Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
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 neu...
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Format: | Article |
Language: | English |
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Elsevier
2016-09-01
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Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716311020 |
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author | Marco Onorati Zhen Li Fuchen Liu André M.M. Sousa Naoki Nakagawa Mingfeng Li Maria Teresa Dell’Anno Forrest O. Gulden Sirisha Pochareddy Andrew T.N. Tebbenkamp Wenqi Han Mihovil Pletikos Tianliuyun Gao Ying Zhu Candace Bichsel Luis Varela Klara Szigeti-Buck Steven Lisgo Yalan Zhang Anze Testen Xiao-Bing Gao Jernej Mlakar Mara Popovic Marie Flamand Stephen M. Strittmatter Leonard K. Kaczmarek E.S. Anton Tamas L. Horvath Brett D. Lindenbach Nenad Sestan |
author_facet | Marco Onorati Zhen Li Fuchen Liu André M.M. Sousa Naoki Nakagawa Mingfeng Li Maria Teresa Dell’Anno Forrest O. Gulden Sirisha Pochareddy Andrew T.N. Tebbenkamp Wenqi Han Mihovil Pletikos Tianliuyun Gao Ying Zhu Candace Bichsel Luis Varela Klara Szigeti-Buck Steven Lisgo Yalan Zhang Anze Testen Xiao-Bing Gao Jernej Mlakar Mara Popovic Marie Flamand Stephen M. Strittmatter Leonard K. Kaczmarek E.S. Anton Tamas L. Horvath Brett D. Lindenbach Nenad Sestan |
author_sort | Marco Onorati |
collection | DOAJ |
description | 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. |
first_indexed | 2024-04-13T02:12:50Z |
format | Article |
id | doaj.art-7ed0523b8c024cdea2dcfa2c3cd7c835 |
institution | Directory Open Access Journal |
issn | 2211-1247 |
language | English |
last_indexed | 2024-04-13T02:12:50Z |
publishDate | 2016-09-01 |
publisher | Elsevier |
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series | Cell Reports |
spelling | doaj.art-7ed0523b8c024cdea2dcfa2c3cd7c8352022-12-22T03:07:14ZengElsevierCell Reports2211-12472016-09-0116102576259210.1016/j.celrep.2016.08.038Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial GliaMarco Onorati0Zhen Li1Fuchen Liu2André M.M. Sousa3Naoki Nakagawa4Mingfeng Li5Maria Teresa Dell’Anno6Forrest O. Gulden7Sirisha Pochareddy8Andrew T.N. Tebbenkamp9Wenqi Han10Mihovil Pletikos11Tianliuyun Gao12Ying Zhu13Candace Bichsel14Luis Varela15Klara Szigeti-Buck16Steven Lisgo17Yalan Zhang18Anze Testen19Xiao-Bing Gao20Jernej Mlakar21Mara Popovic22Marie Flamand23Stephen M. Strittmatter24Leonard K. Kaczmarek25E.S. Anton26Tamas L. Horvath27Brett D. Lindenbach28Nenad Sestan29Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USAUNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USACellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USASection of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USASection of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USAInstitute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE13BZ, UKDepartment of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USAUNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USASection of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USAInstitute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, SloveniaInstitute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, SloveniaDepartment of Virology, Institut Pasteur, 75724 Paris Cedex 15, FranceCellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USAUNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USADepartment of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USADepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USAThe 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.http://www.sciencedirect.com/science/article/pii/S2211124716311020 |
spellingShingle | Marco Onorati Zhen Li Fuchen Liu André M.M. Sousa Naoki Nakagawa Mingfeng Li Maria Teresa Dell’Anno Forrest O. Gulden Sirisha Pochareddy Andrew T.N. Tebbenkamp Wenqi Han Mihovil Pletikos Tianliuyun Gao Ying Zhu Candace Bichsel Luis Varela Klara Szigeti-Buck Steven Lisgo Yalan Zhang Anze Testen Xiao-Bing Gao Jernej Mlakar Mara Popovic Marie Flamand Stephen M. Strittmatter Leonard K. Kaczmarek E.S. Anton Tamas L. Horvath Brett D. Lindenbach Nenad Sestan Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia Cell Reports |
title | Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia |
title_full | Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia |
title_fullStr | Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia |
title_full_unstemmed | Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia |
title_short | Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia |
title_sort | zika virus disrupts phospho tbk1 localization and mitosis in human neuroepithelial stem cells and radial glia |
url | http://www.sciencedirect.com/science/article/pii/S2211124716311020 |
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