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

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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.
Publisher
CELL PRESS
Issue Date
2017-09
Language
English
Article Type
Article
Keywords

NEURAL STEM-CELLS; DEVELOPING NEOCORTEX; INTERACTION NETWORKS; BRAIN ORGANOIDS; MICE; IDENTIFICATION; SCHIZOPHRENIA; DEGRADATION; PROGENITORS; INFECTION

Citation

CELL STEM CELL, v.21, no.3, pp.349 - +

ISSN
1934-5909
DOI
10.1016/j.stem.2017.07.014
URI
http://hdl.handle.net/10203/246052
Appears in Collection
BS-Journal Papers(저널논문)
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