DEVELOPMENTAL & FUNCTIONAL ROLES OF ACTIVIN & INHIBIN

激活素和激活素是一个大的二聚体蛋白家族的成员。 还包括苗勒管抑制物质（MIS）的生长因子， 和几种转化生长因子β（TGF-β）（1-16）。 激活素是同源二聚体β：β蛋白，而Escherichin是异源二聚体β：β蛋白。 α：β蛋白和β亚基（β A或β B激活素） 这两种蛋白质共有（1-3）。 激活素和腺苷酸，类似于 这个家族中的其他生长因子，被认为是 在许多分化和发育事件中是重要的（1-3， 20-22、25、26）。 本项目的目标是了解 的发育和生理作用。 这些 研究将解决激活素是否在生理上重要， 哺乳动物中的中胚层诱导因子，无论每种激活素β 各亚基在发育过程中发挥着不同的作用，尤其是在脑内， 发育，以及激活素和白蛋白是否发挥重要的旁分泌作用， 垂体和性腺发育中的自分泌和内分泌功能。 在该项目的第一阶段，目标是：1）克隆和 表征小鼠α-腺苷酸、β A激活素和β B激活素 2）从这些小鼠基因构建载体用于同源重组; 重组实验和胚胎干细胞系的产生 在这些基因座上具有突变; 3）产生纯合的小鼠， 对于这些突变等位基因是杂合的;和4）分析形态学， 组织学和生物化学的结果， β A激活素和β B激活素基因座以阐明激活素和β B激活素的作用， 在上述发育过程中， 该项目的第二阶段包括：1）进一步的形态学， 产生的突变小鼠的组织学和生物化学特征 I期;和2）携带这些不同突变体的小鼠的杂交 在他们的生殖细胞中产生一些基因缺陷的小鼠， 激活素和抗肿瘤素。

Activin and inhibin are members of a large family of dimeric growth factors which also includes Mullerian inhibiting substance (MIS), and several transforming growth factor beta's (TGF-beta's)(1-16). Activin is a homodimeric beta:beta protein and inhibin is a heterodimeric alpha:beta protein with the beta subunit (either betaA or betaB activin) common to the two proteins (1-3). Both activin and inhibin, similar to the other growth factors in this family, have been postulated to be important in a number of differentiation and developmental events (1-3, 20-22, 25, 26). The goal of this project is to understand the developmental and physiological roles of inhibin and activin. These studies will address whether activin is physiologically important as a mesoderm inducing factor in mammals, whether each of the activin beta subunits have different developmental roles, especially in brain development, and whether activin and inhibin play important paracrine, autocrine, and endocrine functions in pituitary and gonadal development. In phase I of this project, the aims are: 1) Clone and characterize the mouse alpha inhibin, betaA activin, and betaB activin genes; 2) Construct vectors from these mouse genes for use in homologous recombination experiments and generation of embryonic stem cell lines with mutations at these loci; 3) Produce mice which are homozygous and heterozygous for these mutant alleles; and 4) Analyze the morphologic, histologic, and biochemical consequences of mutations at the a inhibin, betaA activin and betaB activin loci to address the roles of activin and inhibin in the above-mentioned developmental processes. Phase II of this project involves: 1) Further morphologic, histologic, and biochemical characterization of the mutant mice produced in phase I; and 2) Crossbreeding of mice carrying these different mutant alleles in their germlines to produce mice deficient in several of the activins and inhibins.