Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

Ki Jun Yoon, Guang Song, Xuyu Qian, Jianbo Pan, Dan Xu, Hee Sool Rho, Nam Shik Kim, Christa Habela, Lily Zheng, Fadi Jacob, Feiran Zhang, Emily M. Lee, Wei Kai Huang, Francisca Rojas Ringeling, Caroline Vissers, Cui Li, Ling Yuan, Koeun Kang, Sunghan Kim, Junghoon YeoYichen Cheng, Sheng Liu, Zhexing Wen, Cheng Feng Qin, Qingfeng Wu, Kimberly M. Christian, Hengli Tang, Peng Jin, Zhiheng Xu, Jiang Qian, Heng Zhu, Hongjun Song, Guo li Ming

Research output: Contribution to journalArticlepeer-review

Abstract

Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain. Zika virus infects neural stem cells and causes microcephaly. In this study, Yoon et al. showed that NS2A protein encoded by Zika virus, but not by Dengue virus, impairs proliferation of radial glial cells in both embryonic mouse cortex and human forebrain organoids. Mechanistically, ZIKV-NS2A disrupts adherens junction formation.

Original languageEnglish (US)
Pages (from-to)349-358.e6
JournalCell stem cell
Volume21
Issue number3
DOIs
StatePublished - Sep 7 2017

Keywords

  • Zika virus
  • adherens junction
  • cortical neurogenesis
  • flavivirus
  • human organoid
  • human protein microarray
  • microcephaly
  • neural stem cell
  • neuronal migration
  • radial glial cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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