Mauriac, SA;
Hien, YE;
Bird, JE;
Carvalho, SD-S;
Peyroutou, R;
Lee, SC;
Moreau, MM;
... Montcouquiol, M; + view all
(2017)
Defective Gpsm2/G alpha(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
Nature Communications
, 8
, Article 14907. 10.1038/ncomms14907.
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Abstract
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 Gαi3, 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 Gαi3, 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/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.
Type: | Article |
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Title: | Defective Gpsm2/G alpha(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1038/ncomms14907 |
Publisher version: | http://dx.doi.org/10.1038/ncomms14907 |
Language: | English |
Additional information: | 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/ |
Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, Hair-Cell Stereocilia, Hearing-Loss, Unconventional Myosin, Inner-Ear, Spindle Orientation, Deafness Dfnb3, Protein, Whirlin, Elongation, Mouse |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute |
URI: | https://discovery.ucl.ac.uk/id/eprint/1553033 |
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