@article{6e5148fcfc2b490abc859492c13f0340,
title = "Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins",
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.",
keywords = "Zika virus, adherens junction, cortical neurogenesis, flavivirus, human organoid, human protein microarray, microcephaly, neural stem cell, neuronal migration, radial glial cell",
author = "Yoon, {Ki Jun} and Guang Song and Xuyu Qian and Jianbo Pan and Dan Xu and Rho, {Hee Sool} and Kim, {Nam Shik} and Christa Habela and Lily Zheng and Fadi Jacob and Feiran Zhang and Lee, {Emily M.} and Huang, {Wei Kai} and Ringeling, {Francisca Rojas} and Caroline Vissers and Cui Li and Ling Yuan and Koeun Kang and Sunghan Kim and Junghoon Yeo and Yichen Cheng and Sheng Liu and Zhexing Wen and Qin, {Cheng Feng} and Qingfeng Wu and Christian, {Kimberly M.} and Hengli Tang and Peng Jin and Zhiheng Xu and Jiang Qian and Heng Zhu and Hongjun Song and Ming, {Guo li}",
note = "Funding Information: We thank members of Ming and Song laboratories for suggestions, L. Liu and Y. Cai for technical support, J. Schnoll for manuscript editing, and Dr. Park for help with statistical analysis. This work was supported by NIH grants R35NS097370 and R01MH105128 (G.M.), U19AI131130 (G.M., H.T., P.J., and Z.W.), R37NS047344 (H.S.), U19MH106434 (G.M., J.Q., and H.S.), P01NS097206 (H.S., J.Q., and P.J.), R01GM111514 (H.Z. and J.Q.), R25NS065729 and K12NS098482 (C.H.), and AI119530 (H.T.); the Simons Foundation (SFARI grant 308988 to H.S.); the Maryland Stem Cell Research Fund (MSCRF) (G.M. and H.S.); start-up funding from Emory (Z.W.); start-up funding from IGDB of CAS (Q.W.); China NSF ( 31430037 ) and the MOST “973” program ( 2014CB942801 and 2012YQ03026006 to D.X. and 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 an NSF fellowship and T32GM007445 . Funding Information: We thank members of Ming and Song laboratories for suggestions, L. Liu and Y. Cai for technical support, J. Schnoll for manuscript editing, and Dr. Park for help with statistical analysis. This work was supported by NIH grants R35NS097370 and R01MH105128 (G.M.), U19AI131130 (G.M., H.T., P.J., and Z.W.), R37NS047344 (H.S.), U19MH106434 (G.M., J.Q., and H.S.), P01NS097206 (H.S., J.Q., and P.J.), R01GM111514 (H.Z. and J.Q.), R25NS065729 and K12NS098482 (C.H.), and AI119530 (H.T.); the Simons Foundation (SFARI grant 308988 to H.S.); the Maryland Stem Cell Research Fund (MSCRF) (G.M. and H.S.); start-up funding from Emory (Z.W.); start-up funding from IGDB of CAS (Q.W.); China NSF (31430037) and the MOST ?973? program (2014CB942801 and 2012YQ03026006 to D.X. and 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 an NSF fellowship and T32GM007445. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = sep,
day = "7",
doi = "10.1016/j.stem.2017.07.014",
language = "English (US)",
volume = "21",
pages = "349--358.e6",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",
}