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

• Type of Material: Article
• Authors: Ki-Jun Yoon, Johns Hopkins University; Guang Song, Johns Hopkins University; Xuyu Qian, Johns Hopkins University; Jianbo Pan, Johns Hopkins University; Dan Xu, Chinese Academy of Sciences; Hee-Sool Rho, Johns Hopkins University; Nam-Shik Kim, Johns Hopkins University; Christa Habela, Johns Hopkins University; Lily Zheng, Johns Hopkins University; Fadi Jacob, Johns Hopkins University; Feiran Zhang, Emory University; Emily M. Lee, Florida State University; Wei-Kai Huang, Johns Hopkins University; Francisca Rojas Ringeling, Johns Hopkins University; Caroline Vissers, Johns Hopkins University; Cui Li, Chinese Academy of Sciences; Ling Yuan, Chinese Academy of Sciences; Koeun Kang, Johns Hopkins University; Sunghan Kim, Johns Hopkins University; Junghoon Yeo, Johns Hopkins University; Yichen Cheng, Florida State University; Sheng Liu, Johns Hopkins University; Zhexing Wen, Emory University; Cheng-Feng Qin, Beijing Institute of Microbiology and Epidemiology; Qingfeng Wu, Chinese Academy of Sciences; Kimberly M. Christian, University of Pennsylvania; Hengli Tang, Florida State University; Peng Jin, Emory University; Zhiheng Xu, Chinese Academy of Sciences; Jiang Qian, Johns Hopkins University
• Language: English
• Date: 2017-09-07
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stem.2017.07.014
• Title of Journal or Parent Work: Cell Stem Cell
• ISSN: 1934-5909
• Volume: 21
• Issue: 3
• Start Page: 349
• End Page: +
• Grant/Funding Information: This work was supported by National Institutes of Health grants R35NS097370 and R01MH105128 (G-l.M.), U19AI131130 (G-l.M., H.T, P.J., & Z.W.), R37NS047344 (H.S.), U19MH106434 (G-l.M., J.Q., & H.S.), P01NS097206 (H.S., J.Q., & P.J.), R01GM111514 (H.Z & J.Q.), R25NS065729 and K12NS098482 (C.H)., and AI119530 (H.T.), Simons Foundation (SFARI Grant 308988 to H.S.), Maryland Stem Cell Research Fund (MSCRF; G-l.M. & H.S.), start-up fund from Emory (Z.W.), start-up fund from IGDB of CAS (Q.W)., China NSF (31430037) and MOST “973” program (2014CB942801 and 2012YQ03026006 to Y.W. & Z.X.), and Zika seed funding from Florida State University (H.T.); K-J.Y. was supported by a postdoctoral fellowship from MSCRF and by a Young Investigator Award from Brain & Behavior Research Foundation.; C.V. was partially supported by a NSF fellowship and T32GM007445.
• Keywords: DEGRADATION; SCHIZOPHRENIA; MICE; IDENTIFICATION; PROGENITORS; Cell Biology; BRAIN ORGANOIDS; Cell & Tissue Engineering; Science & Technology; INTERACTION NETWORKS; DEVELOPING NEOCORTEX; INFECTION; NEURAL STEM-CELLS; Life Sciences & Biomedicine
• Research Categories: Biology, Neuroscience; Biology, Genetics; Health Sciences, Pharmacology

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.