Dmrt1 in mammalian sexual development

Dmrt1 在哺乳动物性发育中的作用

• 批准号: 7887488
• 负责人: David A. Zarkower
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887488
• 关键词: 129/Sv Mouse; Adult; Binding; Body part; Cell Differentiation process; Cells; Chromosome Deletion; DNA; DNA Binding; Data; Defect; Development; Diagnosis; Embryo; Engineering; Failure; Family; Female; Fertility; Gametogenesis; Gene Family; Gene Targeting; Genes; Genetic; Germ Cells; Germ Lines; Gonadal Disorders; Health; Hormones; Human; Incidence; Infertility; Lead; Life; Maintenance; Malignant neoplasm of testis; Medical; Modeling; Molecular Profiling; Mouse Strains; Mus; Mutant Strains Mice; Neonatal; Pattern; Phenotype; Play; Process; Production; Proteins; Regenerative Medicine; Reproduction; Role; Sexual Development; Site; Somatic Cell; Source; Spermatocytic Seminoma; Spermatogenesis; Spermatogonia; Staging; Stem cells; Supporting Cell; System; Techniques; Testicular Teratoma; Testing; Testis; Therapeutic Uses; Transcription Repressor/Corepressor; Vertebrates; Work; base; cell type; chemotherapy; chromatin immunoprecipitation; chromosome 9p deletion syndrome; innovation; mRNA Expression; male; mouse model; mutant; novel; null mutation; pluripotency; prevent; research study; restoration; self-renewal; sertoli cell; sex; sperm cell; therapeutic cloning

DESCRIPTION (provided by applicant): The 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. We discovered the Dmrt family of conserved transcriptional regulators and have shown that several DMRT proteins are important for gonadal development in vertebrates. Loss of DMRT1 causes severe defects in testis development and, in humans, is associated with male-to- female sex reversal. Recently we found that Dmrt1 is required in the 129/Sv mouse strain to control germ cell pluripotency, preventing these cells from forming other cell types of the body rather than sperm. The main hypothesis of this proposal is that Dmrt1 plays a central role in controlling germ line stem cells, acting at different stages both in the stem cells themselves and in surrounding support cells called Sertoli cells. We have four aims. Aim 1 asks how DMRT1 controls germ cell pluripotency in the embryo. We will identify changes in Dmrt1 mutant embryonic germ cells as they lose their normal fate commitment, determine whether Dmrt1 controls this process in the germ cells or the Sertoli cells, and identify candidate regulators of germ cell pluripotency. Aim 2 tests the function of DMRT1 during adult spermatogenesis, focusing on adult germ line stem cells. We will use an innovative genetic strategy to determine the role of Dmrt1 in adult germ line stem cells. Aim 3 seeks to illuminate the function of DMRT1 by identifying the genes it directly regulates in the neonatal testis. Aim 4 tests the hypothesis that Dmrt1 acts with the adjacent Dmrt3 gene to coordinately direct embryonic testis development, assessing the phenotype of Dmrt3 and Dmrt1Dmrt3 double mutants on sensitized genetic backgrounds. This will provide a mouse model for human sex-reversing deletions that remove the two genes. The work we propose is highly relevant to human health. DMRT1 is implicated in human infertility, in testicular dysgenesis, and in testicular cancer. Our studies may permit better diagnosis and treatment of these conditions. Furthermore, because Dmrt1 plays a role in controlling germ line pluripotency, our work may aid in the use of germ line stem cells for therapeutic cloning and for restoration of fertility after chemotherapy.

描述(由申请人提供)：拟议工作的目标是了解DMRT1基因如何控制睾丸的发育和功能。睾丸有两个基本功能：产生精子，即作为雄性生殖系DNA永生载体的细胞；以及产生荷尔蒙，引导身体其他部位以男性特有的方式发育。我们发现了DMRT家族的保守转录调节因子，并表明DMRT蛋白在脊椎动物的性腺发育中起重要作用。DMRT1的缺失会导致严重的睾丸发育缺陷，在人类中，与男性到女性的性逆转有关。最近，我们发现DMRT1在129/Sv小鼠品系中是必需的，以控制生殖细胞的多能性，防止这些细胞形成身体的其他细胞类型，而不是精子。这一建议的主要假设是DMRT1在控制生殖系干细胞方面发挥核心作用，在干细胞本身和周围的支持细胞(称为支持细胞)中都在不同的阶段发挥作用。我们有四个目标。目的1研究DMRT1如何控制胚胎中生殖细胞的多能性。我们将确定DMRT1突变胚胎生殖细胞失去正常命运承诺时的变化，确定DMRT1是在生殖细胞还是在Sertoli细胞中控制这一过程，并确定生殖细胞多能性的候选调节因子。目的2以成体生殖系干细胞为研究对象，检测DMRT1在成体精子发生过程中的功能。我们将使用一种创新的遗传策略来确定DMRT1在成年生殖系干细胞中的作用。目的3通过鉴定DMRT1在新生儿睾丸中直接调控的基因来阐明DMRT1的功能。目的验证DMRT1与相邻DMRT3基因协同指导胚胎睾丸发育的假说，评价Dmrt1和Dmrt1Dmrt3双突变体在致敏遗传背景下的表型。这将为人类性别逆转缺失移除这两个基因提供小鼠模型。 我们建议的工作与人类健康高度相关。DMRT1与人类不育症、睾丸发育不全和睾丸癌有关。我们的研究可能会对这些疾病进行更好的诊断和治疗。此外，由于DMRT1在控制生殖系多能性方面发挥作用，我们的工作可能有助于利用生殖系干细胞进行治疗性克隆和恢复化疗后的生育能力。