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Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

Lookup NU author(s): Dr Steven LisgoORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including singlecell 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.


Publication metadata

Author(s): Onorati M, Li Z, Liu FC, Sousa AMM, Nakagawa N, Li MF, Dell'Anno MT, Gulden FO, Pochareddy S, Tebbenkamp ATN, Han WQ, Pletikos M, Gao TLY, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang YL, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2016

Volume: 16

Issue: 10

Pages: 2576-2592

Print publication date: 06/09/2016

Online publication date: 24/08/2016

Acceptance date: 12/08/2016

Date deposited: 10/11/2016

ISSN (print): 2211-1247

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.celrep.2016.08.038

DOI: 10.1016/j.celrep.2016.08.038


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Funding

Funder referenceFunder name
Kavli Foundation
Falk Medical Research Trust
099175/Z/12/ZJoint MRC/Wellcome Trust
15-RMA-YALE-31Connecticut Innovations' Regenerative Medicine Research Fund
AG047270NIH
AG034924NIH
AI089826NIH
AI120113NIH
DC01919NIH
HD0008836NIH
MH105972NIH
MH060929NIH
MH103339NIH
MH106934NIH
NS076503NIH
NS080388NIH
SFARI 307705Simons Foundation

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