The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules

Davidovic, Laetitia; Jaglin, Xavier H.; Lepagnol-Bestel, Aude-Marie; Tremblay, Sarah; Simonneau, Michel; Bardoni, Barbara; Khandjian, Édouard W.

doi:10.1093/hmg/ddm263

Cited by 121 publications

(95 citation statements)

References 57 publications

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“…We used an EGFP-FMRP construct, described previously (75), for the direct visualization of FMRP cellular trafficking. Importantly, it was previously shown that EGFP-FMRP has RNA binding properties and transport characteristics indistinguishable from the native protein (3,19,21,75). EGFP-FMRP was found to localize primarily within the cytoplasm of transfected cells (Fig.…”

Section: Resultsmentioning

confidence: 82%

Fragile X Mental Retardation Protein FMRP Binds mRNAs in the Nucleus

Kim

Bellini

Ceman

2009

Molecular and Cellular Biology

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The fragile X mental retardation protein FMRP is an RNA binding protein that associates with a large collection of mRNAs. Since FMRP was previously shown to be a nucleocytoplasmic shuttling protein, we examined the hypothesis that FMRP binds its cargo mRNAs in the nucleus. The enhanced green fluorescent protein-tagged FMRP construct (EGFP-FMRP) expressed in Cos-7 cells was efficiently exported from the nucleus in the absence of its nuclear export sequence and in the presence of a strong nuclear localization sequence (the simian virus 40 [SV40] NLS), suggesting an efficient mechanism for nuclear export. We hypothesized that nuclear FMRP exits the nucleus through its bound mRNAs. Using silencing RNAs to the bulk mRNA exporter Tap/NXF1, we observed a significantly increased number of cells containing EGFP-FMRP in the nucleus, which was further augmented by removal of FMRP's nuclear export sequence. Nuclear-retained SV40-FMRP could be released upon treatment with RNase. Further, Tap/NXF1 coimmunoprecipitated with EGFP-FMRP in an RNA-dependent manner and contained the FMR1 mRNA. To determine whether FMRP binds pre-mRNAs cotranscriptionally, we expressed hemagglutinin-SV40 FMRP in amphibian oocytes and found it, as well as endogenous Xenopus FMRP, on the active transcription units of lampbrush chromosomes. Collectively, our data provide the first lines of evidence that FMRP binds mRNA in the nucleus.Fragile X syndrome is one of the most common forms of inherited mental retardation, affecting approximately 1/4,000 males and 1/8,000 females (reviewed in reference 34). Fragile X syndrome is caused by the loss of expression of the fragile X mental retardation protein FMRP (32,40,64,77,84), which is a highly conserved RNA binding protein with two KH domains and an RGG box (6,70,71). The N terminus (2, 86), KH1 domain (1), KH2 domain (17), and the RGG box (12,18,69) have all been reported to bind RNA. FMRP is estimated to associate with approximately 4% of brain mRNAs (6, 12), and two large collections of associated mRNAs have been described (12, 58). FMRP is primarily cytoplasmic by both immunostaining and biochemical fractionation (22, 30); however, it contains a functional, nonclassical nuclear localization sequence (NLS) near its N terminus (7,24,73). Immunogold studies have shown that FMRP is present in the neuronal nucleoplasm and within nuclear pores (30). In addition, the presence of FMRP in the nucleus is regulated temporally, such that at specific times during development, FMRP is predominantly nuclear. Studies in Xenopus tropicalis embryos showed that FMRP was largely nuclear 2 h postfertilization (stage 6), suggesting a special nuclear function during this developmental period (9). Zebrafish embryos also demonstrated predominantly nuclear FMRP staining very early in development, 3 h postfertilization (81). Interestingly, these time points coincide with times in development when no zygotic transcription is taking place (62), providing indirect evidence that FMRP export from the nucleus might depend on mRNA synthe...

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Section: Resultsmentioning

confidence: 82%

Fragile X Mental Retardation Protein FMRP Binds mRNAs in the Nucleus

Kim

Bellini

Ceman

2009

Molecular and Cellular Biology

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“…2C Right). The apparent increase in unidirectional Fmr1 mRNA movement might indicate a regulatory interaction between FMRP and motor proteins and mRNA in response to stimulation (17)(18)(19). It is important to note that total granule number and the percentage of motile granules were not significantly different between WT and fmr1 KO neurons.…”

Section: Study Of Mrna Dynamic Motions In Wt and Fmr1 Ko Hippocampalmentioning

confidence: 93%

“…Upon neuronal stimulation, FMRP may regulate protein levels by mediating translational regulation and mRNA trafficking (11,15). FMRP, mRNA, and other RNA binding proteins can form ribonucleoprotein (RNP) or granule structures and couple with motor proteins to be transported in dendrites (16)(17)(18). Dendritic transport of FMRP and associated mRNAs, such as Fmr1, CaMKIIα, and MAP1b, are regulated by group I mGluR signaling (15,19).…”

mentioning

confidence: 99%

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Kao¹,

Aldridge

Weiler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

109

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Fragile X syndrome is caused by the absence of functional fragile X mental retardation protein (FMRP), an RNA binding protein. The molecular mechanism of aberrant protein synthesis in fmr1 KO mice is closely associated with the role of FMRP in mRNA transport, delivery, and local protein synthesis. We show that GFP-labeled Fmr1 and CaMKIIα mRNAs undergo decelerated motion at 0-40 min after group I mGluR stimulation, and later recover at 40-60 min. Then we investigate targeting of mRNAs associated with FMRP after neuronal stimulation. We find that FMRP is synthesized closely adjacent to stimulated mGluR5 receptors. Moreover, in WT neurons, CaMKIIα mRNA can be delivered and translated in dendritic spines within 10 min in response to group I mGluR stimulation, whereas KO neurons fail to show this response. These data suggest that FMRP can mediate spatial mRNA delivery for local protein synthesis in response to synaptic stimulation.fragile X syndrome | dendritic mRNA targeting | local translation F ragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP) (1). FXS affects 1 in 4,000 males and 1 in 6,000 females on average and is characterized by hyperactivity, attention deficits, autistic-like behaviors, and seizures (2). Dendritic spine morphology in the cerebral cortex of FXS patients and in the fmr1 KO mouse model shows more immature long thin spines than mature stubby, mushroom-shaped spines (3). Furthermore, group I mGluR-dependent long-term depression in the hippocampus is exaggerated in the fmr1 KO model (4). These findings suggest that FMRP functions in synaptic development and plasticity.Activity-dependent local translation is a fundamental mechanism underlying synaptic plasticity (5, 6). Inhibition of protein synthesis attenuates specific types of long-term plasticity (7,8). Morphological changes in dendritic spines can be blocked by protein synthesis inhibitors (9). In the fmr1 KO model, it has been shown that aberrant synthesis of individual proteins such as CaMKIIα, PSD-95, and MAP1b, upon group I mGluR stimulation, is associated with defective long-term plasticity (10-12). Here we have studied specific molecular mechanisms to elucidate aberrant localized translation in the fmr1 KO model. The molecular basis of FMRP's role in translation-dependent plasticity remains unclear despite extensive study. FMRP is a ribosome-associated RNA binding protein with selective affinity (13,14). Upon neuronal stimulation, FMRP may regulate protein levels by mediating translational regulation and mRNA trafficking (11, 15). FMRP, mRNA, and other RNA binding proteins can form ribonucleoprotein (RNP) or granule structures and couple with motor proteins to be transported in dendrites (16-18). Dendritic transport of FMRP and associated mRNAs, such as Fmr1, CaMKIIα, and MAP1b, are regulated by group I mGluR signaling (15, 19). It is not yet fully understood how and when mRNA is delivered to th...

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“…Through interactions with Kinesin, FMRP is able to travel between distal neurites and the soma of neurons and thereby regulate protein synthesis locally within specific cellular compartments [12] .…”

Section: Fragile X Syndromementioning

confidence: 99%

“…Microarray studies suggest that FMRP has hundreds of putative RNA targets (432 in mouse) [12] and a mass of protein interactors. However, only a handful of the encoded pro-teins have been demonstrated to be regulated in vivo, including the myelin basic protein [17,18] , cytoskeletal proteins Arc/Arg3.1 and MAP1B [19] , and the kinase α-CaMKII.…”

Section: Altered Expression Of Fmrp's Target Mrnas May Exert a Pro-efmentioning

confidence: 99%

Fragile X syndrome and epilepsy

et al. 2008

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Fragile X syndrome (FXS) is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.

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The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules

Cited by 121 publications

References 57 publications

Fragile X Mental Retardation Protein FMRP Binds mRNAs in the Nucleus

Fragile X Mental Retardation Protein FMRP Binds mRNAs in the Nucleus

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Fragile X syndrome and epilepsy

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