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Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(6):835-844; doi:10.1093/hmg/ddi077
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts

Marie Castets1, Céline Schaeffer2, Elias Bechara1, Annette Schenck1, Edward W. Khandjian3, Sylvie Luche4, Hervé Moine2, Thierry Rabilloud4, Jean-Louis Mandel1 and Barbara Bardoni1,*,{dagger}

1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, 1 rue Laurent Fries, BP10142 67404 Illkirch Cedex, France, 2Institut de Biologie Moléculaire et Cellulaire, UPR 9002 CNRS, 15 rue René Descartes, 67000 Strasbourg, France. 3Unité de Recherche en Génétique Humaine et Moléculaire, Pavillon St François d'Assise du CHUQ, Université Laval, Québec, Canada G1L 3L5 and 4CEA, DRDC, Laboratoire de Bioénergétique Cellulaire et Pathologique, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France

* To whom correspondence should be addressed. Tel: +33 388653412; Fax: +33 388653246; Email: bardoni{at}igbmc.u-strasbg.fr Correspondence may also be addressed to Jean-Louis Mandel. Tel: +33 388653210; Fax: +33 388653201; Email: mandeljl{at}igbmc.u-strasbg.fr

Received December 13, 2004; Accepted January 27, 2005

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, whereas 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 pp2acß 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 patient's brain.

{dagger} Present address: CNRS FRE 2720, Faculté de Médecine, Avenue de Valombrose, 06107 Nice, France.


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