Abstract - GIGA - Université de Liège

Dev Cell. 2015 Jul 14. pii: S1534-5807(15)00423-2. doi: 10.1016/j.devcel.2015.06.016.
[Epub ahead of print]
Modulation of Ciliary Phosphoinositide
Content Regulates Trafficking and Sonic
Hedgehog Signaling Output.
Chávez M1, Ena S2, Van Sande J3, de Kerchove d'Exaerde A2, Schurmans S4, Schiffmann
SN5.
Author information





1
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de
Bruxelles (ULB), Brussels 1070, Belgium. Electronic address: [email protected].
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: [email protected].
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.