TY  - JOUR
AU  - Alpuche-Lazcano, Sergio P.
AU  - Saliba, James
AU  - Costa, Vivian V.
AU  - Campolina-Silva, Gabriel H.
AU  - Marim, Fernanda M.
AU  - Secchim Ribeiro, Lucas
AU  - Blank, Volker
AU  - Mouland, Andrew J.
AU  - Teixeira, Mauro M.
AU  - Gatignol, Anne
TI  - Profound downregulation of neural transcription factor Npas4 and Nr4a family in fetal mice neurons infected with Zika virus
JO  - PLoS neglected tropical diseases
VL  - 15
IS  - 5
SN  - 1935-2727
CY  - Lawrence, Kan.
PB  - PLoS
M1  - DZNE-2026-00091
SP  - e0009425
PY  - 2021
AB  - Zika 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.
KW  - Animals
KW  - Basic Helix-Loop-Helix Transcription Factors: genetics
KW  - Basic Helix-Loop-Helix Transcription Factors: metabolism
KW  - Cell Line, Tumor
KW  - Cells, Cultured
KW  - Down-Regulation
KW  - Embryo, Mammalian: virology
KW  - Gene Expression Profiling
KW  - Mice
KW  - MicroRNAs: genetics
KW  - Neurons: metabolism
KW  - Orphan Nuclear Receptors: genetics
KW  - Orphan Nuclear Receptors: metabolism
KW  - RNA, Messenger: genetics
KW  - Transcription Factors: genetics
KW  - Transcription Factors: metabolism
KW  - Zika Virus: pathogenicity
KW  - Zika Virus Infection: pathology
KW  - Basic Helix-Loop-Helix Transcription Factors (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - Npas4 protein, mouse (NLM Chemicals)
KW  - Orphan Nuclear Receptors (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1371/journal.pntd.0009425
UR  - https://pub.dzne.de/record/284083
ER  -