1. Developmental Biology
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Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant

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Cite this article as: eLife 2019;8:e44889 doi: 10.7554/eLife.44889

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.

Article and author information

Author details

  1. Elvira Diamantopoulou

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9336-7965
  2. Sarah Baxendale

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6760-9457
  3. Antonio de la Vega de León

    Information School, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  4. Anzar Asad

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  5. Celia J Holdsworth

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  6. Leila Abbas

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  7. Valerie J Gillet

    Information School, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    No competing interests declared.
  8. Giselle R Wiggin

    Sosei Heptares, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  9. Tanya T Whitfield

    Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    For correspondence
    t.whitfield@sheffield.ac.uk
    Competing interests
    Tanya T Whitfield, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1575-1504

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).

Reviewing Editor

  1. David A Lyons, University of Edinburgh, United Kingdom

Publication history

  1. Received: January 4, 2019
  2. Accepted: June 8, 2019
  3. Accepted Manuscript published: June 10, 2019 (version 1)

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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