Similar Datasets
Project description:FMRP recruits AGO2, modulating access to miRNA recognition elements in G-Quadruplexes through association with Mov10.
| PRJNA533090 | ENA
Project description:The fragile X mental retardation protein FMRP regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway, and we show here that it associates with the RNA helicase MOV10, also associated with the microRNA pathway. FMRP associates with MOV10 directly and in an RNA-dependent manner and facilitates MOV10's association with RNAs in brain and cells, suggesting a cooperative interaction. We identified the RNAs recognized by MOV10 using RNA immunoprecipitation and iCLIP. Examination of the fate of MOV10 on RNAs revealed a dual function for MOV10 in regulating translation: it facilitates microRNA-mediated translation of some RNAs, but it also increases expression of other RNAs by preventing AGO2 function. The latter subset was also bound by FMRP in close proximity to the MOV10 binding site, suggesting that FMRP prevents MOV10-mediated microRNA suppression. We have identified a mechanism for FMRP-mediated translational regulation through its association with MOV10.
| S-EPMC4268400 | biostudies-literature
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
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.
2014-11-20 | GSE50499 | GEO
Project description:The Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein that regulates translation and is required for normal cognition. FMRP upregulates and downregulates the activity of microRNA (miRNA)-mediated silencing in the 3' UTR of a subset of mRNAs through its interaction with RNA helicase Moloney leukemia virus 10 (MOV10). This bi-functional role is modulated through RNA secondary structures known as G-Quadruplexes. We elucidated the mechanism of FMRP's role in suppressing Argonaute (AGO) family members' association with mRNAs by mapping the interacting domains of FMRP, MOV10 and AGO and then showed that the RGG box of FMRP protects a subset of co-bound mRNAs from AGO association. The N-terminus of MOV10 is required for this protection: its over-expression leads to increased levels of the endogenous proteins encoded by this co-bound subset of mRNAs. The N-terminus of MOV10 also leads to increased RGG box-dependent binding to the SC1 RNA G-Quadruplex and is required for outgrowth of neurites. Lastly, we showed that FMRP has a global role in miRNA-mediated translational regulation by recruiting AGO2 to a large subset of RNAs in mouse brain.
| S-EPMC7145700 | biostudies-literature
Project description:Fragile X syndrome results from the loss of expression of the Fragile X Mental Retardation Protein (FMRP). FMRP and RNA helicase Moloney Leukemia virus 10 (MOV10) are important Argonaute (AGO) cofactors for miRNA-mediated translation regulation. We previously showed that MOV10 functionally associates with FMRP. Here we quantify the effect of reduced MOV10 and FMRP expression on dendritic morphology. Murine neurons with reduced MOV10 and FMRP phenocopied Dicer1 KO neurons which exhibit impaired dendritic maturation Hong J (2013), leading us to hypothesize that MOV10 and FMRP regulate DICER expression. In cells and tissues expressing reduced MOV10 or no FMRP, DICER expression was significantly reduced. Moreover, the Dicer1 mRNA is a Cross-Linking Immunoprecipitation (CLIP) target of FMRP Darnell JC (2011), MOV10 Skariah G (2017) and AGO2 Kenny PJ (2020). MOV10 and FMRP modulate expression of DICER1 mRNA through its 3'untranslated region (UTR) and introduction of a DICER1 transgene restores normal neurite outgrowth in the Mov10 KO neuroblastoma Neuro2A cell line and branching in MOV10 heterozygote neurons. Moreover, we observe a global reduction in AGO2-associated microRNAs isolated from Fmr1 KO brain. We conclude that the MOV10-FMRP-AGO2 complex regulates DICER expression, revealing a novel mechanism for regulation of miRNA production required for normal neuronal morphology.
| S-EPMC8631628 | biostudies-literature
Project description:Fragile X syndrome (FXS) is a rare disease but is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein mainly involved in translational control. Even if this molecular defect is known, no specific therapy is available for FXS. The first alteration observed in the brain of FXS patients and of Fmr1 KO mice, model for FXS, is represented by an abnormal dendritic morphology that is associated with an altered synaptic plasticity. These findings led to numerous studies focused on mature neurons. However, recently, an increasing body of evidence is pointing out the importance of FMRP in the early steps of brain development. Thus, with the purpose to decipher the earliest molecular events leading to FXS we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem (ES) cells. To gain insights in the pathways that are affected when FMRP is repressed, we performed a gene expression profile analysis comparing total RNA from shFmr1 and shControl ES cells using whole genome mouse microarrays. Transcripts were clustered according to their Gene Ontology classification using the DAVID software. Surprisingly, the most altered functional category was Nervous system development and function, highlighting the role of FMRP also during the earliest steps of neural development. To study the precise role of FMRP in Embryonic stem (ES) cells, we used an RNAi-based loss-of-function strategy by transducing mouse ES cells with a lentivirus expressing GFP and a shRNA targeting the constitutive exon 1 of Fmr1 (shFmr1). A random shRNA (shCT) was used as a control sequence. Transduced cells were sorted by flow cytometry and established as non-clonal cell populations. RNA samples were harvested and profiling experiments were performed in â??dye-balanceâ?? as indicated for each replicate.
2016-07-04 | E-GEOD-71184 | biostudies-arrayexpress
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
Project description:We report cell-type and compartment-specific TRAP-seq, RNAseq, FMRP-CLIP, and PAPERCLIP from CA1 hippocampal neurons. We use TRAP-seq and PAPERCLIP data to precisely define the dendritic transcriptome, including mRNAs that harbor APA and AS events that are differentially localized. Further, we use FMRP-CLIP in order to define mRNAs that undergo compartment-specific regulation by FMRP.
2022-05-11 | GSE180412 | GEO
Project description:Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP-deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggest IRE1 inhibition as a promising new way to counteract atherosclerosis.
2022-02-15 | PXD030594 | Pride