Exploring the impact of developmental robustness on the severity of congenital defects of eye formation

About the project

About the Project A 2027 Crick PhD project with Stephen Wilson. Project background and description Although abnormalities of eye formation are a major cause of blindness, the genetic and mechanistic bases of such phenotypes are poorly understood. An unusual and common feature of congenital abnormalities of eye formation across species from fish to humans is their remarkably variable penetrance. Most research on the variability inherent in congenital conditions in humans has focused on the impact of differences in either genes or environment leaving a large question mark over why, even after accounting for such factors, there can still be considerable variability in phenotypic outcome. For instance, the genetics and environmental conditions affecting the developing left and right eyes are essentially the same, yet ocular birth defects will often present as one eye showing a severe phenotype whereas the other can be entirely normal. This PhD project will study the developmental mechanisms, that when disrupted, cause eye defects and explore how variability in the robustness of these mechanisms can lead to variability in the severity of eye defects. The project builds on research using zebrafish yap mutants demonstrating that stochasticity inherent in developmental processes is a causative factor in the presence or absence of retinal coloboma, a failure in the final step of eye morphogenesis. Yap functions in the retinal pigment epithelium that surrounds the eye and is necessary for the closure of choroid fissure by ensuring structural integrity of the retina as it undergoes complex morphogenesis. When Yap function is compromised, there is increased, but low probability of catastrophic collapse of the ventral retina. As this is a low probability event in yap mutants, it rarely occurs it both eyes in absence of additional adverse challenges. However, if such challenges are introduced, either through additional genetic mutations or through environmental challenges, then penetrance is enhanced and phenotypes are observed in both eyes. The PhD project will use highly efficient Crispr-based screening to identify genes with roles in modulating the robustness of eye formation, focussing initially on interactions between the extracellular matrix and retinal pigment epithelium. Through ongoing screens, we know that disrupting ECM gene function can impact the penetrance of yap mutant phenotypes but we don’t know how and why this happens. Consequently, in parallel to the genetic screen, the student will also explore the hypothesis that Yap and ECM together ensure robust structural integrity to the optic vesicle as it undergoes massive cellular and tissue rearrangements during eye formation. Candidate background This project would suit a candidate with a background in developmental biology/genetics of model systems and/or in tissue mechanobiology. The candidate should have an interest in using molecular genetics and high-resolution 4D imaging approaches to study complex in vivo developmental events. The project will also explore mechanical aspects of eye morphogenesis and a background, or interest, in mechanobiology and possibly in computational modelling would be great. Lab-specific question What do you consider the experimental approaches in zebrafish best suited to elucidating the genetic basis of complex morphogenetic events?

Research areas