Molecular Mechanisms of Gonadotrope Differentiation

促性腺激素分化的分子机制

• 批准号: 7637860
• 负责人: PAMELA L MELLON
• 金额: $ 30.51万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637860
• 关键词: Anterior Pituitary Gland; Appearance; BHLH Protein; Binding Proteins; Bioinformatics; Cell Line; Cell Lineage; Cell model; Cells; Chromatin; Coupled; DNA-Binding Proteins; Development; Dominant-Negative Mutation; Endocrine; Equilibrium; Family; Follicle Stimulating Hormone; Friends; Gene Expression; Gene Targeting; Genes; Genetic Programming; Genomics; Goals; Gonadotrope Cell; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Growth; Helix-Turn-Helix Motifs; Homeodomain Proteins; Homeostasis; Hormones; Indium; Individual; Lactation; Location; Luteinizing Hormone; Methods; Molecular; Molecular Genetics; Nuclear Orphan Receptor; Occupations; Pattern; Phenotype; Physiological; Pituitary Gland; Process; Proteins; Psyche structure; Regulation; Reproduction; Role; SF1; Staging; Thyrotropin; Time; Transgenic Mice; beta Subunit Follicle Stimulating Hormone; biological adaptation to stress; cell type; genetic manipulation; genetic regulatory protein; genome-wide; helix-loop-helix protein differentiation inhibitor; homeodomain; immortalized cell; in vivo; innovation; member; novel; pituitary gland development; programs; reproductive function; response; tumorigenesis

DESCRIPTION: The anterior pituitary synthesizes hormones that control reproduction, homeostasis, growth, stress response, and lactation. Since each of these physiological responses must be regulated independently, individual pituitary endocrine cell types are specialized to produce distinct hormones. During development, each cell lineage arises in a unique spatial and temporal pattern. The gonadotrope, which regulates reproductive function through the synthesis of the gonadotropins Luteinizing Hormone (LH) and Follicle- Stimulating Hormone (FSH), arises last in this process, as defined by the appearance of the beta subunits of its hallmark proteins. However, its emergence can be traced throughout pituitary development by the sequential appearance of earlier markers of the lineage, first the alpha subunit shared by LH, FSH and Thyroid-Stimulating Hormone, followed by the orphan nuclear receptor Steroidogenic Factor 1, then Gonadotropin-Releasing Hormone Receptor, and finally the LH beta and FSH beta subunits. Using targeted tumorigenesis in transgenic mice, we have developed immortalized cell lines that represent sequential developmental stages of the gonadotrope lineage and the closely related thyrotrope. Utilizing these novel cell models coupled with genetic manipulation in vivo, we propose to elucidate the program of regulators involved in the progression of differentiation to the mature gonadotrope. In the first three aims, we will focus on three select classes of regulatory factors, GATA-binding proteins, basic helix-loop-helix proteins, and LIM-homeodomain proteins. Members of each family are known to directly regulate gonadotropin subunit genes and to be involved in specification of pituitary lineages; however, the balance, interplay, and timing of their actions and those of their co-factors remain to be delineated. These DNA- binding proteins and their associated co-regulators are themselves regulated during lineage progression. Our hypothesis is that programs of closely related factors and their associated co-regulators sequentially occupy control elements in gonadotrope target genes to determine lineage progression and maturation. In the fourth aim, we will take an unbiased approach to defining the mature gonadotrope phenotype at the molecular level, utilizing innovative bioinformatic and molecular methods to identify key components of the gonadotrope differentiation program.

描述：垂体前叶合成控制生殖、体内平衡、生长、应激反应和哺乳的激素。由于每种生理反应都必须独立调节，因此各个垂体内分泌细胞类型专门产生不同的激素。在发育过程中，每个细胞谱系都以独特的空间和时间模式出现。促性腺激素通过合成促性腺激素黄体生成激素 (LH) 和卵泡刺激激素 (FSH) 来调节生殖功能，根据其标志蛋白 β 亚基的出现定义，促性腺激素在此过程中最后出现。然而，它的出现可以在整个垂体发育过程中通过谱系早期标记的连续出现来追踪，首先是 LH、FSH 和促甲状腺激素共享的 α 亚基，然后是孤儿核受体类固醇生成因子 1，然后是促性腺激素释放因子激素受体，最后是 LH β 和 FSH β 亚基。利用转基因小鼠的靶向肿瘤发生，我们开发了代表促性腺素谱系和密切相关的促甲状腺素的连续发育阶段的永生化细胞系。利用这些新颖的细胞模型与体内遗传操作相结合，我们建议阐明参与分化为成熟促性腺激素的调节程序。在前三个目标中，我们将重点关注三类选定的调节因子：GATA 结合蛋白、碱性螺旋-环-螺旋蛋白和 LIM-同源域蛋白。已知每个家族的成员直接调​​节促性腺激素亚基基因并参与垂体谱系的规范；然而，它们及其辅助因素的行动的平衡、相互作用和时机仍有待描述。这些 DNA 结合蛋白及其相关的辅助调节因子本身在谱系进展过程中受到调节。我们的假设是，密切相关的因子及其相关的共同调节因子的程序依次占据促性腺激素靶基因中的控制元件，以确定谱系进展和成熟。在第四个目标中，我们将采取公正的方法在分子水平上定义成熟的促性腺激素表型，利用创新的生物信息学和分子方法来确定促性腺激素分化计划的关键组成部分。