PUBLICATION

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

Authors
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.
ID
ZDB-PUB-190611-12
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
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes