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@ARTICLE{AlpucheLazcano:284083,
      author       = {Alpuche-Lazcano, Sergio P. and Saliba, James and Costa,
                      Vivian V. and Campolina-Silva, Gabriel H. and Marim,
                      Fernanda M. and Secchim Ribeiro, Lucas and Blank, Volker and
                      Mouland, Andrew J. and Teixeira, Mauro M. and Gatignol,
                      Anne},
      title        = {{P}rofound downregulation of neural transcription factor
                      {N}pas4 and {N}r4a family in fetal mice neurons infected
                      with {Z}ika virus},
      journal      = {PLoS neglected tropical diseases},
      volume       = {15},
      number       = {5},
      issn         = {1935-2727},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DZNE-2026-00091},
      pages        = {e0009425},
      year         = {2021},
      abstract     = {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.},
      keywords     = {Animals / Basic Helix-Loop-Helix Transcription Factors:
                      genetics / Basic Helix-Loop-Helix Transcription Factors:
                      metabolism / Cell Line, Tumor / Cells, Cultured /
                      Down-Regulation / Embryo, Mammalian: virology / Gene
                      Expression Profiling / Mice / MicroRNAs: genetics / Neurons:
                      metabolism / Orphan Nuclear Receptors: genetics / Orphan
                      Nuclear Receptors: metabolism / RNA, Messenger: genetics /
                      Transcription Factors: genetics / Transcription Factors:
                      metabolism / Zika Virus: pathogenicity / Zika Virus
                      Infection: pathology / Basic Helix-Loop-Helix Transcription
                      Factors (NLM Chemicals) / MicroRNAs (NLM Chemicals) / Npas4
                      protein, mouse (NLM Chemicals) / Orphan Nuclear Receptors
                      (NLM Chemicals) / RNA, Messenger (NLM Chemicals) /
                      Transcription Factors (NLM Chemicals)},
      ddc          = {610},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1371/journal.pntd.0009425},
      url          = {https://pub.dzne.de/record/284083},
}