| Literature DB >> 27568284 |
Marco Onorati1, Zhen Li1, Fuchen Liu1, André M M Sousa1, Naoki Nakagawa2, Mingfeng Li1, Maria Teresa Dell'Anno3, Forrest O Gulden1, Sirisha Pochareddy1, Andrew T N Tebbenkamp1, Wenqi Han1, Mihovil Pletikos1, Tianliuyun Gao1, Ying Zhu1, Candace Bichsel1, Luis Varela4, Klara Szigeti-Buck4, Steven Lisgo5, Yalan Zhang6, Anze Testen2, Xiao-Bing Gao4, Jernej Mlakar7, Mara Popovic7, Marie Flamand8, Stephen M Strittmatter3, Leonard K Kaczmarek9, E S Anton2, Tamas L Horvath10, Brett D Lindenbach11, Nenad Sestan12.
Abstract
The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27568284 PMCID： PMC5135012 DOI： 10.1016/j.celrep.2016.08.038
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423