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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The G-quadruplex/FMRP complex mediates the repression activity of FMRP in translational regulation.
“Moreover, the G-quadruplex/FMRP complex mediates the repression activity of FMRP in translational regulation (Schaeffer et al., 2001; Brown et al., 2001; Castets et al., 2005; Melko and Bardoni, 2010; Suhl et al., 2015).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Castets et al., 2005
The Discussion reports FMRP binding to G-quartet structures in the pp2acb mRNA 5′-UTR, but says this binding *could* cause translational repression. The cited paper supports the proposed mechanism for this specific mRNA, not the unqualified claim that the complex mediates FMRP’s translational repression generally. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredG-quadruplex mRNA is a structure bound by FMRP and is harbored by some of its critical targets, including MAP1B, PP2AC, FMR1, SHANKL and SEMA3F.
“G-quadruplex mRNA is a structure bound by FMRP harbored by some of its critical targets (MAP1B, PP2AC, FMR1, SHANKL, SEMA3F) (Brown et al., 2001; Castets et al., 2005; Schaeffer et al., 2001; Zhang et al., 2014; Menon and Mihailescu, 2007).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Castets et al., 2005
The Results and Figure 5 report that FMRP binds the G-quartet-containing PP2ACβ mRNA and use a G-quartet-containing FMR1 mRNA fragment as a binding reference. Our copy does not establish the same claim for MAP1B, SHANKL, or SEMA3F, which are also included in the cited sentence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCYFIP1 couples local actin polymerization to membrane budding at subcellular compartments such as the trans-Golgi network.
“CYFIP1 has been previously shown to couple local actin polymerization to membrane budding at subcellular compartments such as the trans-Golgi network.33,62”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [62]
The Results section, “FMRP interacting proteins relocalize to actin ring areas in PDGF-stimulated fibroblasts” (page not available), reports that CYFIP1 relocates to actin ring areas. It does not show that CYFIP1 couples actin polymerization to membrane budding or place that process at the trans-Golgi network. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRac1 activation was shown to translocate CYFIP1 to actin-rich domains involved in cellular protrusions in mouse fibroblasts.
“Rac1 activation was shown to translocate CYFIP1 to actin-rich domains involved in cellular protrusions in mouse fibroblasts (Castets et al., 2005).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Castets et al., 2005
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Cites
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“…under the control of a G-quadruplex structure in its 5 ′ UTR (Schaeffer et al., 2001) was used to transfect fibroblast cell lines (Stek cell lines) (Castets et al., 2005; Bechara et al., 2009; Maurin et al., 2015) either expressing or not expressing FMRP and where Cyfip1 was either depleted or…”
InfluentialSelf-citation
- Authors
- Castets, M., Schaeffer, C., Bechara, E., Schenck, A., Khandjian, E. W., Luche, S., Moine, H., Rabilloud, T., Mandel, J.-L., & Bardoni, B.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Centre hospitalier universitaire de Québec (CA)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Corresponding author
- Bardoni, Barbara
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-02-09
- Volume
- 14
- Issue
- 6
- Pages
- 835-844
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2095872751
- Cited by
- 162
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 13 · 2016: 7 · 2015: 5 · 2014: 9 · 2013: 14 · 2012: 9
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- FMRP, fragile X syndrome, Rac1 GTPase, actin cytoskeleton remodeling, actin rings, cofilin phosphorylation, protein phosphatase 2A, mRNA translation regulation, fibroblasts, dendritic spine morphogenesis, synaptic structure
- MeSH terms
- Actins, Animals, Cell Line, Cytoskeleton, Fibroblasts, Fragile X Syndrome, Humans, Nerve Tissue Proteins, Signal Transduction, RNA-Binding Proteins, rac1 GTP-Binding Protein, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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