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.

生殖和胚胎发育是复杂的过程，涉及 多个基因决定的事件。蛋白质的阐明 参与正常和异常的生殖和早期胚胎 开发是理解这些过程的关键一步。 激活素和抑制素，生长大家族的成员 调节蛋白，包括转化生长因子β， 骨形态发生蛋白和苗勒管抑制物质 涉及在多种组织中发挥内分泌等生理作用， 胚胎和成人生殖过程中的旁分泌和自分泌介质 和发展。特别是，激活素与发挥作用有关。 在中胚层诱导、神经元存活和垂体中发挥重要作用 和性腺功能。 了解激活素在哺乳动物生殖和生殖中的作用 开发中，我采取了多方面的方法来产生转基因 缺乏激活素亚基、激活素 II 型受体和 激活素结合蛋白，卵泡抑素。突变体的种系传播 激活素 betaA、激活素受体 II 和卵泡抑素基因已被 对卵泡抑素缺陷小鼠进行了初步研究，这些小鼠死亡 出生时，表明卵泡抑素在调节激活素中的重要作用 胚胎发育过程中的作用。该提案的目标是 广泛地描述了在这些“损失”中产生的小鼠的表型 功能”实验。与体外测定不同，这些研究将揭示 激活素、激活素受体的基本和生理作用， 和卵泡抑素，特别是解决这些的功能 胚胎发育（例如中胚层诱导）和成人中的蛋白质 生殖生理学（例如垂体性腺稳态）。 这些研究的目的是：1) 描述为什么卵泡抑素缺乏 老鼠出生时就死了； 2) 生成并分析缺乏激活素的小鼠 βA亚基； 3) 生成并分析缺乏激活素类型的小鼠 II受体； 4) 生成并分析多种缺陷的小鼠 激活素亚基（betaA 和 betaB 亚基）或激活素受体（II 型 和IIB）通过杂交来评估功能冗余。 这些 研究将有助于理解激活素的作用 哺乳动物发育中的配体、受体和结合蛋白 繁殖并将识别一些涉及的关键遗传位点 在这些过程中。