DMRT1 in mammalian sexual development

DMRT1在哺乳动物性发育中的作用

• 批准号: 8403013
• 负责人: David A. Zarkower
• 金额: $ 45.83万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403013
• 关键词: Address; Adult; Binding; Biochemical; Biological Process; Body part; Cell Communication; Cells; Clinic; Commit; Contraceptive methods; DNA; DNA Binding; Data; Development; Diagnosis; Down-Regulation; Etiology; Family; Female; Funding; Gametogenesis; Gene Family; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Germ; Germ Cell Cancers; Germ Cells; Germ Lines; Germ cell tumor; Gonadal Disorders; Gonadal structure; Health; Hormones; Human; Infertility; Knowledge; Life; Link; Maintenance; Male Contraceptive Agents; Malignant Neoplasms; Malignant neoplasm of testis; Mammals; Mediator of activation protein; Medical; Meiosis; Mitosis; Modeling; Molecular Genetics; Mus; Organ; Orthologous Gene; Ovary; Population; Prevention; Process; Production; Prophase; Regulation; Reproduction; Rest; Role; Sex Differentiation Disorders; Sexual Development; Spermatocytes; Spermatogenesis; Spermatogonia; Stem cells; Supporting Cell; Technology; Testicular Germ Cell Tumor; Testing; Testis; Tracer; Transgenes; Translations; Vertebrates; Work; chromatin immunoprecipitation; design; fetal; gain of function; genome-wide; gonadal cancer; granulosa cell; mRNA Expression; male; microdeletion; mutant; novel; overexpression; pluripotency; postnatal; prevent; progenitor; research study; sertoli cell; sex; sex determination; sperm cell; stem; stem cell therapy; steroid hormone; tool; transdifferentiation

DESCRIPTION (provided by applicant): The overall objective of the proposed work is to understand how the Dmrt1 gene controls development and function of the testis. The testis has two essential functions: production of sperm, the cells that serve as vehicles for the immortality of male germ line DNA; and production of hormones that direct other parts of the body to develop in a male-specific manner. Dmrt1 belongs to family of conserved transcriptional regulators and controls multiple critical processes in the mammalian testis. This work has direct human health relevance: loss of DMRT1 in humans is associated with male-to-female sex reversal, disorders of sexual differentiation (DSD), infertility, and testicular germ cell tumors (TGCTs). In mice Dmrt1 controls germ cell pluripotency in the fetal gonad and controls the mitosis/meiosis decision in adults. A new discovery is that testis determination must be actively maintained postnatally by Dmrt1 and that Dmrt1 mutant testes undergo massive postnatal reprogramming to become ovary-like organs. This proposal has three aims focused on deepening our understanding of how DMRT1 controls key processes in the testis. Aim 1 asks how DMRT1 prevents transdifferentiation in the postnatal testis. This is a newly discovered and unstudied biological process. The proposed experiments use conditional gene targeting approaches to ask whether DMRT1 prevents reactivation of the fetal sex determination network postnatally, identify new regulators of postnatal sex maintenance, and use ChIP-seq to identify genes that are bound by DMRT1 in the mouse and human testis. Aim 2 tests the hypothesis that DMRT1 is critical for the transition from spermatogonia stem cell to committed progenitor cell, using precisely controlled loss- and gain-of-function approaches. Aim 3 will determine how DMRT1 is inactivated as spermatogonia transition from mitosis to meiosis and will test the consequences when this fails to occur. The results of this study should aid in treatment of gonadal cancer and infertility, and will inform studies of cell fate reprogramming and design of novel male contraceptives.

描述（由申请人提供）：拟议工作的总体目标是了解DMRT1基因如何控制睾丸的发展和功能。睾丸具有两个基本功能：精子的产生，这些细胞是雄性生殖系DNA永生的车辆；以及激素的产生，这些激素指导身体的其他部位以男性特异性方式发展。 DMRT1属于保守的转录调节剂家族，并控制哺乳动物睾丸中的多个关键过程。这项工作具有直接的人类健康相关性：人类中DMRT1的丧失与男性到女性的性逆转，性别分化的疾病（DSD），不育和睾丸生殖细胞肿瘤（TGCT）有关。在小鼠中，DMRT1控制胎儿性腺中的生殖细胞多能性，并控制成人的有丝分裂/减数分裂决定。一个新的发现是，睾丸确定必须在产后通过DMRT1积极维持，并且DMRT1突变睾丸经过大量的产后重编程，以成为卵巢样器官。该提案的三个目的是加深我们对DMRT1如何控制睾丸中的关键过程的理解。 AIM 1询问DMRT1如何阻止产后睾丸中的转变。这是一个新发现且未研究的生物学过程。提出的实验使用条件基因靶向方法询问DMRT1是否会在产后出现胎儿性别确定网络的重新激活，识别出生后性别维持的新调节剂，并使用CHIP-SEQ识别小鼠和人类睾丸中受DMRT1绑定的基因。 AIM 2检验了以下假设：DMRT1对于使用精确控制的损失和功能获得的方法，对于从精子细胞到犯的祖细胞的过渡至关重要。 AIM 3将确定DMRT1是如何将其灭活的，因为精子从有丝分裂到减数分裂的过渡，并将在未能发生时测试后果。这项研究的结果应有助于治疗性腺癌和不育，并将为细胞命运的重新编程和新型男性避孕药设计提供信息。