Regulation of oogenesis by nuclear receptor signaling

项目总结 成体干细胞(SCs)是维持组织内环境稳定和修复损伤所必需的。许多 年龄、感染和饮食等外部刺激会影响SC的行为和功能。流通领域因素 包括类固醇、脂肪酸衍生物和金属，通过核受体(NRs)调节 生物体对环境作出反应的生理学。NRs是广泛表达的转录因子 对发育、新陈代谢过程和生殖都是必不可少的。NRS中的突变与 多种癌症类型和代谢性疾病。然而，任何给定的NR的同时作用如何 多种器官和细胞类型的整合对SC谱系的调控尚不清楚。我们的实验室和其他人 以前已经表明，果蝇卵巢中的NR活性本身就调节卵子的发生。蜕皮激素 由蜕皮激素受体和超级阿司匹林组成的异二聚体受体控制GSC的维持和 GSC后代的分裂和分化。此外，蜕皮激素诱导的蛋白78C还需要 建立正确的GSC编号和卵室存活率；而ECR和E75是 通过卵黄发生的进展。成体组织中NR信号影响机制的研究进展 然而，GSC的血统在很大程度上是未知的。我假设HR4(一种未被研究的NR)活动是 在种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控检查点。为了验证这一假设，我将(1)确定组织和 需要HR4活性来影响卵子发生的细胞类型和(2)确定HR4在 调节卵子发生所需的不同组织。

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.