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INPP5E regulates phosphoinositide-dependent cilia transition zone function
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; howeve...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223597/ https://www.ncbi.nlm.nih.gov/pubmed/27998989 http://dx.doi.org/10.1083/jcb.201511055 |
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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. |
author_facet | 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. |
author_sort | Dyson, Jennifer M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5223597 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-52235972017-07-02 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 Mitchell, Christina A. J Cell Biol Research Articles 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. The Rockefeller University Press 2017-01-02 /pmc/articles/PMC5223597/ /pubmed/27998989 http://dx.doi.org/10.1083/jcb.201511055 Text en © 2017 Dyson et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles 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. INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title | INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title_full | INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title_fullStr | INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title_full_unstemmed | INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title_short | INPP5E regulates phosphoinositide-dependent cilia transition zone function |
title_sort | inpp5e regulates phosphoinositide-dependent cilia transition zone function |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223597/ https://www.ncbi.nlm.nih.gov/pubmed/27998989 http://dx.doi.org/10.1083/jcb.201511055 |
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