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

Guangliang Wang, Surendra Kumar 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

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47 Scopus citations

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 FDA-approved (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)
JournaleLife
Volume4
DOIs
StatePublished - 2015

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    Wang, G., Rajpurohit, S. K., Delaspre, F., Walker, S. L., White, D. T., Ceasrine, A., Kuruvilla, R., Li, R-J., Shim, J. S., Liu, J. O., Parsons, M. J., & Mumm, J. S. (2015). First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. eLife, 4. https://doi.org/10.7554/eLife.08261