Defective Gpsm2/Gα<sub>i3</sub> signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28387217.
- Also identified by DOI 10.1038/ncomms14907 and PMC identifier 5385604.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>i3</sub>, 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<sub>i3</sub>, 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<sub>i3</sub> in the regulation of actin dynamics in epithelial and neuronal tissues.
Medical subject headings
- Actins
- Agenesis of Corpus Callosum
- Arachnoid Cysts
- Carrier Proteins
- Growth Cones
- Hair Cells, Auditory
- Hair Cells, Vestibular
- Hearing Loss, Sensorineural
- Neurons
- Stereocilia