PITUITARY GONADOTROPIN GENE REGULATION

垂体促性腺激素基因调控

• 批准号: 3318400
• 负责人: PAMELA L MELLON
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3318400
• 关键词: DNA footprinting; affinity chromatography; cell transformation; clone cells; cytotoxicity; embryo /fetus; estrogen receptors; follicle stimulating hormone; gel electrophoresis; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; gonadotropin releasing factor; gonadotropins; homeobox genes; hormone binding protein; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; luteinizing hormone; molecular cloning; northern blottings; nucleic acid sequence; peptide hormone biosynthesis; pituitary gland; pituitary hormones; progesterone receptors; steroid hormone receptor; transcription factor; transfection

The anterior pituitary plays a central role in the regulation of reproductive function, growth, lactation, stress response, and endocrine homeostasis. The pituitary also serves as an excellent model in which to study the complex molecular interactions involved in development and organogenesis in mammalian systems. The anterior lobe rises from the somatic ectoderm by formation of Rathke's pouch. Within this primitive organ five distinct endocrine cell types arise. These are, in developmental order of appearance: corticotropes which produce pro- opiomelanocortin, thyrotropes which produce thyrotropin-releasing hormone (TSH), gonadotropes which produce both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), somatotropes which produce growth hormone, and lactotropes which produce prolactin. Substantial information is available concerning the molecular events important for regulation of growth hormone and prolactin gene expression; however, much less is known about the determination of pituitary gene expression of the family of glycoprotein hormones, LH, FSH,and TSH. These hormones are heterodimeric proteins composed of a common a subunit and distinct beta subunits encoded by individual gene. The temporal appearance of the individual subunits is not coordinated and indicated that the alpha-subunit gene may be expressed in a common early progenitor cell for all endocrine lineages of the anterior pituitary. Thus, development of the individual cell types may involve independent activation of specific hormone genes coupled with specific restriction of gene expression. The molecular basis of regulation of the LH and FSH genes in gonadotropes could not be effectively investigated heretofore due to lack of appropriate cell lines. Tumors derived by pituitary-specific expression of the SV40 T- antigen oncogene in transgenic mice have allowed us to isolate clonal cell lines representing cells in the developmental lineage of the gonadotrope which express either the common alpha-subunit or both the alpha and LH beta-subunit genes. In this proposal, we investigate three major issues: A. The mechanisms of developmental and tissue-specific control of the gonadotropin genes in pituitary cells, including the roles of both transcriptional activation and restriction in directing unique patterns of gene expression. B. The molecular basis of hormonal regulation of gonadotropin gene expression, with emphasis on induction of gene expression by hypothalamic gonadotropin-releasing hormone and repression by gonadal steroids. C. The molecular events determining the developmental lineage of the gonadotrope in the anterior pituitary, utilizing approaches transgenic mice including targeted immortalization, cell ablation, and ectopic expression of regulatory proteins. These investigations will lead to detailed understanding of the molecular events governing the developmental and hormonal regulation of the gonadotrope and pituitary development.

前垂体在调节中起着核心作用 生殖功能，生长，泌乳，压力反应和内分泌 稳态。 垂体也是一个出色的模型 研究与发育和 哺乳动物系统中的器官发生。 前叶从 通过形成Rathke的小袋的体细胞外胚层。 在这个原始的内部 器官五种不同的内分泌细胞类型。 这些是 外观的发育顺序：产生促进的皮质机体 甲状腺皮质素，产生甲状腺蛋白释放激素的甲状性 （TSH），促性腺激素既产生黄体生成激素（LH），又产生 卵泡刺激激素（FSH），产生生长的生长体 激素和产生催乳素的乳糖。 大量信息 有关分子事件的可用于调节 生长激素和催乳素基因表达； 但是，少得多 关于确定垂体基因的表达 糖蛋白激素，LH，FSH和TSH。 这些激素是异二聚体 由共同的亚基和独特的β亚基编码的蛋白质组成 由个体基因。 单个亚基的时间外观是 不协调，并表明可以表达α-亚基基因 在一个常见的早期祖细胞中，用于所有内分泌谱系 前垂体。 因此，单个细胞类型的开发可能 涉及特定激素基因的独立激活与 基因表达的特定限制。 促性腺体中LH和FSH基因调节的分子基础 由于缺乏合适的 细胞系。 SV40 T-的垂体特异性表达得出的肿瘤 转基因小鼠中的抗原癌基因使我们能够分离克隆细胞 在性腺的发育谱系中代表细胞的线 表达公共α-屈服或α和LH β-亚基基因。 在此提案中，我们调查了三个主要问题： 答：发育和组织特异性控制的机制 垂体细胞中的促性腺激素基因，包括两者的作用 转录激活和指导独特模式的限制 基因表达。 B.激素调节的分子基础 促性腺激素基因表达，重点是诱导基因表达 通过下丘脑性促性腺激素释放激素和性腺抑制 类固醇。 C.确定发育谱系的分子事件 前垂体中的性腺，利用转基因的方法 包括靶向永生，细胞消融和异位的小鼠 调节蛋白的表达。 这些调查将导致 详细了解有关发展的分子事件 促性腺肿瘤和垂体发展的荷尔蒙调节。