Circular RNA circRERE2 knockdown in rat primary cortical neurons [miRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE261609 | GEO | 2024/03/18
REPOSITORIES: GEO
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Project description:Circular RNAs (circRNAs), a diverse class of ncRNAs highly enriched in developing neurons, play roles in local protein synthesis and synaptic plasticity. However, distinguishing functional from non-functional circRNAs is challenged by their abundance, tissue specificity and splicing variability. To address this, we conducted a RNAi knockdown screen targeting 32 highly expressed, conserved circRNAs enriched in dendritic processes. circRERE isoforms emerged as regulators of dendritic synapse density and electrophysiological characteristics. mRNA-seq supports the dysregulation of synaptic genes, particularly miR-128-3p-sensitive transcripts. MiR-128-3p activity and expression are reduced, with circRERE possessing multiple miR-128-3p binding sites, suggesting a protective interaction supported by a rescue of the synaptic phenotype upon miR-128-3p overexpression. Conversely, circRERE overexpression with intact miR-128-3p sites rescued the synaptic phenotype and independently increased miR-128-3p levels. These findings demonstrate the necessity for the broad characterization of circRNAs in the nervous system to comprehensively understand their influence on essential non-coding RNA regulatory networks.
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Project description:The loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common inherited intellectual disability. How the loss of FMRP alters protein expression and astroglial functions remains essentially unknown. Here we showed that selective loss of astroglial FMRP in vivo up-regulates a brain-enriched miRNA, miR-128-3p, in mouse and human FMRP-deficient astroglia, which suppresses developmental expression of astroglial metabotropic glutamate receptor 5 (mGluR5), a major receptor in mediating developmental astroglia to neuron communication. Selective in vivo inhibition of miR-128-3p in FMRP-deficient astroglia sufficiently rescues decreased mGluR5 function, while astroglial overexpression of miR-128-3p strongly and selectively diminishes developmental astroglial mGluR5 signaling. Subsequent transcriptome and proteome profiling further suggests that FMRP commonly and preferentially regulates protein expression through posttranscriptional, but not transcriptional, mechanisms in astroglia. Overall, our study defines an FMRP-dependent cell-autonomous miR pathway that selectively alters developmental astroglial mGluR5 signaling, unveiling astroglial molecular mechanisms involved in FXS pathogenesis.
2020-09-10 | GSE157724 | GEO
Project description:The loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common inherited intellectual disability. How the loss of FMRP alters protein expression and astroglial functions remains essentially unknown. Here we showed that selective loss of astroglial FMRP in vivo up-regulates a brain-enriched miRNA, miR-128-3p, in mouse and human FMRP-deficient astroglia, which suppresses developmental expression of astroglial metabotropic glutamate receptor 5 (mGluR5), a major receptor in mediating developmental astroglia to neuron communication. Selective in vivo inhibition of miR-128-3p in FMRP-deficient astroglia sufficiently rescues decreased mGluR5 function, while astroglial overexpression of miR-128-3p strongly and selectively diminishes developmental astroglial mGluR5 signaling. Subsequent transcriptome and proteome profiling further suggests that FMRP commonly and preferentially regulates protein expression through posttranscriptional, but not transcriptional, mechanisms in astroglia. Overall, our study defines an FMRP-dependent cell-autonomous miR pathway that selectively alters developmental astroglial mGluR5 signaling, unveiling astroglial molecular mechanisms involved in FXS pathogenesis.
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Project description:Oxaliplatin (oxPt) resistance in colorectal cancers (CRC) is a major unsolved problem. Consequently, predictive markers and a better understanding of resistance mechanisms are urgently needed. To investigate if the recently identified predictive miR-625-3p is functionally involved in oxPt resistance, stable and inducible models of miR-625-3p dysregulation were analyzed. Ectopic expression of miR-625-3p in CRC cells led to increased resistance towards oxPt. The mitogen-activated protein kinase (MAPK) kinase 6 (MAP2K6/MKK6) – an activator of p38 MAPK - was identified as a functional target of miR-625-3p, and, in agreement, was down-regulated in patients not responding to oxPt therapy. The miR-625-3p resistance phenotype could be reversed by anti-miR-625-3p treatment and by ectopic expression of a miR-625-3p insensitive MAP2K6 variant. Transcriptome, proteome and phosphoproteome profiles revealed inactivation of MAP2K6-p38 signaling as a possible driving force behind oxPt resistance. We conclude that miR-625-3p induces oxPt resistance by abrogating MAP2K6-p38 regulated apoptosis and cell cycle control networks.
2017-03-29 | MSV000080762 | MassIVE
Project description:About half of all human and mouse miRNA genes are located within introns of protein-coding genes. Despite this, little is known about functional interactions between miRNAs and their host genes. The intronic miRNA miR-128 regulates neuronal excitability and controls dendrite outgrowth of projection neurons during development of the mouse cerebral cortex. Its host genes R3hdm1 and Arpp21 encode highly conserved, putative RNA-binding proteins. Here we use iCLIP to describe the RNA-binding activity of ARPP21, which recognizes uridine-rich sequences with exquisite sensitivity for 3UTRs. Surprisingly, ARPP21 antagonizes miR-128 activity by co-regulating a subset of miR-128 target mRNAs enriched for neurodevelopmental functions. In contrast to miR-128, we show that ARPP21 acts as a positive post-transcriptional regulator, at least in part through interaction with the eukaryotic translation initiation complex eIF4F. This molecular antagonism is also reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. The regulatory interaction between ARPP21 and miR-128 is a unique example of convergent function by two products of a single gene.
2018-02-23 | E-MTAB-5911 | biostudies-arrayexpress
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2014-03-12 | E-GEOD-55777 | biostudies-arrayexpress
Project description:Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long term memory storage. Activity-dependent post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation, and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity. In this study we demonstrate rapid, post-transtriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3'-UTRs of destablized transcripts, identifies enrichment in sequence motifs corresponding to miRNA binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p, and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further show that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression, and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory. 4 samples analysed, 3 coverslips pooled per sample. Mouse DRG neuron cell bodies and axons were separated in multicompartment cell cultures allowing electrical stimulation of axons, growing under a high-resistance partition between compartments, through platinum electrodes in the lid of the culture dish (Reference: http://www.ncbi.nlm.nih.gov/pubmed/9295372)
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2014-03-12 | E-GEOD-55780 | biostudies-arrayexpress
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