Signal Transduction in Vertebrate Embryogenesis

脊椎动物胚胎发生中的信号转导

基本信息

批准号：
7149182
负责人：
FRANKLIN D COSTANTINI
金额：
$ 34.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7149182
关键词：
AXIN2 protein Address Affect Alleles Binding Binding Sites Biochemical Biological Assay Brain Branchial arch structure C-terminal Cell Line Cell Lineage Cell Proliferation Cells Cephalic Complex Congenital Abnormality Craniofacial Abnormalities DIX Domain Defect Development Dominant-Negative Mutation Embryo Embryonic Development Etiology Excision Face Failure Family Genes Genetic Glycogen Synthase Kinase 3 Human Lead Mediating Mesoderm Methods Modeling Molecular Analysis Mus Mutant Strains Mice Mutation N-terminal Nature Neural Crest Neural Crest Cell Pathway interactions Pattern Phenocopy Phenotype Play Point Mutation Process Prosencephalon Protein Overexpression Proteins Purpose Relative (related person)Role Signal Pathway Signal Transduction Signal Transduction Pathway Staging Structure Surface Ectoderm Testing Time Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins base craniofacial gain of function gene replacement in vivo loss of function migration mutant novel prevent research study response

项目摘要

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.

该提案涉及 Axin 和相关基因 Axin2 在调节经典 Wnt 中的作用哺乳动物胚胎发生过程中的信号转导途径。 Wnt 是一系列分泌因子，在发育过程中的细胞增殖、模式化和分化中发挥重要作用。轴心是关键蛋白质复合物的组成部分，通过调节 Wnts 下游的细胞内信号传导 [_-catenin] 的水平，它是转录辅激活因子和途径中的关键效应子。 Axin2被认为具有类似的功能，尽管其特征不那么明确。人类这两个基因的突变表明它们是肿瘤抑制因子，与它们负向调节 Wnt 通路的作用一致。这对 Axin 和 Axin2 突变小鼠的分析表明，这些基因对于早期发育非常重要。轴向图案，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、中胚层和神经嵴之间相互作用的过程，而且它非常容易受到遗传和环境扰动的影响，因为颅面部异常人类最常见的出生缺陷之一。 Wnt 信号通路与通过几种小鼠突变来实现颅面发育。在这个提案中，假设将得到检验需要 Axin 和 Axin2 来负调节颅神经对某些 Wnt 的反应形成面部大部分的嵴细胞，Axin 和 Axin2 的突变导致不适当的激活 Wnt 通路。这将通过对突变小鼠的分析以及通过条件使用转基因方法操纵颅神经嵴中的 Wnt 通路。要了解如何 Axin 和 Axin 2 在开发过程中合作，定义它们的合作程度很重要功能冗余，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特定结构域的重要性，这些结构域被认为介导其功能与该途径的其他成分相互作用，将产生轴蛋白的几个新的突变等位基因，并检查了它们对小鼠胚胎发生的影响。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multiple isoforms of beta-TrCP display differential activities in the regulation of Wnt signaling.

DOI：
10.1016/j.cellsig.2008.09.009
发表时间：
2009-01
期刊：
CELLULAR SIGNALLING
影响因子：
4.8
作者：
Seo, Eunjeong;Kim, Hyunjoon;Kim, Rokki;Yun, Sangmoon;Kim, Minseong;Han, Jin-Kwan;Costantini, Frank;Jho, Eek-hoon
通讯作者：
Jho, Eek-hoon