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。 在C语言中至少需要两种信号积分的情况。正确的细胞命运规范。 在雌雄同体的外阴中，整合EGF和Wnt通路信号是外阴前体细胞特化所必需的。 在尾部的P12神经外胚层细胞中，EGF和Wnt途径信号的整合再次需要影响P12命运。 在这两种情况下，两种途径的整合导致hox基因的激活，即外阴中的lin-39和P12中的egl-5。这个提议的目的是定义和比较导致hox基因激活的这两种情况下的信号整合模式。 我的目标是通过分离lin-39和egl-5正确表达所需的上游因子，并通过定义lin-39和egl-5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通路在动物细胞增殖和分化中发挥的重要作用需要了解。 已经发现，高达90%的某些类型的癌症具有突变的RAS基因，因此，我们必须了解这些途径如何在正常分化中协同工作，以便我们能够理解由于这些途径的改变而导致的致癌后果。

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.