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.

• Authors: Marie Castets, Céline Schaeffer, Elias Bechara, Annette Schenck, Edward W Khandjian, Sylvie Luche, Hervé Moine, Thierry Rabilloud, Jean-Louis Mandel, Barbara Bardoni
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 14 Issue 6 Pg. 835-44 (Mar 15 2005) ISSN: 0964-6906 [Print] England
• PMID: 15703194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• FMR1 protein, human
• Fmr1 protein, mouse
• Nerve Tissue Proteins
• RNA-Binding Proteins
• Fragile X Mental Retardation Protein
• rac1 GTP-Binding Protein

Topics

• Actins (metabolism)
• Animals
• Cell Line
• Cytoskeleton (metabolism)
• Fibroblasts (metabolism)
• Fragile X Mental Retardation Protein
• Fragile X Syndrome (genetics, metabolism)
• Humans
• Mice
• Nerve Tissue Proteins (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Signal Transduction (genetics)
• rac1 GTP-Binding Protein (metabolism)