GENETIC CONTROL OF VULVAL CELL FATES IN C ELEGANS

这项研究的长期目标是了解细胞是如何 信号传导导致诱导特定的细胞命运， 发展 细胞信号传导的一个充分研究的例子是诱导 雌雄同体外阴的发育过程中C.优雅 遗传和 分子分析表明，对这种感应信号的反应 由受体酪氨酸激酶/Ras信号转导途径介导 在后生动物进化过程中被保存得非常好。 而 导致最后一个信号激活的事件链 转导蛋白（MAP激酶）已被充分描述，但知之甚少 关于MAP激酶激活后发生的事件。因此 最重要但又知之甚少的一步是， 该细胞信号通路中的信号转导分子调节 细胞核中转录因子的活性，最终导致 在细胞分化中。 此外，目前还不清楚如何激活 同一信号转导通路的不同时间点， 发育可以在不同的细胞中引起明显不同的细胞反应。 细胞类型。 拟议的研究旨在确定分子机制 将信号传导级联的激活与特定的 基因表达的变化导致特定细胞的执行， 命运 一个目标是定义两个C的作用。线虫MAP激酶 同源物，最近已被证明在外阴诱导中起作用。 另一个目标是确定MAP激酶如何调节LIN-1的活性。 31，控制外阴基因表达的转录因子。 第三 目的是确定LIN-31如何调节诱导与 在外阴诱导过程中未诱导的细胞命运，以及LIN-31是否起作用。 在定义转录反应的细胞类型特异性中的作用 信号传导级联的激活。 最终目标是 从遗传学上鉴定作用于MAP激酶下游的其它基因， 为了确定MAP激酶的激活与 外阴细胞命运的诱导。 由于受体酪氨酸激酶/Ras信号转导途径是如此的复杂， 高度保守，并且因为这种信号传导的组成性激活 已知该途径在哺乳动物中致癌，因此拟议的研究将 与人类的细胞信号传导过程直接相关， 正常发育和肿瘤发生。

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.