Control by tra-1 of Sexual Differentiation in C. elegans

tra-1 控制线虫性别分化

• 批准号: 8641698
• 负责人: David A. Zarkower
• 金额: $ 31.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641698
• 关键词: Affect; Caenorhabditis elegans; Cell Separation; Cells; ChIP-seq; Congenital Abnormality; Data; Defect; Development; Embryo; Etiology; Event; Failure; Foundations; Funding; Future; Gender; Gene Expression Profile; Gene Family; Gene Targeting; Genes; Genitourinary system; Genomics; Goals; Gonadal Dysgenesis; Gonadal structure; Grant; Health; Homologous Gene; Human; Human Development; Infertility; Knowledge; Larva; Learning; Link; Logic; Maintenance; Malignant Neoplasms; Malignant neoplasm of testis; Mammals; Mediating; Medical; Meiosis; Messenger RNA; Mitosis; Molecular; Molecular Genetics; Mus; Muscle; Nematoda; Oncogene Proteins; Oogenesis; Organ; Organogenesis; Pathway interactions; Pattern; Physiology; Play; Primordium; Psychological Impact; Regulatory Pathway; Reporter; Reproductive Biology; Reproductive Physiology; Research; Resources; Role; Sexual Development; Somatic Cell; Specificity; Technology; Tissue Differentiation; Tissues; Translating; Vertebrates; Work; base; cell type; chromatin immunoprecipitation; genome-wide; gonadal cancer; human disease; innovation; insight; male; malformation; postnatal; precursor cell; programs; reproductive; sex; sex determination; sex development disorder; sexual dimorphism; smoothened signaling pathway; sperm cell; transcription factor

DESCRIPTION (provided by applicant): Sexual differentiation is central to normal development and human disease but the molecular mechanisms controlling it remain poorly understood. The long-term goal of this project is to use C. elegans to understand the molecular basis of sexual dimorphism and sex-specific organogenesis. The overall strategy of the PI is to use C. elegans to define conserved factors regulating sexual dimorphism and reveal mechanisms that control sex-specific development, and then examine how homologous factors control sexual dimorphism in mice. This unique approach has yielded major advances such as the discovery of the vertebrate Dmrt1 genes, which are involved in sex determination, gonadal differentiation, DSD, and testicular cancer. The main foci of this application are how the master sex-determining gene TRA-1 imposes sex-specific development and controls oogenesis in C. elegans, and how gonad-specific regulators control early gonadogenesis. Guided by strong preliminary data, the specific aims are 1) to determine how TRA-1 controls sexual differentiation and oogenesis by identifying the genes regulated by TRA-1 and dissecting their functions in reproductive tissues; and 2) to determine how organ-specific regulators control gonad sexual dimorphism by combining isolated cell transcriptome analysis with functional studies. The proposed research will uncover the molecular basis of a critical but poorly understood aspect of development, using innovative approaches and technologies including genome-wide ChIP analysis (ChIP-seq) and cell type-specific transcriptome analysis. This work has direct relevance to human health: TRA-1 is the nematode homolog of the GLI oncoprotein, which is involved in human cancer and birth defects. Furthermore, failure of sexual differentiation or gonadal differentiation causes human sex reversal, sexual ambiguity, urogenital malformation, infertility, and gonadal cancer, which are common and serious medical conditions but usually of unknown etiology. Work funded by this grant led to the discovery of vertebrate DM domain genes, which are involved in all of these human conditions. The studies in this proposal will continue to advance the mechanistic understanding of how conserved regulators impose sex specificity on organogenesis in C. elegans and will instruct ongoing studies in mammals.

描述(申请人提供)：性别分化是正常发育和人类疾病的核心，但控制它的分子机制仍然知之甚少。该项目的长期目标是利用线虫来了解性别二型性和性别特异性器官发生的分子基础。PI的总体策略是使用线虫来定义调节性二型性的保守因子，并揭示控制性特定发育的机制，然后研究同源因素如何控制性二型性。这种独特的方法已经产生了重大的进展，例如发现了脊椎动物的DMRT1基因，这些基因涉及性别决定、性腺分化、DSD和睾丸癌。这一应用的主要焦点是掌握性别决定基因TRA-1如何在线虫中强制性别特异性发育和控制卵子发生，以及性腺特异性调节因子如何控制早期性腺发生。在强大的初步数据的指导下，具体目标是1)通过鉴定TRA-1调控的基因并剖析其在生殖组织中的功能，确定TRA-1如何控制性分化和卵子发生；2)通过分离细胞转录组分析和功能研究相结合，确定器官特异性调节因子如何控制性腺性二型性。这项拟议的研究将利用创新的方法和技术，包括全基因组芯片分析(CHIP-SEQ)和细胞类型特定转录组分析，揭示一个关键但鲜为人知的发展方面的分子基础。这项工作与人类健康直接相关：tra-1是GLI癌蛋白的线虫同源物，GLI与人类癌症和出生缺陷有关。此外，性分化或性腺分化失败会导致人类性别反转、性模糊、泌尿生殖系统畸形、不孕和性腺癌，这些都是常见和严重的疾病，但通常病因不明。由这笔赠款资助的工作导致了脊椎动物DM域基因的发现，这些基因与所有这些人类疾病有关。这项提案中的研究将继续推进对保守调节因子如何在线虫器官发生中强加性别特异性的机械性理解，并将指导正在进行的哺乳动物研究。