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

Guangliang Wang, Surendra K. Rajpurohit, Fabien Delaspre, Steven L. Walker, David T. White, Alexis Ceasrine, Rejji Kuruvilla, Ruo Jing Li, Joong S. Shim, Jun O. Liu, Michael J. Parsons, Jeff S. Mumm

Research output: Contribution to journalArticlepeer-review

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). In this study, 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 FDAapproved (Federal Drug Administration) drugs that increased the number of insulin-producing β cells in the pancreas. 24 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.

Original languageEnglish (US)
Article numbere08261
JournaleLife
Volume4
Issue numberJULY2015
DOIs
StatePublished - Jul 28 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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