title: Modulation of Ciliary Phosphoinositide Content Regulates Trafficking and Sonic Hedgehog Signaling Output.
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.
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: echavez@ulb.ac.be.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Chávez
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ena
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels 1070, Belgium.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Van Sande
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
authors.forename: Alban
authors.initials: A
authors.lastname: de Kerchove d'Exaerde
authors.affiliation: Laboratory of Functional Genetics, GIGA Research Centre, and WELBIO, Université de Liège, Liège 4000, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: sschiffm@ulb.ac.be.
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002526:Cerebellar Diseases / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities; D002923:Cilia / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D004622:Embryo, Mammalian / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics; D005128:Eye Diseases / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000196:embryology; D008607:Intellectual Disability / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D052177:Kidney Diseases, Cystic / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010409:Penile Diseases / Q000235:genetics; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012160:Retina / Q000002:abnormalities; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D000242:Cyclic AMP; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D000071676:Zinc Finger Protein GLI1; D000099182:Phosphoinositide 5-Phosphatases; C533095:GPR161 protein, mouse; C498520:Gli1 protein, mouse; C465570:Shh protein, mouse; C485499:Tulp3 protein, mouse; C037178:phosphatidylinositol 4-phosphate