title: Defective Gpsm2/Gαi3signalling 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 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/Gαi3in the regulation of actin dynamics in epithelial and neuronal tissues.
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Mauriac
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Yeri E
authors.initials: YE
authors.lastname: Hien
authors.affiliation: Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Bird
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Steve Dos-Santos
authors.initials: SD
authors.lastname: Carvalho
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Peyroutou
authors.affiliation: Department of Otolaryngology, Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Sze Chim
authors.initials: SC
authors.lastname: Lee
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Maite M
authors.initials: MM
authors.lastname: Moreau
authors.affiliation: Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.|Biochemistry and Biophysics Facility of the Bordeaux Neurocampus, F-33077 Bordeaux, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Blanc
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Geyser
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Medina
authors.affiliation: CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 146 rue Leo-Saignat, F-33077 Bordeaux, France.|Univ. Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33077 Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Thoumine
authors.affiliation: Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
authors.affiliation: Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.affiliation: Department of Otolaryngology, Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Rüttiger
authors.affiliation: UCL Ear Institute, London WC1X 8EE, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Forge
authors.affiliation: Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sans
authors.affiliation: INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France.
authors.forename: Mireille
authors.identifier: 0000-0001-8739-6519
authors.initials: M
authors.lastname: Montcouquiol
mesh_terms: D000199:Actins / Q000378:metabolism*; D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D016080:Arachnoid Cysts / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D003638:Deafness / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000378:metabolism*; D018069:Hair Cells, Vestibular / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009218:Myosins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D004856:Postural Balance; D012678:Sensation Disorders / Q000235:genetics; D059547:Stereocilia / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C102754:GPSM2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C502655:LGN protein, mouse; D008565:Membrane Proteins; C114013:Myo15 protein, mouse; C477218:Whrn protein, mouse; D009218:Myosins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse