Molecular and Cellular Basis of Lens Development

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DESCRIPTION: Specific tissue interactions, or "inductive interactions," control the development of all vertebrate organ systems. The first example of this was demonstrated in the context of vertebrate lens development, over 100 years ago. Subsequently, the eye/lens has served as a model system for understanding the general nature of inductive interactions, due to its accessibility to direct experimental manipulation, particularly in amphibian embryos. Although a great deal is known about tissue interactions involved in lens induction, we have just begun to decipher molecular events that control lens cell determination and differentiation. The goal of this study is to identify genes involved in controlling these processes. In some organisms, lenses can regenerate via the transdifferentiation of other differentiated larval or adult cell types. In Xenopus, the cornea epithelium can undergo transdifferentiation to form a new lens when the original lens is removed. We have exploited this process as a convenient one to isolate genes involved in lens formation. A large suite of genes were recovered from a subtracted cDNA library, enriched for those expressed during the process of cornea-lens transdifferentiation. Preliminary studies indicate that many of these genes are also expressed during embryonic lens development. A high-throughput approach employing robotic in situ hybridization will be applied to characterize the expression of these genes during lens development and regeneration. This data will provide an understanding of the molecular relationships between these two lens-forming processes. A number of transcriptional regulators and cell signaling factors are represented amongst those genes, which are likely to play key roles in controlling the processes of lens development and regeneration. We will examine the functions of these genes using specific assays, including: in vivo loss-of-function and gain-of- function analyses. These functional studies will be performed in conjunction with expression analyses to decipher molecular pathways of lens formation. Finally, gene expression and function will be examined in the context of the current model of lens induction, via tissue transplantation and explant culture experiments. An understanding of molecular and cellular relationships between lens development and regeneration, and the genes controlling lens cell determination and differentiation, will ultimately lead to the development of new therapeutic approaches to treat injured and diseased lenses.