FUNCTIONAL ANALYSIS OF ACTIVINS DURING DEVELOPMENT

发育过程中激活素的功能分析

• 批准号: 2204985
• 负责人: MARTIN M. MATZUK
• 金额: $ 25.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-17 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2204985
• 关键词: electron microscopy; gene expression; genetically modified animals; hormone binding protein; hormone receptor; immunocytochemistry; in situ hybridization; inhibin; laboratory mouse; lethal genes; mammalian embryology; mesoderm; northern blottings; phenotype; pituitary gonadal axis; protein structure function; reproductive development

Reproduction and embryonic development are complex processes involving multiple genetically determined events. The elucidation of the proteins involved in normal and abnormal reproductive and early embryonic development is a critical step in the understanding of these processes. The activins and the inhibins, members of a large family of growth regulatory proteins that includes the transforming growth factors beta's, bone morphogenetic proteins, and Mullerian inhibiting substance, have been implicated to play physiologic roles in multiple tissues as endocrine, paracrine, and autocrine mediators during embryonic and adult reproduction and development. In particular, activins have been implicated to play important roles in mesoderm induction, neuronal survival, and pituitary and gonadal function. To understand the roles of the activins in mammalian reproduction and development, I have taken a multifaceted approach to generate transgenic mice deficient in the activin subunits, activin type II receptors, and the activin binding protein, folIistatin. Germline transmission of mutant activin betaA, activin receptor II, and foIlistatin genes has already been achieved initial investigations of follistatin-deficient mice, which die at birth, indicate an essential role for follistatin in modulating activin action during embryonic development. The goal of this proposal is to extensively characterize the phenotype of mice generated in these "loss of function" experiments. Unlike in vitro assays, these studies will reveal the essential and physiologic roles of the activins, activin receptors, and follistatin, and in particular will address the functions of these proteins in embryonic development (e.g., mesoderm induction) and in adult reproductive physiology (e.g., pituitary-gonadal homeostasis). The aims of these studies are: 1) Characterize why follistatin-deficient mice die at birth; 2) Generate and analyze mice deficient in the activin betaA subunit; 3) Generate and analyze mice deficient in the activin type II receptor; and 4) Generate and analyze mice deficient in multiple activin subunits (betaA and betaB subunits) or activin receptors (type II and IIB) by interbreeding to evaluate functional redundancy. These studies will facilitate the understanding of the roles of the activin ligands, receptors, and binding protein in mammalian development and reproduction and will identify some of the critical genetic loci involved in these processes.

繁殖和胚胎开发是涉及复杂的过程 多个遗传确定的事件。阐明蛋白质 参与正常和异常生殖和早期胚胎 发展是对这些过程的理解的关键一步。 激活素和抑制素，大量生长家庭的成员 调节蛋白包括转化增长因子β的蛋白质， 骨形态发生蛋白质和穆勒抑制物质已经是 与内分泌中的多个组织中发挥生理作用有关 胚胎和成人繁殖期间的旁分泌和自分泌介质 和发展。特别是，激活素已被牵涉到玩耍 在中胚层诱导，神经元存活和垂体中的重要作用 和性腺功能。 了解激活素在哺乳动物繁殖中的作用和 开发，我采取了多方面的方法来产生转基因 小鼠缺乏激活素亚基，激活素II型受体和 激活素结合蛋白叶状蛋白。突变的种系传输 激活蛋白βA，激活素受体II和箔蛋白基因已经是 对卵泡缺陷的小鼠进行了初步研究，这些小鼠死了 出生时，表明Follistatin在调节激活素中的重要作用 胚胎发育过程中的作用。该提议的目的是 广泛地表征了这些“丢失的小鼠的表型 功能”实验。与体外测定不同，这些研究将揭示 激活素受体的必不可少的和生理作用， 和follistatin，特别是将解决这些功能 胚胎发育中的蛋白质（例如中胚层诱导）和成人 生殖生理学（例如垂体 - 基达尔体内平衡）。 这些研究的目的是：1）表征为什么缺乏follistatin 小鼠出生时死亡； 2）生成和分析小鼠缺乏激活素 betaa亚基； 3）生成和分析小鼠缺乏激活素类型 II受体； 4）生成和分析多个缺乏的小鼠 激活素亚基（βA和BETAB亚基）或激活素受体（II型 和IIB）通过杂交评估功能冗余。 这些 研究将有助于理解激活素的作用 配体，受体和结合蛋白在哺乳动物发育和 繁殖，并将确定涉及的一些关键遗传基因座 在这些过程中。