Modelling inherited developmental ocular disorders using in vitro organoids

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Inherited developmental disorders account for much of childhood visual impairment, yet knowledge of their molecular and cellular causes is far from complete. During early eye development stem cells must balance fate decisions between proliferation and differentiation at the same time as undergoing cell migration and morphogenesis to prevent such disorders. Cell fate decisions are controlled by intrinsic factors, such as the gene network and extrinsic factors, such as mechanical signals from the surrounding tissue and extracellular matrix. Mechanical signals are crucial during eye development as mutations in the mechano-transducer YAP lead to coloboma in humans, a rare developmental disorder arising from failure in optic cup folding and fusion. Critically, the co-occurrence in many patients of coloboma, a structural disorder, and microphthalmia, a cell fate disorder, suggests a mechanistic link between the mechanical environment and cell fate in the developing eye. The hypothesis is that mutations that primarily lead to morphogenetic complications (i.e coloboma), then feedback to affect cell fate, resulting in co-occurrence of coloboma and microphthalmia. This project will involve introducing mutations from clinical reports into humanESCs and mouseES to set-up an in vitro model of coloboma/microphthalmia in retinal differentiation and optic cup organoid protocols. This will subsequently be used to explore the disease mechanisms and the control of cell fate decisions in the eye. These findings will advance understanding of the aetiology of developmental ocular disorders and will be more broadly applicable to the development and regeneration of other tissues. This project will also pave the way for using in-vitro organoids as a method for molecular diagnosis of developmental eye disorders.Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Zhong, X et al. (2014) Nature Communications.New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders. Holt R et al. (2017) Scientific Reports.