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

描述（由申请人提供）：性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。这个项目的长期目标是使用C。elegans了解两性异形和性别特异性器官发生的分子基础。PI的总体策略是使用C。elegans定义保守的因素调节性二型性和揭示机制，控制性别特异性发展，然后检查同源因子如何控制小鼠的性二型性。这种独特的方法已经取得了重大进展，例如发现了脊椎动物Dmrt 1基因，该基因涉及性别决定，性腺分化，DSD和睾丸癌。本研究的主要焦点是性别决定主基因TRA-1是如何在C.以及性腺特异性调节因子如何控制早期性腺发生。在强有力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）通过将分离细胞转录组分析与功能研究相结合，确定器官特异性调控因子如何控制性腺性二型性。拟议的研究将揭示一个关键但知之甚少的发展方面的分子基础，使用创新的方法和技术，包括全基因组ChIP分析（ChIP-seq）和细胞类型特异性转录组分析。这项工作与人类健康直接相关：TRA-1是GLI癌蛋白的线虫同系物，与人类癌症和出生缺陷有关。此外，性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、不育和性腺癌，这些是常见和严重的医学病症，但通常病因不明。这项资助的工作导致了脊椎动物DM结构域基因的发现，这些基因与所有这些人类疾病有关。本研究将继续推进保守调节因子如何在C.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.