association (0730350N; to M.V.K.), the US National Institutes of Health (HL16634; to M.V.K.) and the Wellcome Trust (to J.J.C. and C.G.W).

Author information

All authors designed the experiments; M.J., J.J.C., S.G., D.J.H., M.B., E.P., P.C. and D.P.-M. performed experiments; all authors analyzed data; M.J., M.A., M.V.K., F.G., J.H.R. and C.G.W. provided essential reagents and/or biological samples; all authors discussed the results; and S.S. wrote the manuscript with J.J.C. and C.G.W.'s help with the first draft.

Correspondence to Serge N Schiffmann or C Geoffrey Woods.

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