Cell Reports (Sep 2016)
Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
- 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
Affiliations
- Marco Onorati
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Zhen Li
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Fuchen Liu
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- André M.M. Sousa
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Naoki Nakagawa
- UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Mingfeng Li
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Maria Teresa Dell’Anno
- Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Forrest O. Gulden
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Sirisha Pochareddy
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Andrew T.N. Tebbenkamp
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Wenqi Han
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Mihovil Pletikos
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Tianliuyun Gao
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Ying Zhu
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Candace Bichsel
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Luis Varela
- Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA
- Klara Szigeti-Buck
- Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA
- Steven Lisgo
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE13BZ, UK
- Yalan Zhang
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA
- Anze Testen
- UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Xiao-Bing Gao
- Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA
- Jernej Mlakar
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
- Mara Popovic
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia
- Marie Flamand
- Department of Virology, Institut Pasteur, 75724 Paris Cedex 15, France
- Stephen M. Strittmatter
- Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Leonard K. Kaczmarek
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA
- E.S. Anton
- UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Tamas L. Horvath
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Brett D. Lindenbach
- Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA
- Nenad Sestan
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.08.038
- Journal volume & issue
-
Vol. 16,
no. 10
pp. 2576 – 2592
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.
