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

描述（由申请人提供）：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秀丽隐杆线虫了解性别二态性和性别特异性器官发生的分子基础。PI的总体策略是利用秀丽隐杆线虫定义调节两性二态的保守因子，揭示控制性别特异性发育的机制，然后研究同源因子如何控制小鼠的两性二态。这种独特的方法已经取得了重大进展，例如发现脊椎动物Dmrt1基因，该基因与性别决定、性腺分化、DSD和睾丸癌有关。该应用的主要焦点是主要性别决定基因TRA-1如何在秀丽隐杆线虫中施加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育。在大量前期数据的指导下，本研究的具体目标是：1)通过鉴定受TRA-1调控的基因并解剖其在生殖组织中的功能，来确定TRA-1如何控制性别分化和卵子发生；2)通过分离细胞转录组分析与功能研究相结合，确定器官特异性调节因子如何控制性腺性二态性。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）和细胞类型特异性转录组分析，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，而GLI癌蛋白与人类癌症和出生缺陷有关。此外，性别分化或性腺分化的失败导致人类性别逆转、性别模糊、泌尿生殖畸形、不孕症和性腺癌，这些都是常见和严重的医学疾病，但通常病因不明。这项资助的工作导致脊椎动物DM结构域基因的发现，这些基因与所有这些人类疾病有关。本提案中的研究将继续推进对秀丽隐杆线虫器官发生中保守调控因子如何施加性别特异性的机制理解，并将指导正在进行的哺乳动物研究。

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. PUBLIC HEALTH RELEVANCE: Defects in sexual differentiation are among the most common causes of human birth defects and are closely linked to human cancer. The genes we study in C. elegans that control sexual differentiation have human counterparts known to be involved in birth defects and cancer and we have previously used C. elegans to discover human genes involved in sexual differentiation and cancer. The detailed mechanistic studies we can perform in C. elegans therefore provide new insights into normal human development and human disease.