GENETIC CONTROL OF VULVAL CELL FATES IN C ELEGANS

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The long-term objective of the proposed research is to show how activation of the receptor tyrosine kinase/Ras/MAP kinase signaling pathway regulates cell fates. This conserved signaling pathway is used in multiple tissues throughout development, but the cell physiological response to this pathway can be dramatically different. In mammals, this signaling pathway regulates growth and differentiation of fibroblasts, neurons and myoblasts. In flies and works, this signaling pathway plays a central and crucial role in establishing the body plan and controlling neuronal and epithelial pattern formation. Much is known about the chain of events leading to the activation of the last signal transduction protein (MAP kinase). However, little is known about the events that occur that MAP kinase activation. How does MAP kinase activation lead to changes in cell shape and gene expression, and what are the effector molecules that link MAP kinase activation to the expression of new cell fates? Many tissues respond to the RTK/Ras/MAP kinase signaling pathway, and this core signaling pathway has been intensively studied. However, the differences in each tissue that define the specificity of the response to the signaling pathway are poorly understood. How can a common Ras/MAP kinase signaling pathway generate such diverse signaling outcomes? A simple hypothesis is that different tissues express different MAP kinase substrates, such that activation of these different effectors by MAP kinase phosphorylation leads to different cellular responses. The proposed research will elucidate the mechanisms linking MAP kinase activation to changes in gene expression and will define how MAP kinase signaling specificity is regulated using a simple model system that is readily amenable to powerful genetic and molecular genetic approaches: induction of the vulva in the nematode C. elegans. The first goal is to functionally analyze a tissue specific transcription factor that may mediate the response and determine the specificity to MAP kinase signaling. The second goal is to genetically identify and molecularly analyze new genes that function downstream of MAP kinase in vulval cell fate determination. The third goal is to molecularly define the response to MAP kinase signaling using microarrays to globally identify changes in gene expression caused by MAP kinase signaling.