GENETIC CONTROL OF VULVAL CELL FATES IN C ELEGANS

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The long-term objective of the proposed research is to understand how cell signalling leads to the induction of specific cell fates during development. A well-studied example of cell signalling is the induction of the hermaphrodite vulva during development in C. elegans. Genetic and molecular analyses have shown that the response to this inductive signal is mediated by a receptor tyrosine kinase/Ras signal transduction pathway that has been remarkably well conserved during metazoan evolution. While the chain of events leading to the activation of the last signal transduction protein (MAP kinase) has been well described, little is known about the events that occur after MAP kinase activation. Thus, a fundamentally important and yet poorly understood step is how the last signal transduction molecule(s) in this cell signaling pathway regulates the activity of transcription factors in the nucleus, ultimately resulting in cellular differentiation. Furthermore, it is not clear how activation of the same signal transduction pathway at multiple times during development can elicit markedly different cellular responses in different cell types. The proposed research is directed at defining the molecular mechanisms that link activation of this signal transduction cascade with specific changes in gene expression that result in the execution of specific cell fates. One goal is to define the role of two C. elegans MAP kinase homologs that have recently been shown to function in vulval induction. Another goal is to determine how MAP kinases regulate the activity of LIN- 31, a transcription factor that controls vulval gene expression. A third goal is to determine how LIN-31 regulates the choice of induced versus uninduced cell fates during vulval induction, and whether LIN-31 plays a role in defining the cell-type specificity of the transcriptional response to activation of the signal transduction cascade. A final goal is to genetically identify additional genes that act downstream of MAP kinases, in order to define additional links between activation of MAP kinases and induction of vulval cell fates. Because the receptor tyrosine kinase/Ras signal transduction pathway is so highly conserved, and because constitutive activation of this signaling pathway is known to be oncogenic in mammals, the proposed studies will be directly relevant to cell signalling processes in humans, both during normal development and in tumorigenesis.