GENETIC CONTROL OF RETINA SPECIFICATION

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The long-term goal of this research proposal is to determine the function of conserved genes required for normal retinal development in humans. We are using two model systems toward this end: the mouse Mus musculus and the fruitfly Drosophila melanogaster. The combination of genetic and molecular techniques afforded by these specifies is of unparalleled power and importance for the development of new tools for early diagnosis and treatment of human retinal disease. Our work focuses on the function of the newly discovered vertebrate homologs of the Drosophila gene dachshund (dac), which encodes a nuclear protein that is both necessary and sufficient for retinal development in Drosophila. Loss of dac funtion produce flies with no eyes whereas targeted expression of dac leads to the development of complete and properly formed compound eyes on most of the major appendages of Drospohila. These results are very similar to those observed with the eyeless gene, which is a functional homolog of human Aniridia. Moreover, we have shown that eyeless induces dac expression and vice versa, suggesting that these genes may form a positive feedback loop during normal retinal development. We have identified multiple vertebrate homologs of dac and have begun to characterize these genes. Most significantly, at least one mouse Dac gene is expressed in the retina throughout development. Given the highly conserved nature of retinal development, it is very likely that the vertebrate Dac genes will also play critical roles in eye development in mammals. We propose the following Specific Aims: 1. Complete the molecular characterization of the mouse and human Dac gene families. 2. Determine the function of mouse Dac by targeted disruption and ectopic expression. 3. Examine interactions between mouse Dac and other genes required for eye development. 4. Screen for proteins that physically interact with mammalian and Drosophila Dac proteins. These experiments outline a strategy to determine the function of the highly conserved Dac gene in mammalian retinal development and are likely to provide valuable information regarding the production of new therapies and approaches for the treatment of human retinal disease.