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16 février 2018: 2 événements

  • Département Biologie Cellulaire

    Vendredi 16 février 11:00-12:30 - Mireille MONTCOUQUIOL - INSERM Bordeaux, invitée par Anne-Marie Tassin

    Identification of a common molecular mechanism leading to hearing deficit and corpus callosum agenesis

    Résumé : The Chudley McCullough syndrome (CMCS) is a rare autosomal recessive neurological disorder characterized by early and severe onset of deafness and brain anomalies (Chudley et al., 1997). Mutations in the G protein signaling modulator 2 (GPSM2) gene were found to be causative of this pathology (Shahin et al., 2010 ; Walsh et al., 2010 ; Doherty et al., 2012) but the molecular and cellular bases of this pathology is unknown.
    Here, we show that Gpsm2 and Gαi3 proteins define a nanodomain (STED microscopy) at the tips of the tallest stereocilia in auditory cells and that this localization requires the presence of myosin 15 and whirlin, well-known regulators of stereocilia elongation. In absence of Gpsm2 the stereocilia elongation process is stopped, leading to a shortening of the hair bundle representing the most probable cause for early and severe deafness in the CMCS patients and in our mouse model. We further report that absence of Gnai3 leads to elevated hearing threshold, correlating with hair bundle elongation defects confined to high-frequency cochlear regions.
    Mechanistically, we identify an interaction between Gpsm2 and whirlin, and we show that this interaction affects the ability of the myosin 15/whirlin complex to generate filopodia in heterologous cells. Because filopodia (like stereocilia) elongation depends on actin polymerization, we further demonstrate that Gpsm2 mutations lead to a reduction in F-actin levels while overexpression of the Gpsm2/Gαi3 complex increases F-actin levels. Our data support the idea that Gpsm2/Gαi3 complex is at the interface between the actin and the membrane to regulate the actin polymerization at the tip of stereocilia or filopodia.
    We speculated that a similar actin-dependent post-mitotic mechanism could cause one of the brain abnormalities observed in patients, an hypoplasia of the corpus callosum and hippocampal commissures. Using Stp-PALM we show that the outgrowth of hippocampal young neurons is indeed reduced in Gpsm2 mutants, and we correlated this reduction with a deficit of actin dynamics, which could explain the defect of the corpus callosum.
    Altogether, our study 1/ identify the cause of the deafness in CMCS patients, 2/ identify a new molecular function for Gpsm2 in the regulation of actin dynamics, and 3/ suggest a post-mitotic cause for one of the central nervous system syndromes observed in patients.

    Lieu : Bibliothèque - bâtiment 34 - Campus de Gif-sur-yvette

    En savoir plus : Département Biologie Cellulaire
  • Département Biochimie, Biophysique et Biologie Structurale

    Vendredi 16 février 14:00-15:30 - Pr Christine Ziegler - University of Regensburg, Germany

    Na+ coupling and K+ regulation in the secondary betaine transporter BetP

    Lieu : Auditorium I2BC - Bâtiment 21 - Campus de Gif-sur-Yvette

    En savoir plus : Département Biochimie, Biophysique et Biologie Structurale

16 février 2018: 1 événement

  • Département Biochimie, Biophysique et Biologie Structurale

    Vendredi 16 février 10:00-12:30 - José Luis Vazquez-Ibar - Laboratoire des Protéines et Systèmes Membranaires, Département B3S, I2BC

    Structural and functional studies of membrane transport proteins

    Lieu : Auditorium I2BC - Bâtiment 21 - Campus de Gif-sur-Yvette

    En savoir plus : Département Biochimie, Biophysique et Biologie Structurale