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Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation

Michael F. Wells, Max R. Salick, Federica Piccioni, Ellen J. Hill, Jana M. Mitchell, Kathleen A. Worringer, Joseph J. Raymond, Sravya Kommineni, Karrie Chan, Daniel Ho, Brant K. Peterson, Marco T. Siekmann, Olli Pietilainen, Ralda Nehme, Ajamete Kaykas, Kevin Eggan
doi: https://doi.org/10.1101/476440
Michael F. Wells
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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  • For correspondence: michaelwells@fas.harvard.edu
Max R. Salick
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Federica Piccioni
4Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Ellen J. Hill
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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Jana M. Mitchell
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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Kathleen A. Worringer
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Joseph J. Raymond
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Sravya Kommineni
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Karrie Chan
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Daniel Ho
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Brant K. Peterson
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Marco T. Siekmann
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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Olli Pietilainen
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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Ralda Nehme
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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Ajamete Kaykas
3Department of Neuroscience, Novartis Institute for BioMedical Research, Cambridge, MA 02139, USA
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Kevin Eggan
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Stem Cell and Regenerative Biology, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA
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SUMMARY

Neural progenitor cells (NPCs) are essential to brain development and their dysfunction is linked to several disorders, including autism, Zika Virus Congenital Syndrome, and cancer. Understanding of these conditions has been improved by advancements with stem cell-derived NPC models. However, current differentiation methods require many days or weeks to generate NPCs and show variability in efficacy among cell lines. Here, we describe human Stem cell-derived NGN2-accelerated Progenitor cells (SNaPs), which are produced in only 48 hours. SNaPs express canonical forebrain NPC protein markers, are proliferative, multipotent, and like other human NPCs, are susceptible to Zika-mediated death. We further demonstrate SNaPs are valuable for large-scale investigations of genetic and environmental influencers of neurodevelopment by deploying them for genome-wide CRISPR-Cas9 screens. Our studies expand knowledge of NPCs by identifying known and novel Zika host factors, as well as new regulators of NPC proliferation validated by re-identification of the autism spectrum gene PTEN.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 22, 2018.
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Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation
Michael F. Wells, Max R. Salick, Federica Piccioni, Ellen J. Hill, Jana M. Mitchell, Kathleen A. Worringer, Joseph J. Raymond, Sravya Kommineni, Karrie Chan, Daniel Ho, Brant K. Peterson, Marco T. Siekmann, Olli Pietilainen, Ralda Nehme, Ajamete Kaykas, Kevin Eggan
bioRxiv 476440; doi: https://doi.org/10.1101/476440
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Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation
Michael F. Wells, Max R. Salick, Federica Piccioni, Ellen J. Hill, Jana M. Mitchell, Kathleen A. Worringer, Joseph J. Raymond, Sravya Kommineni, Karrie Chan, Daniel Ho, Brant K. Peterson, Marco T. Siekmann, Olli Pietilainen, Ralda Nehme, Ajamete Kaykas, Kevin Eggan
bioRxiv 476440; doi: https://doi.org/10.1101/476440

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