Inappropriate cell death is associated with many human eye diseases, including retinitis pigmentosa and aniridia; abnormal cell survival contributes to oncogenic diseases, like retinoblastoma. The long term goal of this research is to understand the molecular mechanisms by which cell survival is controlled during eye development, using combined genetic and molecular methods. The Drosophila eye provides an ideal system in which to approach the molecular control of survival pathways, due to its accessibility to genetic and molecular techniques, and the striking conservation of many developmental genes with human genes. A molecular and genetic analysis of the novel Drosophila gene eyes absent (eya) is proposed. Preliminary studies indicate a gene with striking homology to eya is expressed in human retina. The Drosophila eya gene is required early in eye development for the differentiation of eye progenitor cells. Upon loss of function of the gene, eye progenitor cells die by programmed cell death. These data have led to the hypothesis that the eya gene is either a developmentally-regulated survival factor that functions early in eye progenitor cells, or that the gene is involved in a step of differentiation that is coincidentally or subsequently linked to cell survival control. We will pursue two lines of investigation that elucidate the mechanisms of eya action to link eye differentiation with cell death. First, we will distinguish between the models of eya function by (1a) defining the relationship of eya gene function and that of cell death genes, (1b) defining the relationship of eya function to known genes of eye differentiation conserved to humans, including eyeless the homolog of the human Aniridia gene, and (1c) defining new genes that link cell survival control with eye differentiation, by analysis of six newly-identified suppressors of the eya reduced eye phenotype. Second, we will define the molecular mechanisms of eya action to link cell death and differentiation by (2a) defining in detail the novel nuclear scaffold localization of the eya protein, (2b) defining functional domains of the gene by molecular analysis of eya mutations that affect expression and activity in eye progenitor cells, and (2c) defining domains of eya conserved in human retinal homologs. It is anticipated that the eya gene represents a gene of conserved function from invertebrates to humans. The results gained from this research will contribute to the molecular understanding and design of therapeutic strategies for treating diseases of the human eye that involve aberrant cell death.
