RETINA CELL FATE DETERMINATION AND PATTERN FORMATION

点击翻译按钮获取中文摘要

The long-term goal of this project is to understand the molecular mechanisms of cell-fate determination and pattern formation during retina development. In the United States alone, more than 30 million people suffer from some type of visual disorder. In many cases, designing more effective methods of treatment for eye disease would greatly benefit from a detailed knowledge of the mechanisms of normal retinal development. Substantial gains in our understanding of vertebrate development have often come from studies using a model system. Recently, clear similarities between Drosophila and vertebrate retinal development have been discerned. Murine homologs of three Drosophila genes required for normal eye development have been identified that are specifically expressed in the mouse eye anlage. At least one of these genes (Drosophila eyeless) is required for proper eye development in both mice (small eye) and humans (Aniridia). Thus, at least some of the basic mechanisms of retinal development may have been conserved across phylogeny, from Drosophila to mammals. This proposal outlines a research plan designed to further exploit Drosophila as a model system to identify and understand the function of conserved genes required for normal retinal development. In Drosophila, photoreceptor development occurs in an epithelial monolayer called the eye imaginal disc. Neural differentiation spreads across the eye disc following an indentation in the eye epithelium termed the morphogenetic furrow. Movement of this furrow requires the function of two conserved genes: dpp (a TGFbeta homolog) and hedgehog (a secreted morphogen). We have characterized the gene dachshund (dac), which encodes a novel nuclear protein that is required for normal eye development. In the absence of dac function, initiation of movement of the morphogenetic furrow is aborted and dac mutant adults therefore develop with no eyes. dac is the only gene known to control initiation of this wave of morphogenesis in the eye. Further study of the dac gene is likely to provide important information concerning the function of this conserved intercellular signaling pathway and retinal cell-fate specification. Our specific aims are to: A) Determine whether retinal development can occur in the absence of dac function and if dac is sufficient to induce retinal development; B) Investigate the role of dac in control of the cell cycle; C) Determine what role cell-death plays in the dac mutant eye phenotype; D) Place dac in the known genetic hierarchy controlling retinal development; and E) Conduct genetic studies with dac to identify novel potential interacting proteins. Study of dac function is likely to make significant contributions to our understanding of fundamental mechanisms of normal retinal development.