Small molecule screen in embryonic zebraﬁsh using
modular variations to target segmentation
, Ulrike Schulze
, Pavel Tomançak
& Andrew C. Oates
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.
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden 01307, Germany.
The Francis Crick Institute, 1 Midland
Road, London NW1 1AT, UK.
The Ofﬁce of ALBS, 190 Euston Road, London NW1 2EF, UK.
Department of Cell and Developmental Biology, University
College London, Gower Street, London WC1E 6BT, UK.
Present address: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de
Lausanne (EPFL), Lausanne CH-1015, Switzerland. Correspondence and requests for materials should be addressed to A.C.O. (email: andrew.oates@epﬂ.ch)