RAS MEDIATED SIGNAL TRANSDUCTION IN C ELEGANS

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Our goal is to understand the mechanism of control and execution of cell differentiation and morphogenesis during animal development. Research supported by this grant, as well as work from other laboratories, has shown that vulval differentiation in C. elegans is controlled by a Ras- mediated signal transduction pathway that is extremely similar to pathways that are involved in mammalian cell signaling and cancers. However, how the activities of many commonly used gene products are accurately regulated for specific functions is still poorly understood. Moreover, events occurring downstream of the signaling pathway including execution of cell differentiation and morphogenesis remain largely unexplored. In this proposal, besides continuing to analyze the regulation and function of Ras and Raf, we will use genetic and molecular methods to identify and characterize a number of new genes for their functions in regulating the signaling pathway and in executing vulval differentiation and morphogenesis. The specific aims are: (1) We will clone and analyze the function of two newly identified genes that are likely positive regulators of the pathway and carry out new screens to identify new regulators. We will determine the genetic and molecular nature of several newly isolated Raf mutations and analyze the interaction between the mutant Raf and Ras proteins. We will also try to identify Raf-independent functions of Ras. (2) We will carry out a series of molecular and genetic experiments to determine the function and regulation of the sur-2 gene which acts downstream of Ras/MAPK in vulval signal transduction. We will investigate its expression pattern, dissect its gene and protein structure, and identify its regulators and targets. (3) We will carry out genetic screens for temperature sensitive (TS) and nonTS mutants to identify new genes that act to execute vulval differentiation and morphogenesis. We will characterize genes defined by these mutants by genetic, microscopic and molecular methods. Study of the molecular basis of cell interaction in specifying developmental pattern is closely related to the study of cancers and other human disease. Vulval development provides us a specific assay system to identify factors that would be difficult to identify in mammals and to elucidate their in vivo functions.