Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

Stephanie A. Mauriac, Yeri E. Hien, Jonathan E. Bird, Steve Dos-Santos Carvalho, Ronan Peyroutou, Sze Chim Lee, Maite M. Moreau, Jean-Michel Blanc, Aysegul Gezer, Chantal Medina, Olivier Thoumine, Sandra Beer-Hammer, Thomas B. Friedman, Lukas Rüttiger, Andrew Forge, Bernd Nürnberg, Nathalie Sans and Mireille Montcouquiol ()
Additional contact information
Stephanie A. Mauriac: INSERM, Neurocentre Magendie
Yeri E. Hien: INSERM, Neurocentre Magendie
Jonathan E. Bird: Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health
Steve Dos-Santos Carvalho: INSERM, Neurocentre Magendie
Ronan Peyroutou: INSERM, Neurocentre Magendie
Sze Chim Lee: Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen
Maite M. Moreau: INSERM, Neurocentre Magendie
Jean-Michel Blanc: Univ. Bordeaux, Neurocentre Magendie
Aysegul Gezer: INSERM, Neurocentre Magendie
Chantal Medina: INSERM, Neurocentre Magendie
Olivier Thoumine: CNRS, Interdisciplinary Institute for Neuroscience
Sandra Beer-Hammer: University of Tübingen
Thomas B. Friedman: Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health
Lukas Rüttiger: Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen
Andrew Forge: UCL Ear Institute
Bernd Nürnberg: University of Tübingen
Nathalie Sans: INSERM, Neurocentre Magendie
Mireille Montcouquiol: INSERM, Neurocentre Magendie

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14907

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