EGF AND WNT SIGNAL INTEGRATION BY C ELEGANS HOX GENES

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The specification of cell-fate by the integration of multiple signaling pathways is an emerging paradigm in developmental gene regulation. At least two cases of signal integration are necessary in C. elegans for correct cell fate specification. In the hermaphrodite vulva, integration EGF and Wnt pathway signals are required for specification of the vulval precursor cells. In the P12 neuroectoblast cell in the tail, integration of EGF and Wnt pathway signals are again required to effect P12 fate. In both these cases, integration of the two pathways results in the activation of a hox gene, lin-39 in the vulva and egl-5 in P12. The goal of this proposal is to define and compare the modes of signal integration in these two cases that lead to hox gene activation. I aim to achieve these goals by isolating upstream factors required for correct lin-39 and egl-5 expression and by defining cis-acting elements in lin-39 and egl-5 required for their endogenous expression pattern. The important role the highly conserved EGF/RAS/RAF and Wnt pathways play in animal cell proliferation and differentiation necessitates their understanding. It has been found that up to ninety percent of certain types of carcinomas have mutated RAS genes, thus it is essential we understand how these pathways work in concert in normal differentiation in order that we can understand the oncogenic consequences due to alterations in these pathways.