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

Marcelo Chávez; Sabrina Ena; Jacqueline Van Sande; Alban de Kerchove d'Exaerde; Stéphane Schurmans; Serge N Schiffmann

doi:10.1016/j.devcel.2015.06.016

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

Dev Cell. 2015 Aug 10;34(3):338-50. doi: 10.1016/j.devcel.2015.06.016. Epub 2015 Jul 16.

Authors

Marcelo Chávez¹, Sabrina Ena², Jacqueline Van Sande³, Alban de Kerchove d'Exaerde², Stéphane Schurmans⁴, Serge N Schiffmann⁵

Affiliations

¹ Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: echavez@ulb.ac.be.
² Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
³ IRIBHM, Université Libre de Bruxelles, Brussels 1070, Belgium.
⁴ Laboratory of Functional Genetics, GIGA Research Centre, and WELBIO, Université de Liège, Liège 4000, Belgium.
⁵ Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: sschiffm@ulb.ac.be.

PMID: 26190144
DOI: 10.1016/j.devcel.2015.06.016

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics
Animals
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
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Kidney Diseases, Cystic / genetics
Kruppel-Like Transcription Factors / biosynthesis
Kruppel-Like Transcription Factors / genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neural Stem Cells / metabolism
Obesity / genetics
Penile Diseases / genetics
Phosphatidylinositol 4,5-Diphosphate / metabolism
Phosphatidylinositol Phosphates / metabolism*
Phosphoric Monoester Hydrolases / genetics*
Protein Transport / genetics
Proteins / metabolism*
Receptors, G-Protein-Coupled / metabolism*
Retina / abnormalities
Signal Transduction
Zinc Finger Protein GLI1

Substances

GPR161 protein, mouse
Gli1 protein, mouse
Hedgehog Proteins
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Kruppel-Like Transcription Factors
Phosphatidylinositol 4,5-Diphosphate
Phosphatidylinositol Phosphates
Proteins
Receptors, G-Protein-Coupled
Shh protein, mouse
Tulp3 protein, mouse
Zinc Finger Protein GLI1
phosphatidylinositol 4-phosphate
Cyclic AMP
Phosphoric Monoester Hydrolases
phosphoinositide 5-phosphatase

Supplementary concepts

Agenesis of Cerebellar Vermis
MORM syndrome