PITUITARY GONADOTROPIN GENE REGULATION

垂体前叶在调节脑血管紧张素转换酶活性中起着中心作用。 生殖功能、生长、哺乳、应激反应和内分泌 动态平衡。脑下垂体也是一个很好的模型，在这个模型中 研究发育和发育中涉及的复杂分子相互作用 哺乳动物系统中的器官发生。前叶从前叶升起 由Rathke囊形成的体细胞外胚层。在此原语中 器官出现了五种不同的内分泌细胞类型。这些是，在 出现的发育顺序：产生促肾上腺皮质激素的皮质激素 阿片黑素皮质素，产生促甲状腺激素释放激素的促甲状腺激素 促性腺激素(TSH)，促性腺激素产生黄体生成素(L H)和 卵泡刺激素(FSH)，一种能产生生长的生长激素 荷尔蒙，以及产生催乳素的催乳素。实质性信息 是关于分子事件的重要调节的 生长激素和催乳素基因的表达；然而，我们知道的要少得多 关于家系垂体腺基因表达的测定 糖蛋白激素、黄体生成素、卵泡刺激素和促甲状腺激素。这些激素是异二聚体。 由共同的a亚基和不同的β亚基组成的蛋白质 由个体基因决定。各个亚基的时间外观为 不协调，表明α-亚基基因可能表达 在一个共同的早期祖细胞中，所有的内分泌血统 脑下垂体前叶。因此，各个细胞类型的发育可以 涉及特定荷尔蒙基因的独立激活 基因表达的特定限制。 促性腺激素中促黄体生成素和卵泡刺激素基因调控的分子基础 迄今为止，由于缺乏适当的调查，无法进行有效的调查 细胞系。脑垂体特异性表达SV40 T-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 代表促性腺激素发育谱系中的细胞的系 它们要么表达共同的阿尔法亚单位，要么同时表达阿尔法和黄体生成素 β亚单位基因。在这项建议中，我们调查了三个主要问题： A.发育和组织特异性控制的机制 促性腺激素基因在垂体细胞中的作用 转录激活和限制在指导独特的模式 基因表达。B.激素调节的分子基础 促性腺激素基因表达，重点是基因表达的诱导 下丘脑促性腺激素释放激素与性腺抑制 类固醇。C.决定胚胎发育谱系的分子事件 利用转基因途径在垂体前叶促性腺激素 小鼠包括靶向永生化、细胞消融和异位 调节蛋白的表达。这些调查将导致 对控制发育的分子事件有详细的了解 以及激素对促性腺激素和脑下垂体发育的调节。

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.