Neuro-specific HuR-deficient mice spontaneously develop motor neuron disease
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ABSTRACT:
PROVIDER: PRJNA448705 | ENA |
REPOSITORIES: ENA
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Project description:To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. These mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength Genome-wide microarray and RT-PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth The additional enriched GO terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including interferon-induced genes and complement components.
2018-04-05 | GSE112678 | GEO
Project description:Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and ? motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.
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Project description:Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses
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Project description:Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability In this dataset, we employed two distinct experiments. 1) HuR RIP-chip to identify mRNA targets of HuR. 2) HuR knockdown to identify mRNAs whose expression are dependent on HuR. All 12 samples were normalized with PLIER using Affymetrix power tools. To identify RNA targets of HuR, HuR RIP samples were compared to Mock RIP samples. To identify RNA regulated by HuR, HuR knockdown samples were compared to mock knockdown samples.
2011-08-18 | E-GEOD-29778 | biostudies-arrayexpress
Project description:Comprehensive meta-analysis and target screening confirmed that the mRNA-binding protein of ELAV-family HuR is oncogenic and universally upregulated in brain tumors, which highlight HuR as an universal chemotherapeutic target. HuR functionality in cancer cells is strictly dependent on HuR nuclear/cytoplasmic shuttling and dimerization; therefore, we developed a new class of inhibitors of HuR protein dimerization by utilizing medicinal chemistry techniques and reporter cell-based assay of HuR dimerization. The therapeutic potentials of lead compound (SRI-42127) were evaluated in five primary patient-derived glioma xenolines of classic, proneural, and mesenchymal subtypes, in vitro, and in mouse glioma model, in vivo. The Illumina global RNA-Sequencing was performed on PDGx-derived glioma neurospheres of different subtypes after treatment with DMSO (control) or SRI-42127 (3 uM) for 12 h to analysis transcripts and cell-signaling pathways affected by new inhibitor of HuR dimerization.
2020-11-05 | GSE158271 | GEO
Project description:Integrative regulatory mapping indicates that the RNA-binding protein HuR (ELAVL1) couples pre-mRNA processing and mRNA stability In this dataset, we employed two distinct experiments. 1) HuR RIP-chip to identify mRNA targets of HuR. 2) HuR knockdown to identify mRNAs whose expression are dependent on HuR.
2011-08-19 | GSE29778 | GEO
Project description:Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP)-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO) mouse embryonic fibroblast (MEF) cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced) with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart) within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle) indicative of their concerted function in mRNA metabolism. Ribonucleoprotein Immunoprecipitation (RIP) using hnRNP A1 specific antibody was performed in nuclear extracts from HuR WT and HuR KO Mouse Embryonic Fibroblasts (MEFs). RNA isolated from these IPs together with nuclear RNA from the two cell types, was subjected to microarray analysis. Three biological replicates, representing three independent experiments, are available for each condition except in the case of nuclear RNA isolated from HuR WT MEFs that one replicate didn’t pass the quality control.
2013-11-01 | E-GEOD-49225 | biostudies-arrayexpress
Project description:The purpose of the study was to identify mRNA bound to HuR in the presence of doxorubicin in MCF7 cells. We collected cytoplasmic RNA from untreated and treated cells and detected differentially expressed genes (DEGs). We also coimmunoprecipitated HuR and IgG (as control) from doxorubicin treated cells. Comparison between HuR RIP and IgG RIP signals was used to discriminate specific mRNA bound to HuR. HuR coimmmunoprecipitated material was hybridized together with cytoplasmic mRNA of doxorubicin treated cells, enabling the fold enrichment calculation and the selection of mRNAs bound to HuR. Keywords: RIP-Chip, HuR, doxorubicin, MCF7, HuR consensus binding, post-transcriptional regulation. We subjected MCF7 cells to starvation for 24h and then we added doxorubicin at final concentration of 10 uM, profiling before and after 4 hours of treatment in biological quadruplicate (only on cytoplasmic mRNAs, as HuR was found in the cytoplasm). Differentially expressed genes, altered during the treatment, were identified. Data derived from HuR RIP-Chip and IgG RIP-Chip (in biological quadruplicate) allowed the identification of specific mRNAs bound to HuR. The comparison between HuR RIP-Chip and cytoplasmic extracts from doxorubicin treated cells (in biological triplicate) identified those genes that were more strictly bound to HuR independently from their expression levels.
2011-12-31 | E-GEOD-33055 | biostudies-arrayexpress
Project description:The purpose of the study was to identify mRNA bound to HuR in the presence of doxorubicin in MCF7 cells. We collected cytoplasmic RNA from untreated and treated cells and detected differentially expressed genes (DEGs). We also coimmunoprecipitated HuR and IgG (as control) from doxorubicin treated cells. Comparison between HuR RIP and IgG RIP signals was used to discriminate specific mRNA bound to HuR. HuR coimmmunoprecipitated material was hybridized together with cytoplasmic mRNA of doxorubicin treated cells, enabling the fold enrichment calculation and the selection of mRNAs bound to HuR. Keywords: RIP-Chip, HuR, doxorubicin, MCF7, HuR consensus binding, post-transcriptional regulation.
2011-12-31 | GSE33055 | GEO
Project description:The Human antigen R protein (HuR) is a RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product Dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamic simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNAs binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3’UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity.
2017-12-20 | GSE94360 | GEO