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Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [RiboTag]

ABSTRACT: A central question in protein synthesis–dependent synaptic plasticity is how translation of neuronal mRNAs is dynamically regulated in time and space. Here, we develop Opto-CLIP, integrating optogenetic stimulation with cell-type-specific crosslinking immunoprecipitation (CLIP) of FMRP in CA1 neurons to define activity-dependent RNA regulation. Following patterned neuronal activation, we identify dynamic changes in FMRP-mediated translational control at minute-scale resolution. Within five minutes, FMRP is released from synaptic transcripts, accompanied by increased ribosome association. By 30 minutes, FMRP dissociates from transcripts encoding nuclear and RNA regulatory factors, also accompanied by increased ribosome association. At this stage, despite a marked reduction in protein levels, FMRP selectively reassociates with synaptic transcripts, coincident with reduced ribosome association. These coordinated shifts define temporally structured waves of translational control linking synaptic and nuclear programs. Our findings reveal a biphasic program of FMRP-mediated translational control that couples local synaptic responses to delayed nuclear regulation, providing a mechanistic framework linking activity-dependent RNA regulation, its disruption in Fragile X syndrome, and homeostatic plasticity.

ORGANISM(S): Mus musculus

PROVIDER: GSE286381 | GEO | 2025/01/15

REPOSITORIES: GEO

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Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [FMRP-CLIP]

Project description:A central question in protein synthesis–dependent synaptic plasticity is how translation of neuronal mRNAs is dynamically regulated in time and space. Here, we develop Opto-CLIP, integrating optogenetic stimulation with cell-type-specific crosslinking immunoprecipitation (CLIP) of FMRP in CA1 neurons to define activity-dependent RNA regulation. Following patterned neuronal activation, we identify dynamic changes in FMRP-mediated translational control at minute-scale resolution. Within five minutes, FMRP is released from synaptic transcripts, accompanied by increased ribosome association. By 30 minutes, FMRP dissociates from transcripts encoding nuclear and RNA regulatory factors, also accompanied by increased ribosome association. At this stage, despite a marked reduction in protein levels, FMRP selectively reassociates with synaptic transcripts, coincident with reduced ribosome association. These coordinated shifts define temporally structured waves of translational control linking synaptic and nuclear programs. Our findings reveal a biphasic program of FMRP-mediated translational control that couples local synaptic responses to delayed nuclear regulation, providing a mechanistic framework linking activity-dependent RNA regulation, its disruption in Fragile X syndrome, and homeostatic plasticity.

2025-01-15 | GSE286379 | GEO

Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [FMRP-CLIP]

Project description:Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [FMRP-CLIP]

| PRJNA1209012 | ENA

FMRP cTag CLIP from mouse CA1 pyramidal neurons

Project description:Loss of the neuronal RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown which brain regions and cell types within them contribute to disease pathophysiology. We used conditional tagging of FMRP and CLIP (cTag FMRP CLIP) to examine FMRP targets specifically in CA1 hippocampal neurons, a critical cell type for learning and memory known to have altered synaptic function in FXS. Integrating this data with analysis of ribosome-bound transcripts from the same neuronal population revealed CA1-enriched binding of autism-relevant mRNAs, and unexpected CA1-specific regulation of transcripts encoding circadian proteins.

2020-01-07 | GSE127846 | GEO

Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [RiboTag]

Project description:Neuronal activation triggers rapid biphasic FMRP-mediated translational control linking synaptic and nuclear regulation [RiboTag]

| PRJNA1209014 | ENA

The Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase in neurons

Project description:In this study, we sought to identify the mRNAs associated to FMRP protein in mouse cortical neuron using a cross linking immunoprecipitation and microarray (CLIP-microarray). The mRNAs crosslinked at 254 nm to FMRP in mouse cortical neurons cultured 8 days in vitro (8 DIV) were immunoprecipitated with H120 anti-FMRP (Santa Cruz) and reverse transcribed to labeled cDNAs with Ovation Pico WTA system V2 (Nugen) and hybridized on Mouse Gene 1.0ST (Affymetrix) We analyzed total RNA (Input) and FMRP-CLIPed RNA (Clip) from 10 primary cortical neuron mouse cultures (5 Wt Input, 5 FMR1-KO Input, 5 Wt Clip, 5 FMR1-KO Clip). Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.

2016-06-01 | E-GEOD-51649 | biostudies-arrayexpress

Regulatory Discrimination of mRNAs by FMRP Controls Adult Neural Stem Cell Differentiation

Project description:Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), a translation-inhibitor RNA binding protein. The impact of FMRP-deficiency on neural function is widespread, including its regulation of adult neural stem cell (aNSC) differentiation. To assess FMRP activity, we performed ribosome profiling of aNSCs from normal and Fmr1 knockout mice, which revealed diverse gene expression changes at the mRNA and translation levels. Many mitosis and neurogenesis genes were dysregulated primarily at the mRNA level, while numerous synaptic genes were mostly dysregulated at the translation level. Translational “buffering” was also evident, whereby changes in ribosome association with mRNA is compensated by alterations in RNA abundance. Our data revealed that FMRP-regulated neurogenesis is mediated by the transcriptional factor necdin and that FMRP determines mitochondrial mRNA expression and energy homeostasis. Thus, FMRP controls diverse transcriptional and post-transcriptional gene expression programs critical for the adult neural stem cell differentiation.

2018-11-20 | GSE112502 | GEO

FMRP-associated MOV10 facilitates and antagonizes miRNA-mediated regulation

Project description:The fragile X mental retardation protein FMRP is an RNA binding protein that regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway and we show here that it is associated with MOV10, a putative helicase that is also associated with the microRNA pathway. We show that FMRP associates with MOV10 in an RNA-dependent manner and facilitates MOV10-association with RNAs in brain. We identified the RNA sequences recognized by MOV10 using iCLIP and found an increased number of G-quadruplexes in the CLIP sites. We provide evidence that MOV10 facilitates microRNA-mediated translation regulation and also has the novel role of increasing the expression of a subset of RNAs by sterically hindering Argonaute2 association. In summary, we have identified a new mechanism for FMRP-mediated translational regulation through its association with MOV10. Comparison of MOV10 siRNA knockdown, irrelevant siRNA control and MOV10 overexpression on total RNA levels

2014-11-20 | E-GEOD-50499 | biostudies-arrayexpress

FMRP-associated MOV10 facilitates and antagonizes miRNA-mediated regulation

2014-11-20 | GSE50499 | GEO

Negative allosteric modulation of mGluR5 partially corrects pathophysiology in a mouse model of Rett Syndrome

Project description:Rett syndrome is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here we report a test of the hypothesis of shared pathophysiology of Rett syndrome and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein synthesis-dependent synaptic plasticity is similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated ‘translatome’. We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that are functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5 negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In the Mecp2 KO mice we found that mGluR5 NAM treatment significantly reduces the level of overexpressed ribosome-associated transcripts, particularly those that are also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and life span. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through co-regulation of a subset of genes relevant to synaptic functions.

2016-12-31 | GSE82068 | GEO

FMRP phosphorylation modulates neuronal translation through YTHDF1

Project description:Translation activation of local synaptic mRNA is critical to learning and memory. Despite extensive studies on how phosphorylations of ribosome units and translation factors enable fast response to exogenous stimuli, our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation of N6-methyladenosine (m6A)-modified transcripts. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized with low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide translation alterations with the inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.

2023-10-31 | GSE214882 | GEO

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