Journal Article

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

Marie Castets, Céline Schaeffer, Elias Bechara, Annette Schenck, Edward W. Khandjian, Sylvie Luche, Hervé Moine, Thierry Rabilloud, Jean-Louis Mandel and Barbara Bardoni

in Human Molecular Genetics

Volume 14, issue 6, pages 835-844
Published in print March 2005 | ISSN: 0964-6906
Published online February 2005 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddi077
FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts

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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 pp2acβ 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.

Journal Article.  6782 words.  Illustrated.

Subjects: Genetics and Genomics

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