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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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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Zebrafish
Screening
Throughput
Drug Discovery
Cell Proliferation
Pharmaceutical Preparations
Cell proliferation
Robotics
Larva
Pancreas
Insulin
Medical problems
Assays
Therapeutics

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First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. / Wang, Guangliang; Rajpurohit, Surendra Kumar; Delaspre, Fabien; Walker, Steven L; White, David T; Ceasrine, Alexis; Kuruvilla, Rejji; Li, Ruo-Jing; Shim, Joong S; Liu, Jun O; Parsons, Michael J; Mumm, Jeff S.

In: eLife, Vol. 4, 2015.

Research output: Contribution to journalArticle

Wang, G, Rajpurohit, SK, Delaspre, F, Walker, SL, White, DT, Ceasrine, A, Kuruvilla, R, Li, R-J, Shim, JS, Liu, JO, Parsons, MJ & Mumm, JS 2015, 'First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass', eLife, vol. 4. https://doi.org/10.7554/eLife.08261
Wang, Guangliang ; Rajpurohit, Surendra Kumar ; Delaspre, Fabien ; Walker, Steven L ; White, David T ; Ceasrine, Alexis ; Kuruvilla, Rejji ; Li, Ruo-Jing ; Shim, Joong S ; Liu, Jun O ; Parsons, Michael J ; Mumm, Jeff S. / First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. In: eLife. 2015 ; Vol. 4.
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AU - White, David T

AU - Ceasrine, Alexis

AU - Kuruvilla, Rejji

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AU - Shim, Joong S

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AU - Parsons, Michael J

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