DMRT1 IN MAMMALIAN SEXUAL DEVELOPMENT

DMRT1 在哺乳动物性发育中的作用

• 批准号: 6386428
• 负责人: David A. Zarkower
• 金额: $ 27.83万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386428
• 关键词: DNA binding protein; Klinefelter's syndrome; Turner's syndrome; chromosome deletion; cytogenetics; developmental genetics; gene expression; gene interaction; gene mutation; gene rearrangement; genetic regulation; genetically modified animals; human genetic material tag; human subject; laboratory mouse; protein structure function; sex determination; sex differentiation; tissue /cell culture; transcription factor; yeast two hybrid system

DESCRIPTION: (Adapted from investigator's abstract) The investigator has previously identified a mammalian gene, DMRT1, likely to play a role in sex determination by virtue of its relatedness to both the male abnormal 3 (mab-3) gene of C.elegans and the doublesex (dsx) gene of Drosophila. The investigator originally cloned the mab-3 gene and showed that it plays a role in the well-defined sex development pathway of C. elegans, where it is needed for the formation of male sense organs and to prevent males from making yolk proteins. He also cloned a human relative, DMRT1, which he showed to be testis-specific in adults. The human gene maps to a region of chromosome 9 required for male development. The mouse homologue, Dmrt1, was also cloned and has been shown to be expressed in the embryonic gonad as soon as this tissue begins to form. Mab-3, dsx and DMRT1 all contain one or two DNA binding domains which chelate zinc but are distinct from zinc finger domains. The objective of the proposed work is to test the role of DMRT1/Dmrt1 in human and mouse sex determination. The first aim will test whether sex-reversed people, XY female and XX males, have mutations in the DMRT1 gene. The second aim is to knock out the Dmrt1 gene in mouse and test the consequences on sexual development and on expression of other sex determining genes. The third aim is to investigate the DNA binding and transcriptional regulatory properties of Dmrt1 both in vitro and in cultured cells, to test whether it physically interacts with other sex determining proteins, and to ask what genes it regulates.

描述：（根据调查员的摘要改编） 研究者以前已经确定了哺乳动物基因DMRT1， 可能会凭借其在性别决定中发挥作用 与C.级的雄性异常3（MAB-3）基因的相关性 和果蝇的Doublesex（DSX）基因。调查员 最初将MAB-3基因克隆，并表明它在 秀丽隐杆线虫的定义明确的性发展途径 形成男性感觉器官并防止男性所需的 从制作蛋黄蛋白。他还克隆了一个人的亲戚DMRT1， 他在成年人中表明这是特定于睾丸的。人类基因 向男性发育所需的9染色体区域的地图。这 小鼠同源物DMRT1也被克隆，已被证明是 该组织开始在胚胎性腺中表达 形式。 MAB-3，DSX和DMRT1都包含一个或两个DNA结合 螯合锌但不同于锌指的域 域。 拟议工作的目的是测试 人和小鼠性别确定中的DMRT1/DMRT1。第一个目标 将测试以性转向的人，XY女性和XX男性是否有 DMRT1基因中的突变。第二个目的是淘汰 小鼠中的DMRT1基因并测试对性发展的后果 以及其他性别确定基因的表达。第三个目标是 研究DNA结合和转录调节 DMRT1在体外和培养细胞中的特性，以测试 它是否与其他性别确定 蛋白质，并询问其调节的基因。