Dmrt1 in mammalian sexual development

Dmrt1 在哺乳动物性发育中的作用

• 批准号: 7914044
• 负责人: David A. Zarkower
• 金额: $ 47.58万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914044
• 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）：拟议工作的目的是了解Dmrt 1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，作为男性生殖系DNA永生的载体的细胞;以及产生激素，指导身体的其他部分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，并已表明，几个DMRT蛋白是重要的脊椎动物性腺发育。DMRT 1的缺失会导致睾丸发育的严重缺陷，在人类中，与男性到女性的性别逆转有关。最近，我们发现129/Sv小鼠品系需要Dmrt 1来控制生殖细胞多能性，防止这些细胞形成身体的其他细胞类型而不是精子。该提议的主要假设是，Dmrt 1在控制生殖系干细胞中起着核心作用，在干细胞本身和周围支持细胞（称为Sertoli细胞）的不同阶段起作用。我们有四个目标。目的1询问DMRT 1如何控制胚胎中的生殖细胞多能性。我们将确定Dmrt 1突变胚胎生殖细胞的变化，因为他们失去了正常的命运承诺，确定是否Dmrt 1控制这一过程中的生殖细胞或支持细胞，并确定候选调节生殖细胞多能性。目的2检测DMRT 1在成年人精子发生中的作用，重点是成年生殖系干细胞。我们将使用一种创新的遗传策略来确定Dmrt 1在成体生殖系干细胞中的作用。目的3旨在通过鉴定DMRT 1在新生儿睾丸中直接调控的基因来阐明DMRT 1的功能。目的4验证Dmrt 1与相邻的Dmrt 3基因协同作用指导胚胎睾丸发育的假设，评估Dmrt 3和Dmrt 1-Dmrt 3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提供一个小鼠模型，去除这两个基因。 我们提出的工作与人类健康高度相关。DMRT 1与人类不育、睾丸发育不全和睾丸癌有关。我们的研究可能允许更好地诊断和治疗这些疾病。 此外，由于Dmrt 1在控制生殖系多能性中起作用，我们的工作可能有助于生殖系干细胞用于治疗性克隆和化疗后恢复生育能力。