Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons
2016
Tabet, Ricardos | Moutin, Enora | Becker, Jérôme | Heintz, Dimitri | Fouillen, Laetitia | Flatter, Eric | Krężel, Wojciech | Alunni, Violaine | Koebel, Pascale | Dembélé, Doulaye | Tassone, Flora | Bardoni, Barbara | Mandel, Jean-Louis | Vitale, Nicolas | Muller, Dominique | Le Merrer, Julie | Moine, Hervé | Université de Strasbourg (UNISTRA) | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) ; Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Department of Basic Neuroscience ; Université de Genève = University of Geneva (UNIGE) | Physiologie de la reproduction et des comportements [Nouzilly] (PRC) ; Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS) | Institut de Biologie Moléculaire des Plantes (IBMP) ; Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) | Laboratoire de biogenèse membranaire (LBM) ; Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS) | Université de Bordeaux (UB) | Medical Investigation of Neurodevelopmental Disorders Institute ; University of California [Davis] (UC Davis) ; University of California (UC)-University of California (UC) | Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA) | Université de Nice Sophia-Antipolis (UNSA) | Institut de génétique et biologie moléculaire et cellulaire (IGBMC) ; Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Collège de France - Chaire Génétique Humaine ; Collège de France (CdF (institution)) | Institut des Neurosciences Cellulaires et Intégratives (INCI) ; Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) | ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010) | ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010) | ANR-12-BSV8-0022,So-FragileX,Rôle du complexe SoSLIP/FMRP (Fragile X Mental Retardation Protein) dans la régulation de la traduction.(2012) | ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011)
Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.
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