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PMID: 19668215 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 41 ·No. 9 ·2009-09-00 ·Pages 1027-31

Jacoby M, Cox JJ, Gayral S, Hampshire DJ, Ayub M, Blockmans M, Pernot E, Kisseleva MV, Compère P, Schiffmann SN, Gergely F, Riley JH, Pérez-Morga D, Woods CG, Schurmans S

Abstract

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.

MeSH Terms
Animals Bardet-Biedl Syndrome/genetics Cell Line Cell Nucleus/metabolism Cells, Cultured Chromones/pharmacology Cilia/genetics,metabolism,pathology,ultrastructure Culture Media, Serum-Free Embryo, Mammalian/cytology,metabolism Enzyme Inhibitors/pharmacology Fibroblasts/cytology,metabolism,ultrastructure Fluorescent Antibody Technique, Direct Fluorescent Dyes/metabolism Genetic Linkage Genetic Markers Green Fluorescent Proteins/metabolism Humans Indoles/metabolism Intellectual Disability/genetics Male Mice Mice, Mutant Strains Mice, Transgenic Microsatellite Repeats Morpholines/pharmacology Mutation Obesity/genetics Penis/abnormalities Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Phosphoric Monoester Hydrolases/genetics Pigment Epithelium of Eye/cytology,metabolism Polymorphism, Single Nucleotide Receptor, Platelet-Derived Growth Factor alpha/metabolism Retinal Degeneration/genetics Signal Transduction/physiology Transfection Tubulin/metabolism
Chemicals
Chromones Culture Media, Serum-Free Enzyme Inhibitors Fluorescent Dyes Genetic Markers Indoles Morpholines Phosphoinositide-3 Kinase Inhibitors Tubulin Green Fluorescent Proteins 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one DAPI Receptor, Platelet-Derived Growth Factor alpha Phosphoric Monoester Hydrolases phosphoinositide 5-phosphatase
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Jacoby Monique
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
Gayral Stéphanie
Hampshire Daniel J
Ayub Mohammed
Blockmans Marianne
Pernot Eileen
Kisseleva Marina V
Compère Philippe
Schiffmann Serge N
Gergely Fanni
Riley John H
Pérez-Morga David
Woods C Geoffrey
Schurmans Stéphane
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.427
Published
2009-09-00
Epub
2009-00-09
Pages
1027-31
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Grants
NHLBI NIH HHS · HL16634 · United States
External Links
PubMed source DOI: 10.1038/ng.427 View journal details
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