Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant
- University of Sheffield, United Kingdom
- Sosei Heptares, United Kingdom
Abstract
Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican-gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican-b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Table 1 and Figure1-figure supplement 1, Figure 3, Figure 7 and Figure 7-figure supplements. Links to interactive files are given in the manuscript and in a supplemental file.
Article and author information
Author details
Elvira Diamantopoulou
Funding
Biotechnology and Biological Sciences Research Council (Project grant BB/J003050/1)
- Sarah Baxendale
- Tanya T Whitfield
University of Sheffield (PhD studentship 314420)
- Tanya T Whitfield
Medical Research Council (G0802527)
- Sarah Baxendale
- Celia J Holdsworth
- Leila Abbas
- Tanya T Whitfield
European Union's Seventh Framework Programme (Grant agreement no. 612347)
- Valerie J Gillet
Biotechnology and Biological Sciences Research Council (BB/R50581X/1)
- Sarah Baxendale
- Anzar Asad
- Giselle R Wiggin
- Tanya T Whitfield
Wellcome (VIP award 084551)
- Leila Abbas
- Tanya T Whitfield
Medical Research Council (G0700091)
- Sarah Baxendale
- Celia J Holdsworth
- Leila Abbas
- Tanya T Whitfield
Biotechnology and Biological Sciences Research Council (Project grant BB/M01021X/1)
- Sarah Baxendale
- Tanya T Whitfield
Biotechnology and Biological Sciences Research Council (ALERT14 equipment award BB/M012522/1)
- Sarah Baxendale
- Tanya T Whitfield
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was performed under licence from the UK Home Office (P66302E4E), and approved by the University of Sheffield Ethical Review Committee (ASPA Ethical Review Process).
Copyright
© 2019, Diamantopoulou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant
eLife 8:e44889.
https://doi.org/10.7554/eLife.44889
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