Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3619-28. doi: 10.1073/pnas.1522631113. Epub 2016 May 27.

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

Author information

1
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;
2
Department of Basic Neuroscience, University of Geneva, 1211 Geneva 4, Switzerland;
3
Institut de Biologie Moléculaire des Plantes, Plateforme Métabolomique, Unité Propre de Recherche (UPR) 2357 CNRS, Université de Strasbourg, 67082 Strasbourg, France;
4
Laboratoire de Biogènese Membranaire; UMR 5200 CNRS, Plateforme Métabolome, Université de Bordeaux, 33140 Villenave D'Ornon, France;
5
Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento, CA 95817;
6
CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, University of Nice Sophia-Antipolis, CNRS Laboratoire International Associé (LIA) Neogenex, 06560 Valbonne, France;
7
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;
8
Institut des Neurosciences Cellulaires et Intégratives, UPR3212 CNRS, Université de Strasbourg, 67084 Strasbourg, France.
9
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.

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.

KEYWORDS:

CLIP; FMRP; diacylglycerol kinase; fragile X syndrome; translation control

PMID:
27233938
PMCID:
PMC4932937
DOI:
10.1073/pnas.1522631113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center