Morphogenesis and growth of the eye in health and disease

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Although our eyes have a very different appearance to our brain, they originate as outpocketings of brain tissue during early embryonic development. The neuroepithelial tissue destined to form the eyes is initially a coherent group of cells within the neural plate, the precursor of the central nervous system. As the neural plate folds up to form the brain and spinal cord, the eyefield cells bulge out laterally to the left and right to form the two eyes. Each eye undergoes dramatic shape changes as it forms. These include a tissue fusion that closes a fissure present on one side of the eye (the choroid fissure), and leads to the formation of the intact globe of the eye. The complex orchestration of cell movements required to form the eyes is an example of tissue morphogenesis - the process by which embryonic cells form into tissues and organs. The genes that regulate the specification and morphogenesis of the eye and the cell and tissue behaviours that accompany eye formation are poorly understood. One of the reasons that this lack of knowledge needs to be addressed is that congenital malformations of the eye, such as anophthalmia, microphthalmia and coloboma, are relatively common in humans and can cause severe visual impairment or more severe craniofacial phenotypes. For instance the failure of the choroid fissure to close results in eye colobomas that encompass a group of common eye defects affecting people of all ages, but especially young children. Colobomas are usually congenital conditions diagnosed by detection of a notch, gap, hole or fissure in any of the structures of the eye, including the cornea, retina and optic nerve. These pathologies are a common cause of visual problems, can cause retinal detachment and cataracts and often lead to blindness in affected patients. In this project, we will use zebrafish embryos to identify genes important for eye formation and to characterise the cell behaviours that accompany various stages of this process. Zebrafish embryos are small, transparent and develop externally facilitating the study of normal development and disease in the intact animal. Together with their amenability to genetic analysis, these features make fish embryos an excellent model system to study eye formation in normal and pathological conditions. Indeed, highly sophisticated imaging techniques allow us to visualise all of the cells in the developing eye in the living zebrafish embryo. Coupled with this, we have generated a novel collection of families of fish that give rise to progeny exhibiting a variety of defects including absence of the eyes, abnormal morphogenesis and coloboma.We will identify the genetic mutations in the families of fish with eye defects and this will give us insights into the genes and genetic pathways that regulate normal eye formation. The human versions of these genes are candidates for causing congenital eye abnormalities when mutated and so, with collaborators, we will screen patients with eye defects for mutations in the genes. As eye defects often arise as a consequence of defective function of more than one gene, one of our aims will be to look at the genetic interactions between pairs of genes implicated in eye formation. In parallel to the gene identification, we will characterise the cell and tissue movements that accompany eye formation to gain an understanding of the mechanistic bases of this complex process. As our understanding increases, we will then be able to use the acquired knowledge to resolve why the congenital eye defects arise when certain genes are not functioning correctly.Overall, our research will help to bridge the gap between the highest quality basic research in model systems and human disease phenotypes. These analyses will enable us to establish new models for human eye diseases and will allow us to gain further insight into normal eye development and into the causes of hereditary ocular malformations.