Isolation and characterisation of retina specific genes

The complex process of eye development involves the formation of the neural retina, pigmented epithelium and lens from a pair of brain outgrowths and the overlaying surface ectoderm. The development of the neural retina involves the production of seven different cell types, found in three separate cell layers. Specification and differentiation of these different cell types is regulated by a combination of extrinsic and intrinsic factors. Evidence is accumulating that transcription factors play a major role in the intrinsic role of retinal cell fate. The Forkhead-box (Fox) genes are a family of transcription factors that have been implicated in mouse and human disease. This thesis describes the isolation of novel clones from an embryonic mouse eye cDNA library and their expression patterns in the developing eye. In particular, two new members of the Fox transcription factor family, mouse Foxn4 and human FoxN4. At the protein level mouse Foxn4 and human FoxN4 are 75% identical. Sequence analysis of these two genes shows the presence of three conserved domains, a DNA binding domain, an activation domain and a domain of unknown function. The two genes map to homologous regions in the mouse and human genome with mouse Foxn4 mapping to mouse chromosome 5 and human FoxN4 to human chromosome 12q24.1 Mouse Foxn4 and human FoxN4 are both expressed in the developing retina. Here, Foxn4 expression is localised to the ventricular zone during the early but not late stages of histogenesis. Foxn4 is downregulated in the mouse mutant ocular retardationj and is not expressed at all in Small eye homozygous mice. Taken together, the experiments in this thesis suggest that Foxn4 is a new transcription factor expressed at the beginning of the differentiation of cells fated to become early-born cell types such as ganglion, cone, amacrine and horizontal cells. CORRECTION This thesis does not use the correct nomenclature for human and mouse genes and proteins. The correct nomenclature is as follows: Human genes are written in uppercase and italicised e.g. PAX6. Human proteins are written in uppercase and not italicised e.g. PAX6. Mouse genes are written with the fist letter in uppercase, further letters are in lower case and the name is italicised e.g. Pax6. Mouse proteins are written with the fist letter in uppercase, further letters are in lower case and the name is not italicised e.g. Pax