TRANSCRIPTIONAL REGULATION OF GONADOTROPIN BETA SUBUNITS DURING DEVELOPMENT

发育过程中促性腺激素β亚基的转录调控

• 批准号: 6108826
• 负责人: MICHAEL W WOLFE
• 金额: $ 10.81万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108826
• 关键词: chorionic gonadotropin; developmental genetics; follicle stimulating hormone; gene expression; genetic promoter element; genetic transcription; genetically modified animals; gonadotropin releasing factor; gonadotropins; hormone regulation /control mechanism; laboratory mouse; luteinizing hormone; nucleic acid sequence; pituitary gland; reporter genes

The gonadotropins, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and chorionic gonadotropin (CG), are essential to mammalian reproduction. LH and FSH are synthesized and secreted from the anterior pituitary gland function to regulate gonadal gametogenesis and steroidogenesis, while CG is synthesized and secreted from the placenta and has a role in maintaining pregnancy. The gonadotropins are heterodimeric glycoprotein hormones composed of a common alpha-subunit noncovalently linked to a unique beta-subunit. A considerable amount of attention has been focused on regulation of expression of the alpha- subunit gene, however, little is known about the mechanisms that regulate expression of the gonadotropin beta-subunits. This has been due to a lack of cell lines that express gonadotropin beta-subunits. Transgenic mice have proven to be extremely valuable for the study of the alpha-subunit and recently have been reported to be a useful model in which to investigate regulation of the beta-subunits. These studies have examined transgene expression in adult mice, but have failed to address spatiotemporal expression patterns. The overall goal of the present proposal is to identify regions in the LHbeta and FSHbeta proximal promoters that direct the appropriate spatiotemporal pattern of expression in transgenic mice. Accordingly, experiments have been proposed to: 1) identify the segment of the equine LH/CGbeta-subunit gene that directs the correct spatial and temporal pattern of expression in the pituitary and to determine whether this region of the gene is also responsible for GnRH regulation of gene expression, and 2) define a small region of the ovine FSHbeta-subunit proximal promoter that retains the correct temporal pattern of gonadotrope-specific expression. Transgenes will be evaluated in adult mice for gonadotrope-specific expression and during embryonic development for the correct onset of expression as well as gonadotrope-specific expression. This segment of proximal promoter must then contain the DNA response elements responsible for directing the correct pattern of gene expression. These promoter fragments will subsequently serve as valuable test constructs in which the physiological relevance of various cis- elements can be evaluated. Several such elements have been identified in the eLH/CGbeta and oFSHbeta proximal promoters and await such testing. The functional significance of these putative elements in the oFSHbeta gene have not been determined.

促性腺激素、促黄体生成素（LH）、促卵泡激素 (FSH)和绒毛膜促性腺激素（CG），是哺乳动物 生殖 LH和FSH由前额叶合成和分泌， 脑下垂体调节性腺配子发生的功能， 类固醇生成，而CG是从胎盘合成和分泌的 并在维持妊娠中发挥作用。 促性腺激素是 由共同的α-亚基组成的异二聚体糖蛋白激素 与独特的β亚基非共价连接。 相当数量的 人们的注意力集中在α- 然而，对于亚基基因的调节机制知之甚少。 促性腺激素β亚基的表达。 这是由于缺乏 表达促性腺激素β亚单位的细胞系。 转基因小鼠 已被证明是非常有价值的研究的α-亚基 最近被报道是一个有用的模型， 研究β亚基的调节。 这些研究检查了 转基因表达在成年小鼠，但未能解决 时空表达模式 本提案的总体目标是确定联合国系统内的区域， LH β和FSH β近端启动子，其指导适当的 在转基因小鼠中表达时空模式。 因此，委员会认为， 已经提出了以下实验：1）识别马的节段 LH/CG β亚基基因，指导正确的空间和时间 垂体中的表达模式，并确定这是否 该基因的一个区域也负责GnRH对基因的调节， 表达，和2）定义绵羊FSH β亚基的小区域 保持正确的时间模式的近端启动子 促性腺激素特异性表达。 将在成人中评价转基因 小鼠促性腺激素特异性表达和胚胎发育期间 对于表达的正确开始以及促性腺激素特异性 表情 然后，近端启动子的这一片段必须包含DNA 负责指导基因正确模式的反应元件 表情 这些启动子片段随后将作为有价值的 测试构建体，其中各种顺式- 可以对元素进行评估。 若干这样的要素已在 eLH/CG β和oFSH β近端启动子，并等待这样的测试。 这些推定元件在oFSH β中的功能意义 基因尚未确定。