Regulation of oogenesis by nuclear receptor signaling

项目摘要 成体干细胞（SC）是维持组织稳态和修复损伤所必需的。许多 外部刺激如年龄、感染和饮食可影响SC的行为和功能。循环因子 包括类固醇、脂肪酸衍生物和金属，通过核受体（NR）作用以调节 生物体对环境的生理反应。核受体是广泛表达的转录因子 对发育、代谢过程和繁殖至关重要。NR中的突变与 多种癌症类型和代谢性疾病。然而，如何同时行动的任何给定的自然资源， 整合多种器官和细胞类型以调节SC谱系仍然未知。我们的实验室和其他 先前已经表明果蝇卵巢中的NR活性本身调节卵子发生。蜕皮激素 由蜕皮激素受体和超气门组成的异二聚体受体控制GSC的维持， 分裂和GSC后代的分化。此外，蜕皮激素诱导的蛋白78 C是必需的， 建立正确的GSC数量和卵室活力;而EcR和E75是必需的， 通过卵黄发生进行。成年体细胞组织中NR信号传导影响 然而，GSC谱系在很大程度上是未知。我假设HR 4（一种未充分研究的NR）活性是 在生殖系和一个或多个体细胞组织中（通过下游分泌因子）都需要， 控制卵子发生过程中的关键调节检查点。为了验证这一假设，我将（1）识别组织， 需要HR 4活性来影响卵子发生的细胞类型和（2）确定HR 4在卵子发生中的下游靶点。 不同的组织来调节卵子发生。

PROJECT SUMMARY Adult stem cells (SCs) are required to maintain tissue homeostasis and for repair in response to injury. Many external stimuli such as age, infection, and diet can influence SC behavior and function. Circulating factors including steroids, fatty acid derivatives, and metals act through nuclear receptors (NRs) to modulate the physiology of an organism in response to the environment. NRs are widely expressed transcription factors essential for development, metabolic processes, and reproduction. Mutations in NRs are associated with multiple cancer types and metabolic diseases. However, how the simultaneous actions of any given NR in multiple organs and cell types are integrated to regulate SC lineages remains unknown. Our lab and others have previously shown that NR activity in the Drosophila ovary itself regulates oogenesis. The ecdysone heterodimeric receptor composed of the Ecdysone Receptor and Ultraspiracle controls GSC maintenance and division, and differentiation of GSC progeny. In addition, Ecdysone-induced protein 78C is required for establishing the correct GSC number and for egg chamber viability; whereas, EcR and E75 are required for progression through vitellogenesis. The mechanisms whereby NR signaling in adult somatic tissues influence the GSC lineage, however, are largely unknown. I hypothesize that HR4 (an understudied NR) activity is required both in the germline and in one or more somatic tissues (through downstream secreted factors) to control key regulatory checkpoints during oogenesis. To test this hypothesis, I will (1) identify the tissues and cell types that require HR4 activity to influence oogenesis and (2) determine the downstream targets of HR4 in different tissue required to regulate oogenesis.