Genetic Control of Symmetry in the Eye

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DESCRIPTION (provided by applicant): Axial patterning in organ primordium is essential for its growth and development. The fruit fly, Drosophila, provides an ideal model for genetic analysis of dorsoventral (DV) patterning and growth of the eye primordium. Our goal is to utilize this powerful genetic system to identify key genes involved in early eye patterning and reveal the molecular mechanisms of genetic interactions underlying this important event which marks first lineage restriction in developing eye. In early eye imaginal disc, the DV patterning is established by initiation of expression of a dorsal selector gene, pannier (pnr), which controls the expression of wingless (wg) signaling gene and Iroquois family transcription factors. The dorsal genes antagonize the function of ventral genes including Lobe (L), Serrate (Ser) and fringe (fng). The interaction of these two groups of genes leads to preferential activation of Notch signaling at the DV border to induce growth and differentiation. One of the major questions to be addressed is the molecular genetic basis for such regulatory interactions. Based on antagonistic relationship between the dorsal and ventral genes, we propose that the major function of genes involved in DV patterning is to either promote or suppress the Pnr-mediated Wg signaling in the dorsal and ventral domains, respectively. These genes are further regulated by factors involved in the control of cell survival and/or cell growth. To test these hypotheses, we will analyze (i) relationship between L and Dpp in the negative regulation of Wg signaling, (ii) the function of L and Homothorax (Hth) in the control of eye growth and retinal fate determination, (iii) function of L and Cullin-4 ubiquitin ligase in the control of ventral cell survival, and (iv) the regulation of L function by Fng and Akt kinase in cell growth. Most of the genes studied here are highly conserved as they are present in higher mammals including humans, and genetic control of DV patterning is an important event during mammalian eye development. This study will help in revealing mechanisms of genetic interactions involved in early eye development. Thus, our study will also contribute to the understanding of mammalian eye development and etiology of early childhood retinal diseases.