Defective Gpsm2/Gα_i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.

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 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.

SUBMITTER: Mauriac SA 

PROVIDER: S-EPMC5385604 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature