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000284083 1001_ $$00000-0002-5958-2880$$aAlpuche-Lazcano, Sergio P.$$b0
000284083 245__ $$aProfound downregulation of neural transcription factor Npas4 and Nr4a family in fetal mice neurons infected with Zika virus
000284083 260__ $$aLawrence, Kan.$$bPLoS$$c2021
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000284083 520__ $$aZika virus (ZIKV) infection of neurons leads to neurological complications and congenital malformations of the brain of neonates. To date, ZIKV mechanism of infection and pathogenesis is not entirely understood and different studies on gene regulation of ZIKV-infected cells have identified a dysregulation of inflammatory and stem cell maintenance pathways. MicroRNAs (miRNAs) are post-transcriptional regulators of cellular genes and they contribute to cell development in normal function and disease. Previous reports with integrative analyses of messenger RNAs (mRNAs) and miRNAs during ZIKV infection have not identified neurological pathway defects. We hypothesized that dysregulation of pathways involved in neurological functions will be identified by RNA profiling of ZIKV-infected fetal neurons. We therefore used microarrays to analyze gene expression levels following ZIKV infection of fetal murine neurons. We observed that the expression levels of transcription factors such as neural PAS domain protein 4 (Npas4) and of three members of the orphan nuclear receptor 4 (Nr4a) were severely decreased after viral infection. We confirmed that their downregulation was at both the mRNA level and at the protein level. The dysregulation of these transcription factors has been previously linked to aberrant neural functions and development. We next examined the miRNA expression profile in infected primary murine neurons by microarray and found that various miRNAs were dysregulated upon ZIKV infection. An integrative analysis of the differentially expressed miRNAs and mRNAs indicated that miR-7013-5p targets Nr4a3 gene. Using miRmimics, we corroborated that miR-7013-5p downregulates Nr4a3 mRNA and protein levels. Our data identify a profound dysregulation of neural transcription factors with an overexpression of miR-7013-5p that results in decreased Nr4a3 expression, likely a main contributor to ZIKV-induced neuronal dysfunction.
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000284083 650_7 $$2NLM Chemicals$$aBasic Helix-Loop-Helix Transcription Factors
000284083 650_7 $$2NLM Chemicals$$aMicroRNAs
000284083 650_7 $$2NLM Chemicals$$aNpas4 protein, mouse
000284083 650_7 $$2NLM Chemicals$$aOrphan Nuclear Receptors
000284083 650_7 $$2NLM Chemicals$$aRNA, Messenger
000284083 650_7 $$2NLM Chemicals$$aTranscription Factors
000284083 650_2 $$2MeSH$$aAnimals
000284083 650_2 $$2MeSH$$aBasic Helix-Loop-Helix Transcription Factors: genetics
000284083 650_2 $$2MeSH$$aBasic Helix-Loop-Helix Transcription Factors: metabolism
000284083 650_2 $$2MeSH$$aCell Line, Tumor
000284083 650_2 $$2MeSH$$aCells, Cultured
000284083 650_2 $$2MeSH$$aDown-Regulation
000284083 650_2 $$2MeSH$$aEmbryo, Mammalian: virology
000284083 650_2 $$2MeSH$$aGene Expression Profiling
000284083 650_2 $$2MeSH$$aMice
000284083 650_2 $$2MeSH$$aMicroRNAs: genetics
000284083 650_2 $$2MeSH$$aNeurons: metabolism
000284083 650_2 $$2MeSH$$aOrphan Nuclear Receptors: genetics
000284083 650_2 $$2MeSH$$aOrphan Nuclear Receptors: metabolism
000284083 650_2 $$2MeSH$$aRNA, Messenger: genetics
000284083 650_2 $$2MeSH$$aTranscription Factors: genetics
000284083 650_2 $$2MeSH$$aTranscription Factors: metabolism
000284083 650_2 $$2MeSH$$aZika Virus: pathogenicity
000284083 650_2 $$2MeSH$$aZika Virus Infection: pathology
000284083 7001_ $$00000-0003-0450-9616$$aSaliba, James$$b1
000284083 7001_ $$00000-0002-0175-642X$$aCosta, Vivian V.$$b2
000284083 7001_ $$00000-0002-4473-3340$$aCampolina-Silva, Gabriel H.$$b3
000284083 7001_ $$00000-0002-9778-554X$$aMarim, Fernanda M.$$b4
000284083 7001_ $$0P:(DE-2719)9001782$$aSecchim Ribeiro, Lucas$$b5$$udzne
000284083 7001_ $$00000-0002-7029-2462$$aBlank, Volker$$b6
000284083 7001_ $$00000-0002-1828-0296$$aMouland, Andrew J.$$b7
000284083 7001_ $$00000-0002-6944-3008$$aTeixeira, Mauro M.$$b8
000284083 7001_ $$00000-0002-4553-0836$$aGatignol, Anne$$b9
000284083 773__ $$0PERI:(DE-600)2429704-5$$a10.1371/journal.pntd.0009425$$gVol. 15, no. 5, p. e0009425 -$$n5$$pe0009425$$tPLoS neglected tropical diseases$$v15$$x1935-2727$$y2021
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