Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi077
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1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, 1 rue Laurent Fries, BP10142 67400 Illkirch Cedex, France
* To whom correspondence should be addressed. Fragile X syndrome, the most common form of inherited mental retardation, is caused by absence of FMRP, an RNA-binding protein implicated in regulation of mRNA translation and/or transport. We have previously shown that dFMR1, the Drosophila ortholog of FMRP, is genetically linked to the dRac1 GTPase, a key player in actin cytoskeleton remodeling. Here, we demonstrate that FMRP and the Rac1 pathway are connected in a model of murine fibroblasts. We show that Rac1 activation induces relocalization of four FMRP partners to actin ring areas. Moreover, Rac1-induced actin remodeling is altered in fibroblasts lacking FMRP or carrying a point-mutation in the KH1 or in the KH2 RNA-binding domain. In absence of wild-type FMRP, we found that phospho-ADF/Cofilin (P-Cofilin) level, a major mediator of Rac1 signaling, is lowered, while the level of Protein Phosphatase 2A catalytic subunit (PP2Ac), a P-Cofilin phosphatase, is increased. We show that FMRP binds with high affinity to the 5'-UTR of pp2ac
Article
FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts
2 Institut de Biologie Moléculaire et Cellulaire, UPR 9002 CNRS, 15 rue René Descartes, 67000 Strasbourg, France
3 Unité de Recherche en Génétique Humaine et Moléculaire, Pavillon St François d'Assise du CHUQ, Université Laval, Québec, Canada G1L 3L5
4 CEA, DRDC, Laboratoire de Bioénergétique Cellulaire et Pathologique, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France
Jean-Louis Mandel, E-mail: mandel{at}igbmc.u-strasbg.fr
Barbara Bardoni, E-mail: bardoni{at}igbmc.u-strasbg.fr
Abstract 
mRNA, and is thus a likely negative regulator of its translation. The molecular mechanism unraveled here points to a role for FMRP in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines, synaptic structures abnormally developed in Fragile X Syndrome patients brain.
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