DMRT1 IN MAMMALIAN SEXUAL DEVELOPMENT

描述：(改编自调查员摘要) 研究人员此前发现了一种哺乳动物基因DMRT1， 可能在性别决定中发挥作用，因为它的 线虫雄性异常3(mab-3)基因的相关性研究 和果蝇的双性(Dsx)基因。调查员 最初克隆了mab-3基因，并表明它在 线虫明确的性发育途径，它在哪里 形成男性感觉器官所需，并防止男性 用来制造蛋黄蛋白。他还克隆了一个人类亲戚DMRT1， 他发现这种基因是成人睾丸所特有的。人类基因 映射到9号染色体上男性发育所需的区域。这个 小鼠的同源物DMRT1也被克隆了，并被证明是 一旦这种组织开始在胚胎性腺中表达 形式。MAb-3、DsX和DMRT1都含有一个或两个DNA结合 螯合锌但不同于锌指的结构域 域名。 拟议工作的目标是测试 DMRT1/DMRT1在人和小鼠性别决定中的作用第一个目标 将测试变性人，XY女性和XX男性，是否有 DMRT1基因突变。第二个目标是击倒 检测DMRT1基因对小鼠性发育的影响 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 DMRT1在体外和培养细胞中的性质测试 它是否与其他性别决定有身体上的相互作用 蛋白质，并询问它调节哪些基因。

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.