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Mov10 in developing brain suppresses retroelements and regulates neuronal development and function

ABSTRACT: RNA helicase MOV10 participates in RNA-induced gene silencing, nonsense-mediated decay and suppression of retrotransposition in cultured cells. We describe a critical role for MOV10 in early postnatal brain, where there is an ~40 fold increase in MOV10 protein levels along with a nucleo-cytoplasmic localization pattern. The isolation of MOV10-associated RNAs from this stage showed a preponderance of retrotransposon encoded RNAs along with messenger RNAs. Furthermore, reduced MOV10 expression led to an increase in genomic L1 levels in P2 brain. We show that MOV10 likely suppresses retrotransposition by binding to the LINE1 reverse transcriptase and blocking cDNA synthesis. MOV10 also binds cytoskeletal mRNAs and is required for normal neurite outgrowth in both Neuro2A and cultured hippocampal neurons. Finally, standard MOV10 levels in brain are required for normal mouse behavior. We provide the first evidence of a role for MOV10 in retrotransposon control in brain and in neuronal development and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE87862 | GEO | 2017/05/16

SECONDARY ACCESSION(S): PRJNA347915

REPOSITORIES: GEO

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MOV10 knockout and gene expression

Project description:Transposable elements constitute nearly half of the mammalian genome and play important roles in genome evolution. While a multitude of both transcriptional and post-transcriptional mechanisms exist to silence transposable elements, control of transposition in vivo remains poorly understood. MOV10, an RNA helicase, is an inhibitor of mobilization of retrotransposons and retroviruses in cell culture assays. Here we report that MOV10 restricts LINE1 retrotransposition in mice. Although MOV10 is broadly expressed, its loss causes only incomplete penetrance of embryonic lethality, and the surviving MOV10-deficient mice are healthy and fertile. Biochemically, MOV10 forms a complex with UPF1, a key component of the nonsense-mediated mRNA decay pathway, and primarily binds to the 3' UTR of somatically expressed transcripts in testis. Consequently, loss of MOV10 results in an altered transcriptome in testis. Analyses using a LINE1 reporter transgene reveal that loss of MOV10 leads to increased LINE1 retrotransposition in somatic and reproductive tissues from both embryos and adult mice. Moreover, the degree of LINE1 retrotransposition inhibition is dependent on the Mov10 gene dosage. Furthermore, MOV10 deficiency reduces reproductive fitness over successive generations. Our findings demonstrate that MOV10 attenuates LINE1 retrotransposition in a dosage-dependent manner in mice.

2023-03-07 | GSE217336 | GEO

immunoprecipitation coupled with a mass spectrometry (MS) approach to identify cellular proteins associated with MOV10

Project description:To understand the detailed mechanism underlying MOV10-mediated restriction of LINE-1 retrotransposition, we first performed immunoprecipitation coupled with a mass spectrometry (MS) approach to identify cellular proteins associated with MOV10.

2023-08-30 | PXD041814 | Pride

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

Identification of the cellular RNAs bound by MOV10

Project description:Using the iCLIP protocol we have identified the cellular RNA entities that are bound by MOV10. We report the location and sequence of the MOV10 binding region on each RNA entity. To identify the RNAs that bound MOV10, we UV-cross-linked HEK293F cells and immunoprecipitated with an irrelevant antibody (ir or "control") followed by a MOV10-specific antibody (MOV10) to isolate associated RNAs after stringent washing.

2014-11-20 | E-GEOD-51443 | biostudies-arrayexpress

Identification of the RNAs that bind MOV10 in postnatal murine brain

Project description:These are the repetitve element RNAs and mRNAs found associated with MOV10 by RNA IP (RIP)

2017-05-16 | GSE84523 | GEO

Biological and RNA Regulatory Function of MOV10 in Mammalian Germ Cells

Project description:Background: RNA regulation by RNA-binding proteins (RBPs) involve extremely complicated mechanisms. MOV10 and MOV10L1 are two homologous RNA helicases implicated in distinct intracellular pathways. MOV10L1 participates specifically in Piwi-interacting RNA (piRNA) biogenesis and protects mouse male fertility. In contrast, the functional complexity of MOV10 remains incompletely understood, and its role in the mammalian germline is unknown. Here we report a study of the biological and molecular functions of the RNA helicase MOV10 in mammalian male germ cells. Results: MOV10 is a nucleocytoplasmic protein mainly expressed in spermatogonia. Knockdown and transplantation experiments show that MOV10 deficiency has a negative effect on spermatogonial progenitor cells (SPCs), limiting proliferation and in vivo repopulation capacity. This effect is concurrent with a global disturbance of RNA homeostasis and downregulation of factors critical for SPC proliferation and/or self-renewal. Unexpectedly, microRNA (miRNA) biogenesis is impaired due partially to decrease of miRNA primary transcript levels and/or retention of miRNA via splicing control. Genome-wide analysis of RNA targetome reveals that MOV10 binds preferentially to mRNAs with long 3'-UTR, and also interacts with various non-coding RNA species including those in the nucleus. Intriguingly, nuclear MOV10 associates with an array of splicing factors, particularly with SRSF1, and its intronic binding sites tend to reside in proximity to splice sites. Conclusions: These data expand the landscape of MOV10 function and highlight a previously unidentified role initiated from the nucleus, suggesting that MOV10 is a versatile RBP involved in a broader RNA regulatory network.

2017-08-08 | GSE102303 | GEO

Identification of the cellular RNAs bound by MOV10

2014-11-20 | GSE51443 | GEO

MOV10 Is a 5' to 3' RNA Helicase Contributing to UPF1 mRNA Target Degradation by Translocation along 3'UTRs (expression)

Project description:RNA helicases are important regulators of gene expression that act by remodeling RNA secondary structures and as RNA-protein interactions. Here, we demonstrate that MOV10 has an ATP-dependent 5' to 3' in vitro RNA unwinding activity and determine the RNA-binding sites of MOV10 and its helicase mutants using PAR-CLIP. We find that MOV10 predominantly binds to 3' UTRs upstream of regions predicted to form local secondary structures and provide evidence that MOV10 helicase mutants are impaired in their ability to translocate 5' to 3' on their mRNA targets. MOV10 interacts with UPF1, the key component of the nonsense-mediated mRNA decay pathway. PAR-CLIP of UPF1 reveals that MOV10 and UPF1 bind to RNA in close proximity. Knockdown of MOV10 resulted in increased mRNA half-lives of MOV10-bound as well as UPF1-regulated transcripts, suggesting that MOV10 functions in UPF1-mediated mRNA degradation as an RNA clearance factor to resolve structures and displace proteins from 3' UTRs. Flp-In T-REx HEK293 cells expressing FLAG/HA-tagged MOV10 WT, MOV10 K530A, MOV10 D645N and UPF1 were used to determine the protein-RNA interaction sites of RNA helicases MOV10 and UPF1 as well as MOV10 inactive variants using PAR-CLIP in combination with next generation sequencing. mRNA half-life changes of MOV10-targeted mRNA were determined by measuring mRNA half-lives by mRNA sequencing of mock and MOV10-depleted HEK293 cells.

2014-04-11 | E-GEOD-56748 | biostudies-arrayexpress

MOV10 is a 5' to 3' RNA Helicase Contributing to UPF1 mRNA Target Degradation by Translocation Along 3' UTRs (PAR-CLIP)

2014-04-11 | E-GEOD-48245 | biostudies-arrayexpress

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