Signal Transduction in Vertebrate Embryogenesis

超出空间 但前提是。 这一建议涉及Axin及其相关基因Axin2在调节规范Wnt中的作用 哺乳动物胚胎发育过程中的信号转导途径。WNT是一个秘密因素家族， 在发育过程中对细胞的增殖、构型和分化起重要作用。Axin是一个关键的 一种蛋白质复合体的组成部分，通过调节WNTS下游的细胞内信号，控制WNTS下游的细胞内信号 [_-连环蛋白，一种转录共激活因子和途径中的关键效应因子。Axin2被认为具有 一个类似的功能，尽管它的特征不是很好。人类这两个基因的突变已经显示出 它们是肿瘤抑制因子，与它们在负调控Wnt途径中的作用一致。这个 对Axin和Axin2基因突变的小鼠的分析表明，这些基因在早期 轴向模式，以及颅面和大脑发育。颅面发育是一个复杂的过程。 涉及表面外胚层、内胚层、中胚层和神经脊之间相互作用的过程， 而且它非常容易受到遗传和环境的干扰，就像颅面畸形一样 人类最常见的先天缺陷之一。Wnt信号通路被认为与 通过几个小鼠突变实现面部发育。在这项提议中，将检验这一假设 需要Axin和Axin2来负向调节脑神经对某些WNTT的反应 形成面部大部分的冠细胞，Axin和Axin2的突变导致不适当的激活 在WNT小路上。这将通过对突变小鼠的分析以及通过有条件的 使用转基因方法在脑神经脊部操纵Wnt通路。要了解如何 Axin和Axin 2在发育过程中合作，重要的是定义它们在多大程度上 在功能上是多余的，这个问题将通过小鼠的基因替换策略进行研究。 最后，为了在体内测试轴蛋白的特定结构域的重要性，这些结构域被认为是调节其功能的 与该途径的其他组件相互作用时，将产生几个新的Axin突变等位基因， 并检测了它们对小鼠胚胎发育的影响。

EXCEED THE SPACE PROVIDED. This proposal concerns the roles of Axin and the related gene Axin2 in regulating the canonical Wnt signal transduction pathway during mammalian embryogenesis. The Wnts are a family of secreted factors that play important roles in cell proliferation, patterning and differentiation during development. Axin is a critical component of a protein complex that controls intracellular signaling downstream of Wnts, by regulating the levels of [_-catenin, a transcriptional co-activator and a key effector in the pathway. Axin2 is believed to have a similar function, although it is not as well characterized. Mutations in both genes in humans have shown that they are tumor suppressors, consistent with their roles in negatively regulating the Wnt pathway. The analysis of mice with mutations in Axin and Axin2 have revealed that these genes are important for early axial patterning, as well as for craniofacial and brain development. Craniofacial development is a complex process that involves interactions between the surface ectoderm, endoderrn, mesoderm and the neural crest, and it is highly susceptible to genetic and environmental perturbations, as craniofacial abnormalities are among the most common birth defects in humans. The Wnt signaling pathway has been implicated in eraniofacial development through several mouse mutations. In this proposal, the hypothesis will be tested that Axin and Axin2 are required to negatively regulate the response to certain Wnts by the cranial neural crest cells that form much of the face, and that mutations in Axin and Axin2 lead to inappropriate activation of the Wnt pathway. This will be addressed by analysis of mutant mice, as well as through the conditional manipulation of the Wnt pathway in the cranial neural crest, using transgenic approaches. To understand how Axin and Axin 2 cooperate during development, it is important to define the extent to which they are functionally redundant, and this issue will be investigated through a gene replacement strategy in mice. Finally, to test in vivo the importance of specific domains of Axin that are believed to mediate its functional interactions with other components of the pathway, several novel mutant alleles of Axin will be generated, and examined for their effects on mouse embryogenesis.