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Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and ve...

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Autores principales: Mauriac, Stephanie A., Hien, Yeri E., Bird, Jonathan E., Carvalho, Steve Dos-Santos, Peyroutou, Ronan, Lee, Sze Chim, Moreau, Maite M., Blanc, Jean-Michel, Gezer, Aysegul, Medina, Chantal, Thoumine, Olivier, Beer-Hammer, Sandra, Friedman, Thomas B., Rüttiger, Lukas, Forge, Andrew, Nürnberg, Bernd, Sans, Nathalie, Montcouquiol, Mireille
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385604/
https://www.ncbi.nlm.nih.gov/pubmed/28387217
http://dx.doi.org/10.1038/ncomms14907
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author Mauriac, Stephanie A.
Hien, Yeri E.
Bird, Jonathan E.
Carvalho, Steve Dos-Santos
Peyroutou, Ronan
Lee, Sze Chim
Moreau, Maite M.
Blanc, Jean-Michel
Gezer, Aysegul
Medina, Chantal
Thoumine, Olivier
Beer-Hammer, Sandra
Friedman, Thomas B.
Rüttiger, Lukas
Forge, Andrew
Nürnberg, Bernd
Sans, Nathalie
Montcouquiol, Mireille
author_facet Mauriac, Stephanie A.
Hien, Yeri E.
Bird, Jonathan E.
Carvalho, Steve Dos-Santos
Peyroutou, Ronan
Lee, Sze Chim
Moreau, Maite M.
Blanc, Jean-Michel
Gezer, Aysegul
Medina, Chantal
Thoumine, Olivier
Beer-Hammer, Sandra
Friedman, Thomas B.
Rüttiger, Lukas
Forge, Andrew
Nürnberg, Bernd
Sans, Nathalie
Montcouquiol, Mireille
author_sort Mauriac, Stephanie A.
collection PubMed
description Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gα(i3), a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gα(i3), myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gα(i3) in the regulation of actin dynamics in epithelial and neuronal tissues.
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spelling pubmed-53856042017-04-26 Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome Mauriac, Stephanie A. Hien, Yeri E. Bird, Jonathan E. Carvalho, Steve Dos-Santos Peyroutou, Ronan Lee, Sze Chim Moreau, Maite M. Blanc, Jean-Michel Gezer, Aysegul Medina, Chantal Thoumine, Olivier Beer-Hammer, Sandra Friedman, Thomas B. Rüttiger, Lukas Forge, Andrew Nürnberg, Bernd Sans, Nathalie Montcouquiol, Mireille Nat Commun Article Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gα(i3), a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gα(i3), myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gα(i3) in the regulation of actin dynamics in epithelial and neuronal tissues. Nature Publishing Group 2017-04-07 /pmc/articles/PMC5385604/ /pubmed/28387217 http://dx.doi.org/10.1038/ncomms14907 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Mauriac, Stephanie A.
Hien, Yeri E.
Bird, Jonathan E.
Carvalho, Steve Dos-Santos
Peyroutou, Ronan
Lee, Sze Chim
Moreau, Maite M.
Blanc, Jean-Michel
Gezer, Aysegul
Medina, Chantal
Thoumine, Olivier
Beer-Hammer, Sandra
Friedman, Thomas B.
Rüttiger, Lukas
Forge, Andrew
Nürnberg, Bernd
Sans, Nathalie
Montcouquiol, Mireille
Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title_full Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title_fullStr Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title_full_unstemmed Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title_short Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
title_sort defective gpsm2/gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in chudley-mccullough syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385604/
https://www.ncbi.nlm.nih.gov/pubmed/28387217
http://dx.doi.org/10.1038/ncomms14907
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