INPP5E regulates phosphoinositide-dependent cilia transition zone function

Dyson, Jennifer M., Conduit, Sarah E., Feeney, Sandra J., Hakim, Sandra, DiTommaso, Tia, Fulcher, Alex J., Sriratana, Absorn, Ramm, Georg, Horan, Kristy A., Gurung, Rajendra, Wicking, Carol, Smyth, Ian and Mitchell, Christina A. (2017) INPP5E regulates phosphoinositide-dependent cilia transition zone function. The Journal of Cell Biology, 216 1: 247-263. doi:10.1083/jcb.201511055


Author Dyson, Jennifer M.
Conduit, Sarah E.
Feeney, Sandra J.
Hakim, Sandra
DiTommaso, Tia
Fulcher, Alex J.
Sriratana, Absorn
Ramm, Georg
Horan, Kristy A.
Gurung, Rajendra
Wicking, Carol
Smyth, Ian
Mitchell, Christina A.
Title INPP5E regulates phosphoinositide-dependent cilia transition zone function
Journal name The Journal of Cell Biology   Check publisher's open access policy
ISSN 0021-9525
1540-8140
Publication date 2017-01-01
Year available 2017
Sub-type Article (original research)
DOI 10.1083/jcb.201511055
Open Access Status DOI
Volume 216
Issue 1
Start page 247
End page 263
Total pages 17
Place of publication New York, United States
Publisher Rockefeller University Press
Language eng
Abstract Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e(-/-) embryos exhibit aberrant Hedgehog dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e(-/-) ciliopathy phenotypes and "normalizes" Hedgehog signaling. INPP5E's phosphoinositide substrates PI(4,5)P-2 and PI(3,4,5)P-3 accumulated at the transition zone (TZ) in Hedgehog-stimulated Inpp5e(-/-) cells, which was associated with reduced recruitment of TZ scaffolding proteins and reduced Smoothened levels at cilia. Expression of wild-type, but not 5-phosphatase-dead, INPP5E restored TZ molecular organization and Smoothened accumulation at cilia. Therefore, we identify INPP5E as an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains TZ function and Hedgehog-dependent embryonic development.
Formatted abstract
Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e−/− embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e−/− ciliopathy phenotypes and “normalizes” Hedgehog signaling. INPP5E’s phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulated at the transition zone (TZ) in Hedgehog-stimulated Inpp5e−/− cells, which was associated with reduced recruitment of TZ scaffolding proteins and reduced Smoothened levels at cilia. Expression of wild-type, but not 5-phosphatase-dead, INPP5E restored TZ molecular organization and Smoothened accumulation at cilia. Therefore, we identify INPP5E as an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains TZ function and Hedgehog-dependent embryonic development.
Keyword Cell Biology
Cell Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1046174
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 06 Jan 2017, 21:22:08 EST by Susan Allen on behalf of Institute for Molecular Bioscience