SMAD1 AND SMAD2 AND MOUSE DEVELOPMENT

最近鉴定的一个称为Smads的细胞内蛋白家族， TGF β信号通路的关键组成部分。Smad的磷酸化 通过激活TGF β-I型受体， 转运到细胞核，在那里它们充当转录因子， 监管部门不同的Smad蛋白作为下游效应子， 对特定TGF β相关配体的反应。因此Smad 1介导了 骨形态发生蛋白的作用，而Smad 2是激活的， 对TGF β和激活素的反应。该项目旨在进一步提高 深入了解Smad 1和Smad 2提供的功能活动 哺乳动物早期发育过程中的蛋白质一个无效突变， 小鼠Smad 2基因导致早期胚胎死亡。我建议 表征Smad 2缺陷胚胎中的原发性组织缺陷。我 计划分离Smad 2缺陷细胞系。他们的反应能力 与多种TGF β分子的关系。评价 Smad 2途径在中胚层形成中的需求， Smad 2缺陷ES细胞系的分化能力将是 在体外和嵌合体中测试。另外，我计划创建Smad 1 利用基因靶向技术的缺陷胚胎。它们的表型将 与Smad 2突变体相比。总的来说，这些结果 这些实验将进一步加深我们对人类在进化中所扮演的不同角色的理解， 通过不同的Smad途径在胚胎体的建立过程中 计划

A recently identified family of intracellular proteins termed Smads, are key components of TGFbeta signaling pathways. Phosphorylation of Smad proteins by activated TGFbeta-type I receptors lead to their translocation to the nucleus where they act as transcriptional regulators. Different Smad proteins act as downstream effectors in response to specific TGFbeta-related ligands. Thus Smad1 mediates the effects of Bone Morphogenetic Proteins, whereas Smad2 is activated in response to TGFbeta and activin. This project aims to gain further insight into the functional activities provided by Smad1 and Smad2 proteins during early mammalian development. A null mutation in the mouse Smad2 gene results in early embryonic lethality. I propose to characterize the primary tissue defects in Smad2 deficient embryos. I plan to isolate Smad2 deficient cell lines. Their abilities to respond to a variety of TGFbeta molecules will be analyzed. To evaluate the requirement of the Smad2 pathway in mesoderm formation, the differentiation abilities of Smad2 deficient ES cell lines will be tested in vitro and in chimeras. Additionally I plan to create Smad1 deficient embryos using gene targeting techniques. Their phenotype will be compared with that of the Smad2 mutants. Overall, results of these experiments will further our understanding of the diverse roles played by distinct Smad pathways during establishment of the embryonic body plan.