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First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass

  1. Guangliang Wang
  2. Surendra K Rajpurohit
  3. Fabien Delaspre
  4. Steven L Walker
  5. David T White
  6. Alexis Ceasrine
  7. Rejji Kuruvilla
  8. Ruo-jing Li
  9. Joong S Shim
  10. Jun O Liu
  11. Michael J Parsons
  12. Jeff S Mumm  Is a corresponding author
  1. Johns Hopkins University, United States
  2. Georgia Regents University, United States
  3. University of Macau, China
Research Article
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Cite this article as: eLife 2015;4:e08261 doi: 10.7554/eLife.08261

Abstract

Whole-organism chemical screening can circumvent bottlenecks that impede drug discovery. However, in vivo screens have not attained throughput capacities possible with in vitro assays. We therefore developed a method enabling in vivo high-throughput screening (HTS) in zebrafish, termed automated reporter quantification in vivo (ARQiv). Here, ARQiv was combined with robotics to fully actualize whole-organism HTS (ARQiv-HTS). In a primary screen, this platform quantified cell-specific fluorescent reporters in >500,000 transgenic zebrafish larvae to identify FDA-approved drugs that increased the number of insulin-producing β cells in the pancreas. Twenty-four drugs were confirmed as inducers of endocrine differentiation and/or stimulators of β-cell proliferation. Further, we discovered novel roles for NF-κB signaling in regulating endocrine differentiation and for serotonergic signaling in selectively stimulating β-cell proliferation. These studies demonstrate the power of ARQiv-HTS for drug discovery and provide unique insights into signaling pathways controlling β-cell mass, potential therapeutic targets for treating diabetes.

Article and author information

Author details

  1. Guangliang Wang

    McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  2. Surendra K Rajpurohit

    Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States
    Competing interests
    No competing interests declared.

  3. Fabien Delaspre

    McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  4. Steven L Walker

    Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States
    Competing interests
    No competing interests declared.

  5. David T White

    Wilmer Eye Institute, Johns Hopkins University, Augusta, United States
    Competing interests
    No competing interests declared.

  6. Alexis Ceasrine

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  7. Rejji Kuruvilla

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  8. Ruo-jing Li

    Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  9. Joong S Shim

    Faculty of Health Sciences, University of Macau, Macau, China
    Competing interests
    No competing interests declared.

  10. Jun O Liu

    Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  11. Michael J Parsons

    McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  12. Jeff S Mumm

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    For correspondence
    jmumm3@jhmi.edu
    Competing interests
    Jeff S Mumm, acts as a consultant for, Luminomics Inc., a company which uses drug discovery techniques applied in thetext.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved animal care and use committee (ACUC) protocols of Johns Hopkins University and Georgia Regents University

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Publication history

  1. Received: April 21, 2015
  2. Accepted: July 24, 2015
  3. Accepted Manuscript published: July 28, 2015 (version 1)
  4. Version of Record published: August 14, 2015 (version 2)

Copyright

© 2015, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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