The long-term goal of this project is to improve our ability to prevent, diagnose and treat human retinal diseases. Our experimental approach uses the fruit fly Drosophila melanogaster as an animal model system to identify and determine the function of conserved genes that are required for normal retinal cell fate determination and differentiation. Our studies have focused on a group of retinal determination (RD) genes that encode nuclear proteins that function together in complexes to control gene transcription and retinal cell fates. Each of the RD genes, including eyeless, eyes absent, sine oculis and dachshund, is highly conserved in mammals. We have shown that dachshund (dac) is both necessary and sufficient for normal retinal development in Drosophila. That is, in the absence of dac function, flies develop with no eyes. Moreover, targeted expression of dac leads to the induction of properly formed ectopic eyes on the antennae, legs and thorax. These ectopic eyes contain all of the cell types found in the normal fly eye. Thus, dac functions near the top of the genetic hierarchy controlling retinal development in Drosophila. Importantly, dac is highly conserved in mice and humans and is strongly expressed in the mouse neural retina throughout development. In addition, we are investigating how the highly conserved general signaling pathways, such as hedgehog and the TGFI3 homolog dpp, are integrated with the function of the RD genes to control patterning and cell fate determination in the retina. Our continuing studies on the molecular and genetic mechanisms of RD gene function are therefore important steps toward understanding normal retinal development in humans. In addition, we have isolated and are studying Drosophila homologs of two new vertebrate genes that are key players in retinal development.
Our specific aims are to: (1) dissect dac regulatory elements and identify genes directly controlling dac expression; (2) conduct structure/function studies and genetic screens to decipher dac function; (3) integrate the hedgehog signaling pathway with the retinal determination network; and (4) analyze the function of new, conserved genes required for normal retinal development. These studies are designed to further elucidate the molecular and genetic mechanisms controlling retinal cell fate determination in Drosophila, the most powerful genetic model system available. Since all of the genes we study are highly conserved in humans, this work will directly impact our understanding of human retinal development.
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