Dataset Information

MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate.

ABSTRACT: The role of miRNAs in determining human neural stem cell (NSC) fate remains elusive despite their high expression in the developing nervous system. In this study, we investigate the role of miR-137, a brain-enriched miRNA, in determining the fate of human induced pluripotent stem cells-derived NSCs (hiNSCs). We show that ectopic expression of miR-137 in hiNSCs reduces proliferation and accelerates neuronal differentiation and migration. TargetScan and MicroT-CDS predict myocyte enhancer factor-2A (MEF2A), a transcription factor that regulates peroxisome proliferator-activated receptor-gamma coactivator (PGC1?) transcription, as a target of miR-137. Using a reporter assay, we validate MEF2A as a downstream target of miR-137. Our results indicate that reduced levels of MEF2A reduce the transcription of PGC1?, which in turn impacts mitochondrial dynamics. Notably, miR-137 accelerates mitochondrial biogenesis in a PGC1? independent manner by upregulating nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) and transcription factor A of mitochondria (TFAM). In addition, miR-137 modulates mitochondrial dynamics by inducing mitochondrial fusion and fission events, resulting in increased mitochondrial content and activation of oxidative phosphorylation (OXPHOS) and oxygen consumption rate. Pluripotency transcription factors OCT4 and SOX2 are known to have binding sites in the promoter region of miR-137 gene. Ectopic expression of miR-137 elevates the expression levels of OCT4 and SOX2 in hiNSCs which establishes a feed-forward self-regulatory loop between miR-137 and OCT4/SOX2. Our study provides novel molecular insights into NSC fate determination by miR-137.

SUBMITTER: Channakkar AS

PROVIDER: S-EPMC7217206 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate.

Channakkar Asha S AS Singh Tanya T Pattnaik Bijay B Gupta Karnika K Seth Pankaj P Adlakha Yogita K YK

Stem cells (Dayton, Ohio) 20200208 5

The role of miRNAs in determining human neural stem cell (NSC) fate remains elusive despite their high expression in the developing nervous system. In this study, we investigate the role of miR-137, a brain-enriched miRNA, in determining the fate of human induced pluripotent stem cells-derived NSCs (hiNSCs). We show that ectopic expression of miR-137 in hiNSCs reduces proliferation and accelerates neuronal differentiation and migration. TargetScan and MicroT-CDS predict myocyte enhancer factor-2 ...[more]

PMID: 32012382

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Project description:In mammals, new neurons are generated throughout the entire lifespan in two restricted areas of the brain, the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ)-olfactory bulb (OB) system. In both regions newborn neurons display unique properties that clearly distinguish them from mature neurons. Enhanced excitability and increased synaptic plasticity enables them to add specific properties to information processing by modulating the existing local circuitry of already established mature neurons. Hippocampal neurogenesis has been suggested to play a role in spatial-navigation learning, spatial memory, and spatial pattern separation. Cumulative evidences implicate that adult-born OB neurons contribute to learning processes and odor memory. We recently demonstrated that the cell fate determinant TRIM32 is upregulated in differentiating neuroblasts of the SVZ-OB system in the adult mouse brain. The absence of TRIM32 leads to increased progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated OB neurons. Here, we present novel data from behavioral studies showing that such an enhancement of OB neurogenesis not necessarily leads to increased olfactory performance but in contrast even results in impaired olfactory capabilities. In addition, we show at the cellular level that TRIM32 protein levels increase during differentiation of neural stem cells (NSCs). At the molecular level, several metabolic intermediates that are connected to glycolysis, glycine, or cysteine metabolism are deregulated in TRIM32 knockout mice brain tissue. These metabolomics pathways are directly or indirectly linked to anxiety or depression like behavior. In summary, our study provides comprehensive data on how the impairment of neurogenesis caused by the loss of the cell fate determinant TRIM32 causes a decrease of olfactory performance as well as a deregulation of metabolomic pathways that are linked to mood disorders.

Dataset Information

MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate.

Publications

MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate.

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