PITUITARY GONADOTROPIN GENE REGULATION

脑垂体前叶在调节 生殖功能、生长、泌乳、应激反应和内分泌 体内平衡 脑垂体也是一个很好的模型， 研究发育过程中复杂的分子相互作用， 哺乳动物系统中的器官发生。 前叶从 通过Rathke囊形成的体细胞外胚层。 在这个原始的 五种不同的内分泌细胞类型出现。 这些是，在 外观的发育顺序：产生促皮质激素的促皮质激素， 阿黑皮素，产生促甲状腺激素释放激素的促甲状腺激素 (TSH)促性腺激素，产生促黄体激素（LH）和 促卵泡激素（FSH），产生生长的促生长素 激素和产生催乳素催乳素。 大量资料 是关于重要的调节分子事件， 生长激素和催乳素基因表达;然而， 关于垂体基因表达的测定 糖蛋白激素LH、FSH和TSH。 这些激素是异二聚体 由共同的α亚基和不同的β亚基组成的蛋白质， 个体基因。 单个亚单位的时间外观是 不协调，表明α-亚基基因可以表达 在所有内分泌谱系的共同早期祖细胞中， 前叶 因此，单个细胞类型的发育可能 涉及特定激素基因的独立激活， 基因表达的特异性限制。 促性腺激素细胞LH和FSH基因调控的分子基础 由于缺乏适当的 细胞系 通过SV 40 T-1的垂体特异性表达衍生的肿瘤 抗原癌基因的转基因小鼠，使我们能够分离克隆细胞， 代表促性腺细胞发育谱系中的细胞的线 其表达共同的α亚基或α和LH两者， β亚基基因。 在本提案中，我们调查了三个主要问题： A. 植物的发育和组织特异性调控机制 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，重点是诱导基因表达 下丘脑促性腺激素释放激素和性腺抑制 类固醇. C.决定发育谱系的分子事件 垂体前叶促性腺激素，利用转基因方法 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 详细了解控制发育的分子事件 以及促性腺激素和垂体发育的激素调节。

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.