Channakkar, AS and Singh, T and Pattnaik, B and Gupta, K and Seth, Pankaj and Adlakha, Yogita K (2020) MiRNA-137-mediated modulation of mitochondrial dynamics regulates human neural stem cell fate. Stem Cells, 38 (5). pp. 683-697.

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Abstract

The role of miRNAs in determining human neural stem cell (NSC) fate remains elusivedespite their high expression in the developing nervous system. In this study, weinvestigate the role of miR-137, a brain-enriched miRNA, in determining the fate ofhuman induced pluripotent stem cells-derived NSCs (hiNSCs). We show that ectopicexpression of miR-137 in hiNSCs reduces proliferation and accelerates neuronal dif-ferentiation and migration. TargetScan and MicroT-CDS predict myocyte enhancerfactor-2A (MEF2A), a transcription factor that regulates peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) transcription, as a target of miR-137.Using a reporter assay, we validate MEF2A as a downstream target of miR-137. Ourresults indicate that reduced levels of MEF2A reduce the transcription of PGC1α,which in turn impacts mitochondrial dynamics. Notably, miR-137 accelerates mito-chondrial biogenesis in a PGC1αindependent manner by upregulating nuclear factorerythroid 2 (NFE2)-related factor 2 (NRF2) and transcription factor A of mitochon-dria (TFAM). In addition, miR-137 modulates mitochondrial dynamics by inducingmitochondrial fusion and fission events, resulting in increased mitochondrial contentand activation of oxidative phosphorylation (OXPHOS) and oxygen consumptionrate. Pluripotency transcription factors OCT4 and SOX2 are known to have bindingsites in the promoter region of miR-137 gene. Ectopic expression of miR-137 ele-vates 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 providesnovel molecular insights into NSC fate determination by miR-137.

Item Type:	Article
Subjects:	Neurodegenerative Disorders Neuro-Oncological Disorders Neurocognitive Processes Neuronal Development and Regeneration Informatics and Imaging Genetics and Molecular Biology
Depositing User:	Dr. D.D. Lal
Date Deposited:	24 Feb 2020 06:33
Last Modified:	09 Dec 2021 09:34
URI:	http://nbrc.sciencecentral.in/id/eprint/682

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