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

被引:119
作者
Castets, M
Schaeffer, C
Bechara, E
Schenck, A
Khandjian, EW
Luche, S
Moine, H
Rabilloud, T
Mandel, JL
Bardoni, B
机构
[1] ULP, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France
[2] CNRS, UPR 9002, Inst Biol Mol & Cellulaire, F-67000 Strasbourg, France
[3] Univ Laval, CHUQ, Unite Rech Genet Humaine & Mol, Quebec City, PQ G1L 3L5, Canada
[4] CEA, DRDC, Lab Bioenerget Cellulaire & Pathol, F-38054 Grenoble 9, France
关键词
CMV infection; CMV disease; CMV prophylaxis; CMV monitoring; kidney transplantation;
D O I
10.1093/hmg/ddi077
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:835 / 844
页数:10
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