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.

中文翻译：

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寨卡病毒编码的NS2A通过降解粘附连接蛋白破坏哺乳动物的皮质神经发生。

寨卡病毒（ZIKV）直接感染神经祖细胞并损害其增殖。ZIKV如何与宿主分子机制相互作用以影响体内神经发生尚不清楚。在这里，通过系统地将ZIKV编码的单个蛋白质引入胚胎小鼠皮层，我们显示ZIKV-NS2A的表达，而非登革热病毒（DENV）-NS2A的表达，导致放射状胶质细胞的增殖和过早分化减少，以及神经胶质细胞的异常定位。新生神经元。从机理上讲，蛋白质相互作用蛋白的体外作图和生化分析表明ZIKA-NS2A与多个粘附连接复合物（AJ）组件之间存在相互作用。在功能上，ZIKV-NS2A（而不是DENV-NS2A）使AJ复合物不稳定，从而导致AJ形成受损，胚胎小鼠皮质中的径向胶质纤维支架异常。同样，ZIKA-NS2A而不是DENV-NS2A减少了放射状胶质细胞的增殖，并导致人类前脑类器官的AJ缺乏。总之，我们的结果揭示了发育中的哺乳动物脑中ZIKV感染的潜在致病机制。