Modelling a myelination disorder in the zebrafish: drug discovery and gene editing.

Adhesion G protein-coupled receptors (aGPCRs) have exciting potential as therapeutic targets for drug discovery. The aGPCR Adgrg6 (Gpr126) has a conserved role in myelination of the vertebrate peripheral nervous system, and is of considerable clinical interest: mutations in human ADGRG6 are causative for a congenital contracture syndrome characterised by a loss of peripheral myelination. In zebrafish, homozygous mutations in adgrg6 also result in a reduction or loss of peripheral myelination. In addition, mutants have severe morphological malformations of the inner ear. Recently, we have undertaken a successful small molecule screen to identify agonist compounds that can rescue both the ear and myelination defects in zebrafish adgrg6 mutants (Diamantopoulou et al., eLife, 2019). In this PhD project, the student will undertake a new screen, this time to find antagonists for the Adgrg6 receptor. In a second part of the project, the student will introduce disease-causing mutations into the zebrafish using CRISPR/Cas9 technology, and characterise the resultant phenotype. Together, these experiments will form an exciting discovery project, delivering interdisciplinary skills straining, and providing a springboard for a career in neuroscience research or the pharmaceutical industry.