Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782520632732286976 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5385604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mauriacstephaniea defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT hienyerie defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT birdjonathane defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT carvalhostevedossantos defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT peyroutouronan defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT leeszechim defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT moreaumaitem defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT blancjeanmichel defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT gezeraysegul defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT medinachantal defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT thoumineolivier defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT beerhammersandra defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT friedmanthomasb defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT ruttigerlukas defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT forgeandrew defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT nurnbergbernd defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT sansnathalie defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome AT montcouquiolmireille defectivegpsm2gai3signallingdisruptsstereociliadevelopmentandgrowthconeactindynamicsinchudleymcculloughsyndrome |