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

Abstract : 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 pp2acbeta 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.
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Contributor : Jean-Luc Toussaint <>
Submitted on : Wednesday, November 14, 2007 - 4:09:34 PM
Last modification on : Friday, November 27, 2020 - 2:32:02 PM

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Marie Castets, Céline Schaeffer, Elias Bechara, Annette Schenck, Edward W Khandjian, et al.. FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts.. Human Molecular Genetics, Oxford University Press (OUP), 2005, 14 (6), pp.835-44. ⟨10.1093/hmg/ddi077⟩. ⟨hal-00187481⟩



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