DMRT1 IN MAMMALIAN SEXUAL DEVELOPMENT

DMRT1 在哺乳动物性发育中的作用

• 批准号: 2825060
• 负责人: David A. Zarkower
• 金额: $ 27.05万
• 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/2825060
• 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：（改编自研究者摘要） 研究人员先前已经鉴定了哺乳动物基因DMRT 1， 可能在性别决定中发挥作用， 与秀丽隐杆线虫的雄性异常3（mAb-3）基因的相关性 和果蝇的doublemex（dsx）基因。研究者 最初克隆了mAb-3基因，并表明它在以下方面发挥作用： 明确的性发育途径。elegans，它在哪里 男性感觉器官的形成和防止男性 来制造蛋黄蛋白。他还克隆了一个人类亲戚DMRT 1， 他发现这是成年人睾丸特有的。人类基因 映射到男性发育所需的9号染色体区域。的 小鼠同源物Dmrt 1也被克隆，并已被证明是 在胚胎性腺中表达，一旦这个组织开始 form. Mab-3、dsx和DMRT 1均含有一个或两个DNA结合位点 螯合锌但不同于锌指的结构域 域. 拟议工作的目标是测试 DMRT 1/Dmrt 1在人类和小鼠性别决定中的作用第一个目标 将测试性别反转的人，XY女性和XX男性，是否有 DMRT 1基因突变。第二个目标是淘汰 DMRT 1基因在小鼠中的表达及其对性发育的影响 以及其他性别决定基因的表达。第三个目标是 研究DNA结合和转录调控 Dmrt 1在体外和培养细胞中的特性，以测试 它是否与其他决定性别的生物有身体上的相互作用 蛋白质，并询问它调节哪些基因。