DMRT1 in Mammalian Sexual Development

DMRT1 在哺乳动物性发育中的作用

• 批准号: 6880095
• 负责人: David A. Zarkower
• 金额: $ 39.55万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880095
• 关键词: chromosome deletion; cytogenetics; developmental genetics; gene mutation; genetic regulation; genetic transcription; genetically modified animals; laboratory mouse; regulatory gene; sex determination; sex differentiation; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): We identified the first widely conserved class of sexual regulatory genes, transcription factors related to the Drosophila doublesex gene. These share a unique zinc finger DNA binding domain we named the DM domain. In the current funding cycle we have investigated the function of Dmrt1, a mammalian member of this gene family. Human DMRT1 maps to a short segment on chromosome 9p that is deleted in testis dysgenesis. We showed that a null mutation in murine Dmrt1 causes severe defects in testis differentiation and causes sex reversal on at least one strain background. Our expression studies in other species showed that Dmrt1 is probably required for testis development in all vertebrates, including those with highly diverged sex determination mechanisms. The objective of the work we propose is to elucidate the mechanisms by which Dmrt1 and two related genes control mammalian gonad development, at both the genetic and molecular levels. We have four aims. In Aim 1, we investigate which of the known sexual regulatory genes Dmrt1 controls in the embryonic gonad. We also will test the function of a related gene, Dmrt3. Dmrt3 is expressed in the embryonic testis and its human homologue, like DMRT1, is affected by sex reversing human 9p deletions. In Aim 2 we search for additional targets of Dmrt1 regulation in the testis, and test which are regulated directly. In Aim 3 we investigate how the Dmrt1 protein controls transcription, testing the functional importance of candidate transcriptional coregulators that specifically interact with Dmrt1. In Aim 4, we investigate the role in gonad development of Dmrt5, an ovary-specific gene related to Dmrt1, testing whether it plays a role in females analogous to that of Dmrt1 in males. Our work will help to reveal the molecular basis of mammalian sexual differentiation and to establish a pathway of regulatory genes. This will also advance our understanding of the etiology of human congenital defects in this critical process.

描述（由申请人提供）：我们确定了与果蝇Doublesex基因有关的第一类性调节基因，转录因子。它们共享一个独特的锌指DNA结合域，我们将DM域命名为DM域。在当前的资金周期中，我们研究了该基因家族的哺乳动物成员DMRT1的功能。人类DMRT1映射到睾丸发病障碍中被删除的9P染色体上的一个短段。我们表明，鼠DMRT1中的无效突变会导致睾丸分化的严重缺陷，并在至少一个菌株背景下引起性逆转。我们在其他物种中的表达研究表明，所有脊椎动物的睾丸发育可能是必需的，包括具有高度分歧性的性别确定机制的DMRT1。 我们提出的工作的目的是阐明DMRT1和两个相关基因控制遗传和分子水平的哺乳动物性腺发育的机制。 我们有四个目标。在AIM 1中，我们研究了胚胎性腺中哪些已知的性调节基因DMRT1对照。我们还将测试相关基因DMRT3的功能。 DMRT3在胚胎睾丸中表达，其人类同源物（如DMRT1）受到性逆转人类9p缺失的影响。在AIM 2中，我们搜索睾丸中DMRT1调节的其他目标，并直接进行调节。在AIM 3中，我们研究了DMRT1蛋白如何控制转录，测试了特异性与DMRT1相互作用的候选转录核心节目的功能重要性。在AIM 4中，我们研究了DMRT5的性腺发育中的作用，DMRT5是与DMRT1相关的卵巢特异性基因，测试它是否在男性类似于DMRT1的女性中起作用。我们的工作将有助于揭示哺乳动物性别分化的分子基础，并建立调节基因的途径。这也将使我们在这个关键过程中对人类先天性缺陷的病因的理解。