1. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
- Author
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Tamas L. Horvath, Maria Teresa Dell’Anno, Xiao-Bing Gao, Naoki Nakagawa, Anze Testen, Yalan Zhang, Tianliuyun Gao, Mihovil Pletikos, Candace Bichsel, Nenad Sestan, Mingfeng Li, Sirisha Pochareddy, Brett D. Lindenbach, Leonard K. Kaczmarek, Zhen Li, Wenqi Han, Forrest O. Gulden, Fuchen Liu, André M. M. Sousa, Stephen M. Strittmatter, Andrew T.N. Tebbenkamp, Marco Onorati, Steven Lisgo, Jernej Mlakar, Marie Flamand, Mara Popović, Eva S. Anton, Luis Varela, Klara Szigeti-Buck, Ying Zhu, Department of Neuroscience [New Haven], Yale University School of Medicine-Kavli Institute for Neuroscience [New Haven], Department of Cell Biology and Physiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience [New Haven], Yale University School of Medicine, Section of Comparative Medicine [New Haven], Institute of Genetic Medicine, Newcastle University [Newcastle], Departments of pharmacology and molecular biophysics and biochemistry [New Haven], University of Ljubljana, Département de Virologie - Department of Virology, Institut Pasteur [Paris], Departments of Internal Medicine, Cellular & Molecular Physiology, Departments of Medicine and Cell Biology & Physiology, Department of Microbial Pathogenesis, Reproductive Neuroscience Unit, Department of Obstetrics and Gynecology and Department of Neurobiology, Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Kavli Institute for Neuroscience [New Haven], Departments of Psychiatry and Genetics, This work was supported by grants NS076503, MH103339, MH105972, MH106934, MH060929, NS080388, AG034924, AG047270, DC01919, AI120113, and AI089826 from the NIH, SFARI 307705 from the Simons Foundation, and 15-RMA-YALE-31 from Connecticut Innovations’ Regenerative Medicine Research Fund. The Laboratory of Developmental Biology at the University of Washington, Seattle, and Human Developmental Biology Resource were supported by NIH award number HD0008836 and the Joint MRC/Wellcome Trust grant 099175/Z/12/Z, respectively. Additional support was provided by the Kavli Foundation and the Falk Medical Research Trust., Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP), Kavli Institute for Neuroscience, Yale School of Medicine, and Yale School of Medicine [New Haven, Connecticut] (YSM)-Yale School of Medicine [New Haven, Connecticut] (YSM)
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Genetics and Molecular Biology (all) ,Microcephaly ,Transcription, Genetic ,Neocortex ,MESH: Neuroepithelial Cells/ultrastructure ,Biochemistry ,environment and public health ,MESH: Brain/virology ,Neural Stem Cells ,MESH: Centrosome/drug effects ,MESH: Mitochondria/metabolism ,lcsh:QH301-705.5 ,Neurons ,MESH: Protein-Serine-Threonine Kinases/metabolism ,Zika Virus Infection ,Brain ,MESH: Neurons/virology ,MESH: Neural Stem Cells/virology ,MESH: Neural Stem Cells/immunology ,Nucleosides ,MESH: Zika Virus/physiology ,MESH: Virus Replication/drug effects ,Neural stem cell ,3. Good health ,Cell biology ,Neuroepithelial cell ,MESH: Brain/pathology ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Spinal Cord ,MESH: Neocortex/pathology ,MESH: Neuroepithelial Cells/immunology ,Neuroglia ,MESH: Receptor Protein-Tyrosine Kinases/metabolism ,Article ,General Biochemistry, Genetics and Molecular Biology ,MESH: Protein Kinase Inhibitors/pharmacology ,03 medical and health sciences ,MESH: Gene Expression Profiling ,Fetus ,Humans ,MESH: Phosphorylation/drug effects ,Mitosis ,MESH: Neural Stem Cells/ultrastructure ,Biochemistry, Genetics and Molecular Biology (all) ,MESH: Humans ,Receptor Protein-Tyrosine Kinases ,MESH: Zika Virus/pathogenicity ,medicine.disease ,Immunity, Innate ,MESH: Mitosis/drug effects ,030104 developmental biology ,MESH: Neuroprotective Agents/pharmacology ,MESH: Mitochondria/drug effects ,MESH: Spinal Cord/pathology ,MESH: Neuroglia/ultrastructure ,0301 basic medicine ,MESH: Fetus/virology ,viruses ,[SDV]Life Sciences [q-bio] ,Neuroepithelial Cells ,MESH: Zika Virus/ultrastructure ,Virus Replication ,MESH: Neurons/drug effects ,MESH: Neuroepithelial Cells/drug effects ,MESH: Zika Virus Infection/pathology ,MESH: Neurons/pathology ,MESH: Immunity, Innate/drug effects ,Phosphorylation ,Genetics ,Cell Death ,MESH: Transcription, Genetic/drug effects ,MESH: Neuroglia/virology ,MESH: Nucleosides/pharmacology ,Mitochondria ,Neuroprotective Agents ,MESH: Neuroglia/pathology ,lipids (amino acids, peptides, and proteins) ,MESH: Zika Virus Infection/virology ,Stem cell ,Programmed cell death ,MESH: Centrosome/metabolism ,MESH: Brain/embryology ,Protein Serine-Threonine Kinases ,Biology ,Proto-Oncogene Proteins ,MESH: Microcephaly/pathology ,medicine ,MESH: Zika Virus/drug effects ,Protein Kinase Inhibitors ,Centrosome ,MESH: Neural Stem Cells/enzymology ,Gene Expression Profiling ,MESH: Proto-Oncogene Proteins/metabolism ,Zika Virus ,Axl Receptor Tyrosine Kinase ,MESH: Microcephaly/virology ,Gene expression profiling ,MESH: Cell Death/drug effects ,lcsh:Biology (General) ,MESH: Neuroepithelial Cells/virology - Abstract
SummaryThe 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.
- Published
- 2016
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