INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse.
The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing. 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 alpha (PDGFRalpha) 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.
Jacoby
Monique
M
Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
Cox
James J
JJ
Gayral
Stéphanie
S
Hampshire
Daniel J
DJ
Ayub
Mohammed
M
Blockmans
Marianne
M
Pernot
Eileen
E
Kisseleva
Marina V
MV
Compère
Philippe
P
Schiffmann
Serge N
SN
Gergely
Fanni
F
Riley
John H
JH
Pérez-Morga
David
D
Woods
C Geoffrey
CG
Schurmans
Stéphane
S
D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D002923:Cilia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D016895:Culture Media, Serum-Free; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D019085:Fluorescent Antibody Technique, Direct; D005456:Fluorescent Dyes / Q000378:metabolism; D008040:Genetic Linkage; D005819:Genetic Markers; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009765:Obesity / Q000235:genetics; D010413:Penis / Q000002:abnormalities; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D005819:Genetic Markers; D049452:Green Fluorescent Proteins; D007211:Indoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D014404:Tubulin; D000099182:Phosphoinositide 5-Phosphatases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C007293:DAPI