First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass
Rajpurohit, Surendra K.
Walker, Steven L.
White, David T.
Shim, Joong S.
Liu, Jun O.
Parsons, Michael J.
Mumm, Jeff S.
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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.
Is part ofeLife, 2015, vol. 4, p. e08261
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Except where otherwise noted, this item's license is described as cc-by (c) Wang, Guangliang et al., 2015
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