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.

Rho-linked genes and neurological disorders

“…Interestingly, in this regard, is the observation that Rac1 activation in murine fibroblasts leads to relocalization of four FMRPinteracting proteins (CYFIP1, FXR1P, NUFIP and 82-FIP) to actin-containing domains [14]. Taken together, these data suggest a model in which CYFIP and FMRP act together in a dynamic signaling complex to regulate actin dynamics and protein translation, processes that are critical for neuronal morphogenesis and connectivity.…”

Translational Repression of the Disintegrin and Metalloprotease ADAM10 by a Stable G-quadruplex Secondary Structure in Its 5′-Untranslated Region

“…FMRP, an RNA binding protein involved in mRNA translation, splicing, and mRNA transport in the cell, was identified as a G-quadruplex interacting protein (77)(78)(79). FMRP binds tightly to G-quadruplexes in the 5Ј-UTRs of protein phosphatase 2A catalytic subunit and MAP1B (microtubule-associated protein 1B), and it was suggested that this interaction represses translation of both mRNAs (77,80). Furthermore, it was demonstrated that the FMRP-G-quadruplex repressor in the MAP1B 5Ј-UTR was destabilized by an increased FMRP concentration, suggesting that the variation of FMRP concentration in response to neuronal stimulation might act as a regulatory switch from translational repressor to a translational activator (43).…”

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

“…CYFIP2 and CYFIP1 (located on human chromosomes 5q33.3 and 15q11, respectively) encode highly homologous, ubiquitously expressed, and evolutionarily conserved adaptor/scaffolding proteins that lack any known functional domains or motifs. 20 To date, both CYFIP2 and CYFIP1 have been implicated by functional and biochemical studies as regulatory scaffolding proteins for at least four independent complexes associated with the Rac pathway-the FMR mRNP complex important for mRNA translational control; 20,21 and the WAVE1, WAVE2, and WAVE3 complexes each important for ARP2/3 mediated actin nucleation and regulation of cell motility. 14,22,23 While CYFIP1 does not appear to be a p53-regulated gene based upon our real-time PCR data, our data do identify CYFIP2 as a p53-regulated gene.…”