DEVELOPMENTAL & FUNCTIONAL ROLES OF ACTIVIN & INHIBIN

激活素和抑制素是二聚体大家族的成员。 还包括苗勒氏抑制物质(MIS)的生长因子， 和几种转化生长因子β(TGF-β)(1-16)。 激活素是一种同源二聚体：β蛋白，抑制素是一种异二聚体 α：含有β亚基的β蛋白(βA或BETAB激活素) 这两种蛋白质共有(1-3)。激活素和抑制素，类似于 这个家族中的其他增长因素被认为是 在许多分化和发育事件中很重要(1-3， 20-22、25、26)。本项目的目标是了解 抑制素和激活素的发育和生理作用。这些 研究将解决激活素是否作为一种 哺乳动物中的中胚层诱导因子，无论每一种激活素β 亚基有不同的发育作用，特别是在大脑中 以及激活素和抑制素是否发挥重要的旁分泌作用， 自分泌和内分泌在脑下垂体和性腺发育中的作用。 在该项目的第一阶段，目标是：1)克隆和 小鼠α抑制素、βA激活素和BETAB激活素的特性 2)利用这些小鼠基因构建载体，用于同源重组 重组实验与胚胎干细胞系的建立 在这些基因上发生突变；3)产生纯合子和 这些突变等位基因的杂合子；以及4)分析形态， 抑制素基因突变的组织学和生化后果， 激活素和BETAB激活素基因座决定激活素和激活素的作用 抑制素在上述发育过程中的作用。 该项目的第二阶段包括：1)进一步的形态， 产生的突变小鼠的组织学和生化特征 在第一阶段；以及2)携带这些不同突变的小鼠的杂交 他们的种系中的等位基因产生了几个基因缺陷的小鼠 激活素和抑制素。

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.