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

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Mauriac, Stephanie A. | Hien, Yeri E. | Bird, Jonathan E. | dos Santos Carvalho, Steve | Peyroutou, Ronan | Lee, Sze Chim | Moreau, Maite M. | Blanc, Jean-Michel | Gezer, Aysegul | Medina, Chantal | Thoumine, Olivier | Beer-Hammer, Sandra | Friedman, Thomas B. | Ruttiger, Lukas | Forge, Andrew | Nurnberg, Bernd | Sans, Nathalie | Montcouquiol, Mireille

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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