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Bhagat, R and Prajapati, B and Narwal, S and Agnihotri, N and Adlakha, YK and Sen, J and Mani, S and Seth, P (2018) Zika virus E protein alters the properties of human fetal neural stem cells by modulating microRNA circuitry. Cell Death & Differentiation.

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Abstract

Zika virus (ZV) infects neural stem cells (NSCs) and causes quiescence in NSCs, reducing the pool of brain cells, leading to microcephaly. Despite conscientious efforts, the molecular mechanisms for ZV-mediated effects on NSCs lack clarity. This study aimed to explore the underlying mechanisms for ZV-mediated induction of quiescence in the primary cultures of human fetal neural stem cells (fNSCs). We demonstrate that expression of ZV envelope (E) protein displays maximum quiescence in human fNSCs by accumulating cells in the G0/G1 phase of the cell cycle as compared to other non-structural proteins, viz. NS2A, NS4A and NS4B. E protein induces immature differentiation by induction of pro-neuronal genes in proliferating fNSCs, induces apoptosis in differentiating fNSCs 3 days post differentiation, and disrupts migration of cells from differentiating neurospheres. In utero electroporation of mouse brain with E protein shows drastic downregulation of proliferating cells in ventricular and subventricular zone regions. Global microRNA sequencing suggests that E protein modulates miRNA circuitry. Among differentially expressed miRNAs, we found 14 upregulated and 11 downregulated miRNAs. Mir-204-3p and mir-1273g-3p directly regulate NOTCH2 and PAX3 expression, respectively, by binding to their 3′UTR. Bioinformatic analysis using GO analysis for the targets of differentially expressed miRNAs revealed enrichment of cell cycle and developmental processes. Furthermore, WNT, CCKR, PDGF, EGF, p53, and NOTCH signaling pathways were among the top enriched pathways. Thus, our study provides evidence for the involvement of ZV E protein and novel insights into the molecular mechanism through identification of miRNA circuitry.

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: 02 Aug 2018 07:18
Last Modified: 14 Aug 2018 04:19
URI: http://nbrc.sciencecentral.in/id/eprint/415

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