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

G Wang, SK Rajpurohit, F Delaspre, SL Walker… - Elife, 2015 - elifesciences.org
Elife, 2015elifesciences.org
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 a utomated r eporter q uantification inv ivo (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 …
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.
DOI: http://dx.doi.org/10.7554/eLife.08261.001
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