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

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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.

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Guangliang Wang

McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Surendra K Rajpurohit

Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States

Competing interests
No competing interests declared.
Fabien Delaspre

McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Steven L Walker

Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, United States

Competing interests
No competing interests declared.
David T White

Wilmer Eye Institute, Johns Hopkins University, Augusta, United States

Competing interests
No competing interests declared.
Alexis Ceasrine

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Rejji Kuruvilla

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Ruo-jing Li

Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Joong S Shim

Faculty of Health Sciences, University of Macau, Macau, China

Competing interests
No competing interests declared.
Jun O Liu

Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Michael J Parsons

McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
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

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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.