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.
Highlights
IntroductionAdgrg (Gpr126) is an adhesion (B2) class G protein-coupled receptor (aGPCR) with conserved roles in myelination of the vertebrate peripheral nervous system (PNS) (reviewed in Langenhan et al, 2016; Patra et al, 2014)
Adgrg6 (Gpr126) is an adhesion (B2) class G protein-coupled receptor with conserved roles in myelination of the vertebrate peripheral nervous system (PNS)
In homozygous loss-of-function adgrg6 zebrafish and mouse mutants, peripheral myelination is severely impaired: Schwann cells associate with axons, but are unable to generate the myelin sheath, and show reduced expression of the myelin basic protein gene (Glenn and Talbot, 2013; Mogha et al, 2013; Monk et al, 2009; Monk et al, 2011)
Summary
Adgrg (Gpr126) is an adhesion (B2) class G protein-coupled receptor (aGPCR) with conserved roles in myelination of the vertebrate peripheral nervous system (PNS) (reviewed in Langenhan et al, 2016; Patra et al, 2014). In homozygous loss-of-function adgrg zebrafish and mouse mutants, peripheral myelination is severely impaired: Schwann cells associate with axons, but are unable to generate the myelin sheath, and show reduced expression of the myelin basic protein (mbp) gene (Glenn and Talbot, 2013; Mogha et al, 2013; Monk et al, 2009; Monk et al, 2011). Targeted disruption of Adgrg in the mouse results in additional abnormal phenotypes, including limb and cardiac abnormalities, axon degeneration and embryonic lethality (Monk et al, 2011; Patra et al, 2013; Waller-Evans et al, 2010). Peripheral nerves from affected individuals have reduced expression of myelin basic protein, suggesting that the function of ADGRG6 in myelination is evolutionarily conserved from teleosts to humans (Ravenscroft et al, 2015). Human ADGRG6 variants have been proposed to underlie some paediatric musculoskeletal disorders, including adolescent idiopathic scoliosis (Karner et al, 2015) (and references within)
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