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., 2019).
In this PhD project, the successful 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 will form an exciting discovery project, delivering interdisciplinary skills straining, and providing a springboard for a career in neuroscience research or the pharmaceutical industry.

As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit www.sheffield.ac.uk/sgs to learn more