phosphatidylinositol-4-phosphate and Cerebellar-Diseases

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.

Topics: Abnormalities, Multiple; Animals; Cell Movement; Cells, Cultured; Cerebellar Diseases; Cerebellum; Cilia; Cyclic AMP; Embryo, Mammalian; Eye Abnormalities; Eye Diseases; Hedgehog Proteins; Hippocampus; Intellectual Disability; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Kidney Diseases, Cystic; Kruppel-Like Transcription Factors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Stem Cells; Obesity; Penile Diseases; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphoric Monoester Hydrolases; Protein Transport; Proteins; Receptors, G-Protein-Coupled; Retina; Signal Transduction; Zinc Finger Protein GLI1