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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29EY011259-02
Application #
2331670
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1996-02-01
Project End
2001-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Atchison, Lakshmi; Ghias, Ayesha; Wilkinson, Frank et al. (2003) Transcription factor YY1 functions as a PcG protein in vivo. EMBO J 22:1347-58
Bui, Q T; Zimmerman, J E; Liu, H et al. (2000) Molecular analysis of Drosophila eyes absent mutants reveals features of the conserved Eya domain. Genetics 155:709-20
Bui, Q T; Zimmerman, J E; Liu, H et al. (2000) Functional analysis of an eye enhancer of the Drosophila eyes absent gene: differential regulation by eye specification genes. Dev Biol 221:355-64
Zimmerman, J E; Bui, Q T; Liu, H et al. (2000) Molecular genetic analysis of Drosophila eyes absent mutants reveals an eye enhancer element. Genetics 154:237-46
Bonini, N M (1999) A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster. Philos Trans R Soc Lond B Biol Sci 354:1057-60
Bonini, N M; Leiserson, W M; Benzer, S (1998) Multiple roles of the eyes absent gene in Drosophila. Dev Biol 196:42-57
Perez, M K; Paulson, H L; Pendse, S J et al. (1998) Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143:1457-70
Bonini, N M; Bui, Q T; Gray-Board, G L et al. (1997) The Drosophila eyes absent gene directs ectopic eye formation in a pathway conserved between flies and vertebrates. Development 124:4819-26