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Cell reports
09 06, 2016;16 (10): 2576-2592.

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
Author Information
  1. Marco Onorati: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  2. Zhen Li: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  3. Fuchen Liu: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  4. André M M Sousa: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  5. 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.
  6. Mingfeng Li: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  7. Maria Teresa Dell'Anno: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  8. Forrest O Gulden: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  9. Sirisha Pochareddy: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  10. Andrew T N Tebbenkamp: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  11. Wenqi Han: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  12. Mihovil Pletikos: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  13. Tianliuyun Gao: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  14. Ying Zhu: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  15. Candace Bichsel: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  16. Luis Varela: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
  17. Klara Szigeti-Buck: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
  18. Steven Lisgo: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE13BZ, UK.
  19. Yalan Zhang: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
  20. 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.
  21. Xiao-Bing Gao: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
  22. Jernej Mlakar: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
  23. Mara Popovic: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
  24. Marie Flamand: Department of Virology, Institut Pasteur, 75724 Paris Cedex 15, France.
  25. Stephen M Strittmatter: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  26. Leonard K Kaczmarek: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA.
  27. 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.
  28. Tamas L Horvath: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: tamas.horvath@yale.edu.
  29. Brett D Lindenbach: Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: brett.lindenbach@yale.edu.
  30. Nenad Sestan: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Genetics and Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: nenad.sestan@yale.edu.
PMID: 27568284 DOI: 10.1016/j.celrep.2016.08.038

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.

References

  1. Euro Surveill. 2014 Mar 06;19(9): [PMID: 24626205]
  2. Philos Trans R Soc Lond B Biol Sci. 2015 Mar 5;370(1663):20140066 [PMID: 25602070]
  3. Clin Perinatol. 2015 Mar;42(1):77-103, viii [PMID: 25677998]
  4. N Engl J Med. 2016 Apr 21;374(16):1506-9 [PMID: 26959308]
  5. J Neurosci. 2013 Jul 24;33(30):12407-22 [PMID: 23884946]
  6. Biochem Pharmacol. 2006 Nov 30;72(11):1477-84 [PMID: 16876765]
  7. Nat Rev Neurosci. 2010 Mar;11(3):176-87 [PMID: 20107441]
  8. Science. 2016 May 13;352(6287):816-8 [PMID: 27064148]
  9. Neuron. 2013 Oct 30;80(3):588-601 [PMID: 24183012]
  10. Neuropathol Appl Neurobiol. 1986 Jul-Aug;12(4):337-58 [PMID: 3534622]
  11. N Engl J Med. 2016 Mar 10;374(10):951-8 [PMID: 26862926]
  12. Nat Med. 2013 Mar;19(3):313-21 [PMID: 23396211]
  13. Arch Gesamte Virusforsch. 1971;35(2):183-93 [PMID: 5002906]
  14. Nature. 2011 Oct 26;478(7370):483-9 [PMID: 22031440]
  15. Lancet. 2016 Apr 2;387(10026):1482 [PMID: 27115821]
  16. Curr Opin Immunol. 2011 Oct;23(5):564-72 [PMID: 21865020]
  17. Neuron. 2016 Jan 20;89(2):248-68 [PMID: 26796689]
  18. Front Neuroanat. 2012 Sep 13;6:38 [PMID: 22993505]
  19. J Virol. 2016 Jul 27;90(16):7219-7230 [PMID: 27252539]
  20. Cell Host Microbe. 2016 May 11;19(5):720-30 [PMID: 27066744]
  21. JAMA Ophthalmol. 2016 May 01;134(5):529-535 [PMID: 26865554]
  22. Science. 2015 Mar 13;347(6227):aaa2630 [PMID: 25636800]
  23. Cell Rep. 2016 Jun 14;15(11):2315-22 [PMID: 27268504]
  24. MMWR Morb Mortal Wkly Rep. 2016 Jan 29;65(3):59-62 [PMID: 26820244]
  25. PLoS Negl Trop Dis. 2016 May 10;10(5):e0004695 [PMID: 27163257]
  26. J Neurosci. 2000 Mar 15;20(6):2295-306 [PMID: 10704505]
  27. Brain. 2016 Aug;139(Pt 8):2122-30 [PMID: 27357348]
  28. Reproduction. 2013 Oct 01;146(5):R151-62 [PMID: 23884862]
  29. Mol Cell Biol. 2012 Mar;32(6):1032-43 [PMID: 22252317]
  30. J Virol. 2015 Sep;89(17):8880-96 [PMID: 26085147]
  31. Cell Res. 2016 Jun;26(6):645-54 [PMID: 27174054]
  32. Nat Neurosci. 2014 Dec;17(12):1804-15 [PMID: 25383901]
  33. PLoS Pathog. 2013 Feb;9(2):e1003168 [PMID: 23544010]
  34. Cell Stem Cell. 2016 May 5;18(5):587-90 [PMID: 26952870]
  35. Neuron. 2016 Jan 6;89(1):37-53 [PMID: 26687838]
  36. Cell Host Microbe. 2016 Aug 10;20(2):259-70 [PMID: 27476412]
  37. Cell Stem Cell. 2016 Aug 4;19(2):258-265 [PMID: 27162029]
  38. Cell. 2016 May 19;165(5):1238-1254 [PMID: 27118425]
  39. Nat Commun. 2015 Dec 10;6:10072 [PMID: 26656453]
  40. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3225-30 [PMID: 19218428]
  41. Curr Opin Neurobiol. 2004 Feb;14(1):112-7 [PMID: 15018946]
  42. J Infect Dis. 2016 Sep 1;214(5):707-11 [PMID: 27234417]
  43. J Am Acad Dermatol. 1985 Apr;12(4):697-706 [PMID: 2985660]
  44. Nature. 2016 May 11;534(7606):267-71 [PMID: 27279226]
  45. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7285-90 [PMID: 26060301]
  46. Cell Stem Cell. 2016 May 5;18(5):591-6 [PMID: 27038591]
  47. Cell. 2011 Jul 8;146(1):18-36 [PMID: 21729779]
  48. Cell Stem Cell. 2016 Jul 7;19(1):120-6 [PMID: 27179424]
  49. Cell Stem Cell. 2016 May 5;18(5):559-60 [PMID: 27152436]
  50. N Engl J Med. 2016 Mar 10;374(10):984-5 [PMID: 26862812]
  51. Clin Perinatol. 2009 Sep;36(3):503-12 [PMID: 19732610]
  52. J Mol Cell Biol. 2014 Aug;6(4):324-37 [PMID: 24706939]
  53. mBio. 2015 May 12;6(3):e00553-15 [PMID: 25968648]
  54. Dev Cell. 2015 Feb 23;32(4):423-34 [PMID: 25710529]
  55. Nat Commun. 2015 Mar 23;6:6500 [PMID: 25799239]
  56. Am J Reprod Immunol. 2016 Apr;75(4):421-2 [PMID: 26892436]
  57. Nat Immunol. 2009 Nov;10(11):1215-21 [PMID: 19820708]
  58. Mol Cell Neurosci. 2008 Jun;38(2):245-58 [PMID: 18450476]
  59. Cell Mol Life Sci. 2011 May;68(10):1769-83 [PMID: 20981563]
  60. PLoS Pathog. 2013 Jan;9(1):e1003118 [PMID: 23300459]
  61. J Virol. 2015 Dec 16;90(5):2372-87 [PMID: 26676770]
  62. J Neurobiol. 1993 Oct;24(10):1328-40 [PMID: 7901322]
  63. FEBS Lett. 2013 Apr 17;587(8):1230-7 [PMID: 23395801]
  64. Cell. 2016 May 19;165(5):1081-1091 [PMID: 27180225]
  65. Genes Dev. 2008 Jan 15;22(2):152-65 [PMID: 18198334]

Grants

  1. R01 NS076503/NINDS NIH HHS
  2. UL1 TR001863/NCATS NIH HHS
  3. R21 AI120113/NIAID NIH HHS
  4. P50 AG047270/NIA NIH HHS
  5. MC_PC_15004/Medical Research Council
  6. R01 NS080388/NINDS NIH HHS
  7. R01 AI089826/NIAID NIH HHS
  8. R01 MH060929/NIMH NIH HHS
  9. Z01 HD008836/Intramural NIH HHS
  10. /Wellcome Trust
  11. 099175/Z/12/Z/Medical Research Council
  12. P50 MH106934/NIMH NIH HHS
  13. G0700089/Medical Research Council
  14. U01 MH105972/NIMH NIH HHS
  15. U01 MH103339/NIMH NIH HHS
  16. R01 AG034924/NIA NIH HHS
  17. R01 DC001919/NIDCD NIH HHS
  18. R35 NS097283/NINDS NIH HHS

MeSH Term

Brain
Cell Death
Centrosome
Fetus
Gene Expression Profiling
Humans
Immunity, Innate
Microcephaly
Mitochondria
Mitosis
Neocortex
Neural Stem Cells
Neuroepithelial Cells
Neuroglia
Neurons
Neuroprotective Agents
Nucleosides
Phosphorylation
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Spinal Cord
Transcription, Genetic
Virus Replication
Zika Virus
Zika Virus Infection
Axl Receptor Tyrosine Kinase

Chemicals

Neuroprotective Agents
Nucleosides
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
TYRO3 protein, human
Protein Serine-Threonine Kinases
TBK1 protein, human
Axl Receptor Tyrosine Kinase
Journal Article

Links to CNCB-NGDC Resources

GEN: GEND000206 (Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neural Stem Cell Model Systems)

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