Deciphering molecular pathways and cellular events involved in uveal coloboma

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What is Coloboma?Coloboma refers to an eye disorder that affects approximately 1:10,000 children. As the eye develops before birth it will normally close forming a sphere. In the case of coloboma the spherical eye does not fully form leaving small or bigger gaps in its structure, usually in the bottom part of the eye. These can result in the child being blind or partially sighted.Aetiology of Coloboma The causes of coloboma are not fully understood, but it is known that both environmental and genetic factors contribute to it. However, most cases of coloboma seem to be caused during embryonic development by errors, known as mutations, in our hereditary components known as genes. However, there are still many cases of coloboma for which the causative gene has not yet been identified and great effort is being invested in identifying additional genes involved in this condition. As coloboma originates during foetal life, investigating how the cells interact and what genes participate in the closure of the eye during embryonic development can help us understand the causes of this disorder.Research AimThe main aim of this research proposal is to identify new genes and cellular events that may be responsible for coloboma in humans.To achieve this aim we will study eye development using the mouse as our model organism. The mouse is a good model for studying human genetic disorders as it shares many common genes with humans. In many cases, these shared genes contain errors (mutations) in both human and mouse which result in similar defects. This is also the case for some of the genes associated with coloboma in both human and mouse.Objectives- Our first objective is to isolate different sets of genes from the bottom part of the eye of mouse embryos. These genes are potentially crucial for eye closure. Our strategy will compare genes expressed in samples of normal embryos and embryos that are mutant for the Foxg1 gene, which have severe coloboma. This approach will produce a lot of coloboma-candidate genes which we will need to prioritise. Several steps will be followed for narrowing down genes of interest.1. With help from Bioinformaticians from the University of Edinburgh our results will be ranked based on significant differences between our two groups of study.2. We will compare our results with those generated from a screening of patients with coloboma. This will be achieved in collaboration with Prof FitzPatrick, an expert in coloboma at the MRC-Human Genetics Unit in Edinburgh. 3. We will investigate in which areas of the developing mouse eye our best candidate genes are found.4. We will then investigate what are the effects on the mouse of blocking the gene function or increasing the dose of these candidate genes on cultures of mouse developing eyes.5. The genes that will arise from this study as plausible candidates for coloboma will be further tested for mutations on human samples of patients with coloboma. This, again, will be achieved in collaboration with Prof FitzPatrick's group.- We have recently observed that in the Foxg1 mutant mouse we are able to ameliorate the coloboma defect when we subtract another gene known as Wnt8b. This indicates that Wnt8b is involved in coloboma formation and reducing the amount of this gene in mammals may recover the defect. Our second objective is to understand how the Wnt8b gene acts during eye development, its relationship with Foxg1 and with other genes that cause coloboma in mice and human, such as the Pax2 gene. Benefits from the studyWe anticipate to understand the basic biological events behind coloboma and to identify novel genes responsible for human coloboma. Such a discovery will be of great importance to the wider scientific community. Our basic research will generate data that in the future will help ophthalmologists, paediatricians and geneticists to provide better information and support to families with children with coloboma.