ZFIN ID: ZDB-PUB-190611-12
Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant
Diamantopoulou, E., Baxendale, S., de la Vega de León, A., Asad, A., Holdsworth, C.J., Abbas, L., Gillet, V.J., Wiggin, G.R., Whitfield, T.T.
Date: 2019
Source: eLIFE   8: (Journal)
Registered Authors: Abbas, Leila, Asad, Anzar, Baxendale, Sarah, Diamantopoulou, Elvira, Holdsworth, CJ, Whitfield, Tanya T.
Keywords: developmental biology, neuroscience, zebrafish
MeSH Terms:
  • Animals
  • Ear, Inner/drug effects
  • Ear, Inner/embryology
  • Ear, Inner/metabolism*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental/drug effects
  • Molecular Structure
  • Mutation
  • Myelin Sheath/drug effects
  • Myelin Sheath/metabolism*
  • Peripheral Nervous System/drug effects
  • Peripheral Nervous System/metabolism*
  • Proteoglycans/genetics
  • Proteoglycans/metabolism
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism*
  • Schwann Cells/drug effects
  • Schwann Cells/metabolism
  • Signal Transduction/drug effects
  • Signal Transduction/genetics
  • Small Molecule Libraries/chemistry
  • Small Molecule Libraries/pharmacology
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 31180326 Full text @ Elife
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.