The long-term objective of this proposal is to gain a better understanding of the genetic control of eye-tissue determination in Drosophila. Several genes that play important roles in this process have been identified in recent years. These are the genes eyeless (ey), sine oculis (so), eyes absent (eya) and dachshund (dac). These genes are required for eye development, can induce other tissues to form eyes, and are linked in a gene network by interactions at the level of protein-protein contacts and transcriptional regulation. In order to generate a more complete picture of thegenetic circuitry involved in establishing eye identity in the fruit fly, we propose to identify additional genes involved in this process and study their relationship to the genes already known. We are pursuing four different approaches to identify novel factors involved in this process. In the first two approaches, we make use of previously identified components of the eye-specification gene network to identify novel factors through protein-DNA and protein-protein interactions. The other twoarebased on genetic screens to identify gene activities required or sufficient for eye induction within theeye disc (normal eyes) or in other tissues (ectopic eyes). A detailed molecular and functional characterization of the genes identified using these approaches will be carried out. Through a combination of forward genetic and reverse genetic approaches, molecular genetic analysis and ectopic expression studies, we will dissect the function of these novel factors in eye-tissue specification and define their role in the context of the already identified genetic pathways, Interestingly, despite the significant differences in structure and function between the fly and human eyes, the components of this genetic network appear to be evolutionarily conserved. Several related genes have been identified in mouse and humans including Pax6 and multiple Six, Eya and Dac genes and some of these genes have been found to regulate eye development in vertebrates. Thus, mutations in eyeless Pax6 cause Aniridia inhumans, the Small eye phenotype in mice, and the eyeless phenotype in Drosophila. Moreover, Pax6 and Six3 have been shown to induce eye structures (lens and retina) when ectopically expressed in Xenopus and Medaka fish, indicating that the homology at the molecular level may extend to a conservation of function in eye development. The extensive conservation of molecular factors involved in the early steps of eye development indicates that work in Drosophila will provide insights into the genetic mechanisms controlling mammalian eye development.
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