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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / genetics
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Animals
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Cell Movement / genetics
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Cells, Cultured
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Cerebellar Diseases / genetics
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Cerebellum / abnormalities
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Cilia / metabolism*
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Cyclic AMP / biosynthesis
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Embryo, Mammalian / metabolism
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Eye Abnormalities / genetics
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Eye Diseases / genetics
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Hedgehog Proteins / metabolism*
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Hippocampus / embryology
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Intellectual Disability / genetics
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Kidney Diseases, Cystic / genetics
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Kruppel-Like Transcription Factors / biosynthesis
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Kruppel-Like Transcription Factors / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neural Stem Cells / metabolism
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Obesity / genetics
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Penile Diseases / genetics
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Phosphatidylinositol 4,5-Diphosphate / metabolism
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Phosphatidylinositol Phosphates / metabolism*
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Phosphoric Monoester Hydrolases / genetics*
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Protein Transport / genetics
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Proteins / metabolism*
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Receptors, G-Protein-Coupled / metabolism*
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Retina / abnormalities
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Signal Transduction
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Zinc Finger Protein GLI1
Substances
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GPR161 protein, mouse
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Gli1 protein, mouse
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Hedgehog Proteins
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Kruppel-Like Transcription Factors
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Phosphatidylinositol 4,5-Diphosphate
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Phosphatidylinositol Phosphates
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Proteins
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Receptors, G-Protein-Coupled
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Shh protein, mouse
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Tulp3 protein, mouse
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Zinc Finger Protein GLI1
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phosphatidylinositol 4-phosphate
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Cyclic AMP
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Phosphoric Monoester Hydrolases
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phosphoinositide 5-phosphatase
Supplementary concepts
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Agenesis of Cerebellar Vermis
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MORM syndrome