Generating new tools for the prevention, diagnosis, and treatment of retinal diseases requires an increased understanding of the molecular mechanisms of retinal cell fate determination and differentiation. The goal of this competing renewal is to determine the function of the highly conserved mammalian Dach genes during retinal development and in adults. Both mice and humans possess two homologs of the Drosophila gene dachshund, which encodes a novel transcriptional cofactor that is both necessary and sufficient for retinal development in Drosophila. Mouse homologs of dachshund, named Dach1 and Dach2, are expressed in the retina during embryonic and postnatal life. In addition, Dach1 expression is dependent upon Math5, which encodes a DNA-binding transcription factor that is required for ganglion cell specification. We hypothesize that the Dach genes are required for normal retinal development. Although Dach1 null mutants die at birth with no obvious retinal phenotype, analysis later during development is precluded by neonatal lethality. Thus Dach1 may play a late role during eye development or there may be functional redundancy with Dach2. To further explore this possibility and to help elucidate the molecular mechanisms of retinal cell fate control, we will create conditional alleles of both genes using the Cre/loxP system. We propose the following Specific Aims: [unreadable] [unreadable] 1. Analyze Dach1 function during postnatal retinal development.2. Determine the role of Dach2 function during embryonic and postnatal retinal development.3. Place Dach1 and Dach2 in a retinal hierarchy with Pax6, Math5, and Brn3b. [unreadable] [unreadable] These studies are required to characterize the relationships between genes operating during retinal development. A greater understanding of these pathways is essential to our understanding of eye disease. Since our approach focuses on vertebrate homologues of the Drosophila gene dachshund, which is both necessary and sufficient for eye development, it is likely that uncovering the similarities and differences in retinal specification pathways is a key to the future development of diagnostic and therapeutic tools.
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