Modulation of Ciliary Phosphoinositide Content Regulates Trafficking and Sonic Hedgehog Signaling Output

• Published in: Developmental cell Vol. 34; no. 3; pp. 338 - 350
• Main Authors: Chávez, Marcelo, Ena, Sabrina, Van Sande, Jacqueline, de Kerchove d’Exaerde, Alban, Schurmans, Stéphane, Schiffmann, Serge N.
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 10.08.2015; Elsevier Science
• Subjects: Abnormalities, Multiple - genetics; Animals; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Cell Movement - genetics; Cells, Cultured; Cerebellar Diseases - genetics; Cerebellum - abnormalities; Cilia - metabolism; Cyclic AMP - biosynthesis; Embryo, Mammalian - metabolism; Eye Abnormalities - genetics; Eye Diseases - genetics; Hedgehog Proteins - metabolism; Hippocampus - embryology; Intellectual Disability - genetics; Kidney Diseases, Cystic - genetics; Kruppel-Like Transcription Factors - biosynthesis; Kruppel-Like Transcription Factors - genetics; Life sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Stem Cells - metabolism; Obesity - genetics; Penile Diseases - genetics; phosphatase; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphatidylinositol Phosphates - metabolism; phosphoinositide; Phosphoric Monoester Hydrolases - genetics; primary cilium; Protein Transport - genetics; Proteins - metabolism; Receptors, G-Protein-Coupled - metabolism; Retina - abnormalities; Sciences du vivant; Signal Transduction; Zinc Finger Protein GLI1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2015.06.016

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. [Display omitted] •PI4P is the main PIP in NSC primary cilia, whereas PI(4,5)P2 is not detectable•PI(4,5)P2 accumulates in cilia upon INPP5E inactivation with PI4P depletion•TULP3 and the Shh repressor Gpr161 accumulate in cilia upon INPP5E inactivation•INPP5E inactivation results in reduced DG neurogenesis and Shh signaling in NSCs Chávez et al. identify the main phosphoinositide species in neural stem cell primary cilia and show that the PIP phosphatase INPP5E regulates their levels. Loss of INPP5E changes the dominant cilium phosphoinositide species and affects recruitment of the PIP-interacting protein TULP3 and its cargo Gpr161, with effects on Shh signaling.