ZIKV envelope protein is a strong blocker of early directional differentiation in the neural lineage.

Zika virus (ZIKV) infection is an international concern of public health emergency and has been associated with severe neurodevelopmental abnormalities. ZIKV-encoded envelope protein was virulent to neural cells, but its role in the neurodifferentiation process is not well known. Thus, we used mouse embryonic stem cells (mESCs) to mimic early neural differentiation in vitro and comprehensively studied the role of ZIKV envelope protein in the early directional differentiation of the neural lineage. We found that the ZIKV envelope protein does not affect the pluripotency of mESCs, but is a strong blocker of early neural differentiation. In both monolayer and suspension culture neural differentiation models, abnormalities arise from neural lineage commitment to early neuronal differentiation. During differentiation, envelope protein downregulated a large number of neurodevelopmentally relevant genes, therefore inhibiting multiple key biological processes, including neuroactive ligand-receptor interactions, neuron, synaptic processes, and dendritic spine development. ZIKV envelope protein disrupts early directed differentiation within neural lineages, providing key evidence for ZIKV-mediated neurodevelopmental abnormalities such as fetal microcephaly.