Small molecule screen in embryonic zebrafish using modular variations to target segmentation

Sandra Richter, Ulrike Schulze, Pavel Tomançak and Andrew C. Oates ()
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Sandra Richter: Max Planck Institute of Molecular Cell Biology and Genetics
Ulrike Schulze: The Francis Crick Institute
Pavel Tomançak: Max Planck Institute of Molecular Cell Biology and Genetics
Andrew C. Oates: Max Planck Institute of Molecular Cell Biology and Genetics

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Small molecule in vivo phenotypic screening is used to identify drugs or biological activities by directly assessing effects in intact organisms. However, current screening designs may not exploit the full potential of chemical libraries due to false negatives. Here, we demonstrate a modular small molecule screen in embryonic zebrafish that varies concentration, genotype and timing to target segmentation disorders, birth defects that affect the spinal column. By testing each small molecule in multiple interrelated ways, this screen recovers compounds that a standard screening design would have missed, increasing the hit frequency from the chemical library three-fold. We identify molecular pathways and segmentation phenotypes, which we share in an open-access annotated database. These hits provide insight into human vertebral segmentation disorders and myopathies. This modular screening strategy is applicable to other developmental questions and disease models, highlighting the power of relatively small chemical libraries to accelerate gene discovery and disease study.

Date: 2017
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DOI: 10.1038/s41467-017-01469-5

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