EGF AND WNT SIGNAL INTEGRATION BY C ELEGANS HOX GENES

通过整合多种信号通路来指定细胞命运是发育基因调控中的一种新兴范式。线虫至少需要两种情况下的信号整合才能正确地确定细胞命运。在两性外阴中，整合的EGF和Wnt通路信号是外阴前体细胞的规范所必需的。在尾部的P12神经外胚母细胞中，EGF和Wnt通路信号的整合再次需要影响P12的命运。在这两种情况下，两条通路的整合导致了HOX基因的激活，外阴中的LIN-39和P12中的EGL-5。这项建议的目的是定义和比较这两种情况下导致HOX基因激活的信号整合模式。我的目标是通过分离正确表达LIN-39和EGL-5所需的上游因子，并通过定义LIN-39和EGL-5的内源表达模式所需的顺式作用元件来实现这些目标。高度保守的EGF/RAS/RAF和WNT通路在动物细胞的增殖和分化中所起的重要作用需要他们的理解。研究发现，高达90%的某些类型的癌症存在RAS基因突变，因此，我们有必要了解这些通路在正常分化中是如何协同工作的，以便我们能够理解这些通路的变化导致的致癌后果。

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.