While the study of the development of the retina, particularly the genes involved in its formation, is a very active area of study, the earliest processes leading to the formation of the retina remain poorly understood. It is the goal of this proposal to gain significant understanding of the primary mechanisms leading to determination of the embryonic retina in Xenopus embryos: how commitment to form the retina occurs and how the boundaries of this tissue are established. We wish to understand not only how the retina is formed, but also how it forms in such a precisely stereotyped manner since aberrations in this developmental program are implicated in a high fraction of genetically based eye diseases. Our work in recent years concerning this problem focus on four areas: 1) the embryology of eye development;2) a systematic examination of the gene expression patterns of regulatory genes during the stages of eye determination;3) extensive examination of the regulatory elements controlling key eye gene regulation (for example, the homeobox genes Rx, Pax6 and Six3);and 4) the development of new technology for study of gene regulation and manipulating gene expression in the Xenopus system. We propose three aims here. First we wish to define the key parameters that define the embryological state of determination of the retina, which occurs at approximately the neural plate stage, using embryological and molecular genetic assays to evaluate this process. Second we propose to examine the signaling pathways involved in retinal determination, focusing on the roles of Wnt, Hedgehog and IGF pathways in this process. Third, we will examine the regulation of and interactions among a critical group of transcription factors essential for retina formation in order to ascertain their roles in the determination mechanism.
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