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Cell Stem Cell. 2017 Sep 7;21(3):349-358.e6. doi: 10.1016/j.stem.2017.07.014. Epub 2017 Aug 17.

Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins.

Author information

1
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Bioengineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; College of Biological Science and Engineering, Institute of Life Sciences, Fuzhou University, Fuzhou 350116, China.
6
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
The Human Genetic Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
10
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
11
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Human Genetic Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
13
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
14
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
15
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
16
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
17
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
18
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
19
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Bioengineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Human Genetic Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
20
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Bioengineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@mail.med.upenn.edu.

Abstract

Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components. Functionally, ZIKV-NS2A, but not DENV-NS2A, destabilizes the AJ complex, resulting in impaired AJ formation and aberrant radial glial fiber scaffolding in the embryonic mouse cortex. Similarly, ZIKA-NS2A, but not DENV-NS2A, reduces radial glial cell proliferation and causes AJ deficits in human forebrain organoids. Together, our results reveal pathogenic mechanisms underlying ZIKV infection in the developing mammalian brain.

KEYWORDS:

Zika virus; adherens junction; cortical neurogenesis; flavivirus; human organoid; human protein microarray; microcephaly; neural stem cell; neuronal migration; radial glial cell

PMID:
28826723
PMCID:
PMC5600197
DOI:
10.1016/j.stem.2017.07.014
[Indexed for MEDLINE]
Free PMC Article

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