title: Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.
abstract: 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Ricardos
authors.initials: R
authors.lastname: Tabet
authors.affiliation: Department of Basic Neuroscience, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Enora
authors.initials: E
authors.lastname: Moutin
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Jérôme A J
authors.initials: JA
authors.lastname: Becker
authors.affiliation: Institut de Biologie Moléculaire des Plantes, Plateforme Métabolomique, Unité Propre de Recherche (UPR) 2357 CNRS, Université de Strasbourg, 67082 Strasbourg, France;
authors.forename: Dimitri
authors.initials: D
authors.lastname: Heintz
authors.affiliation: Laboratoire de Biogènese Membranaire; UMR 5200 CNRS, Plateforme Métabolome, Université de Bordeaux, 33140 Villenave D'Ornon, France;
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fouillen
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Flatter
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krężel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Violaine
authors.initials: V
authors.lastname: Alunni
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Pascale
authors.initials: P
authors.lastname: Koebel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento, CA 95817;
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, University of Nice Sophia-Antipolis, CNRS Laboratoire International Associé (LIA) Neogenex, 06560 Valbonne, France;
authors.forename: Barbara
authors.initials: B
authors.lastname: Bardoni
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; Collège de France, 75005 Paris, France;
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, UPR3212 CNRS, Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vitale
authors.affiliation: Department of Basic Neuroscience, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Dominique
authors.initials: D
authors.lastname: Muller
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Le Merrer
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR 7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France; moine@igbmc.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Moine
mesh_terms: D000368:Aged; D000818:Animals; D049229:Dendritic Spines / Q000201:enzymology / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019852:Diacylglycerol Kinase; D004075:Diglycerides; D051860:Fragile X Messenger Ribonucleoprotein 1; C011439:1,2-diacylglycerol; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse
keywords: CLIP; FMRP; diacylglycerol kinase; fragile X syndrome; translation control