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

Nat Commun. 2017 Apr 7:8:14907. doi: 10.1038/ncomms14907.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / metabolism
  • Agenesis of Corpus Callosum / physiopathology
  • Animals
  • Arachnoid Cysts / genetics*
  • Arachnoid Cysts / metabolism
  • Arachnoid Cysts / physiopathology
  • Carrier Proteins / genetics*
  • Cell Cycle Proteins
  • Deafness / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Growth Cones / metabolism*
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Vestibular / metabolism*
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / metabolism
  • Hearing Loss, Sensorineural / physiopathology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mutation
  • Myosins / metabolism
  • Neurons / metabolism*
  • Postural Balance
  • Sensation Disorders / genetics
  • Stereocilia / metabolism*

Substances

  • Actins
  • Carrier Proteins
  • Cell Cycle Proteins
  • GPSM2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LGN protein, mouse
  • Membrane Proteins
  • Myo15 protein, mouse
  • Whrn protein, mouse
  • Myosins
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Gnai3 protein, mouse

Supplementary concepts

  • Chudley-Mccullough syndrome