How cells and tissues develop into functional organs (organogenesis) remains an important question in developmental biology. During organogenesis, two distinct processes occur. Each cell adopts a cell type or fate which distinguishes it from other cell types within the organ. All of the cells also acquire an organ identity which distinguishes them from other cells in the animal. The molecular mechanisms that allow for the coordination of these two processes are poorly understood. Some insight has come from the analysis of Fax transcription factors, which play an important role in organ development in all animals and are misregulated in many human cancers. Dr. Chamberlin has recently found evidence that a Pax transcription factor (EGL-38) coordinates cell type specification and organ identity in the nematode C. elegans. Molecular parallels between C. elegans and mammals indicate a similar regulatory network may play a role in the development of the human kidney. EGL-38 is required for the expression of two genes during C. elegans hindgut organogenesis: lin-48 and cdh-3. lin-48 encodes a zinc finger protein necessary for cell type specification. cdh-3 encodes a cadherin cell adhesion molecule which is normally expressed throughout the hindgut and may contribute to intra-organ cohesion. Preliminary results indicate regulation of lin-48 by EGL-38 is direct and that lin-48 and cdh-3 are regulated independent of each other. The proposed experiments will investigate the mechanisms by which EGL-38 regulates these two classes of genes. To determine whether the two genes are subject to different types of regulation by EGL-38, a first aim is to characterize the binding sites for EGL-38 in the lin-48 promoter, and determine whether EGL-38 directly regulates cdh-3. One possibility is that the distinct functions of EGL-38 result from its interaction with other transcription factors. Indeed, genetic results suggest that the Ets protein LIN-1 functions with EGL-38 in the regulation of lin-48. Thus a second aim is to test whether EGL-38 and LIN1 bind the lin-48 promoter as a complex and also investigate the function of two other C. elegans Ets proteins that may interact with Fax proteins. Finally, EGL-38 is the product of one of two Pax-2/5/8-related genes in C. elegans.
A third aim i s to functionally characterize this second gene to determine whether its product shares in vivo functions with EGL-38, or whether it regulates lin-48 and cdh-3 expression in other organs.
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