Notch signaling and germline-soma interactions in the Drosophila ovarian model

项目摘要 不同细胞群之间的细胞间通讯，特别是生殖细胞和体细胞之间的通讯， 是发育出功能性卵子的关键在果蝇生殖细胞-体细胞相互作用的中心 Notch信号通路是卵子发生过程中一系列重要事件的关键通路。 确定Notch信号传导如何调节不同的细胞过程是理解Notch信号传导的基础。 卵子发生的调节另一方面，卵巢模型提供了一个很好的平台， 这一众所周知的重要途径的调节机制，在发育、组织 体内平衡和多种人类疾病的发病机制。尽管经过多年的研究， 这一领域有很多未知数例如，Notch如何调节不同细胞的生长， 发育或病理背景下，细胞周期机制如何反馈调节Notch 以及环境压力如何影响发育和组织过程中的信号输出 体内平衡这项建议旨在解决这些问题，利用遗传上易处理的果蝇， 卵巢模型系统 拟议的研究是基于一系列以前的发现和初步结果。我们有 显示Notch信号通过将卵泡细胞从有丝分裂周期转换到无丝分裂周期来诱导细胞分化。 细胞内复制周期，从而限制细胞增殖。有趣的是，当细胞极性丧失 通过对lgl基因的研究，我们发现Notch促进毛囊上皮细胞中的组织生长。我们还发现String (Stg)，Cdc 25同源物，调节Notch的活性形式的核进入，Notch细胞内 域（NICD）。此外，我们发现，卵泡细胞中Notch的过度激活导致细胞死亡， 通过吞噬作用使生殖细胞退化。这些发现为我们提供了进一步研究的机会。 探索生殖细胞和体细胞的发育如何在正常发育过程中协调， 环境压力，并了解Notch信号如何调节生长和生存在各种 生物和病理条件。以下三个具体目标将使用卵巢 模型1.确定Notch在不同遗传背景下如何调节组织生长。2.以确定 Cdc 25/String如何调节NICD核通路以影响Notch信号传导。和3.以确定如何 毛囊细胞中上调的Notch活性诱导生殖系细胞死亡。成功实现这些目标将 导致对Notch信号传导过程中的不同影响和调节机制的更好理解。 发育和组织稳态。拟议研究的结果将有助于设计新的 用于与异常Notch信号传导相关的疾病的治疗策略。

PROJECT SUMMARY Cell-cell communications among different cell groups, especially between the germline and somatic cells, are key to the development of a functional egg. At the center of germline-soma interactions in the Drosophila model lies the Notch pathway, which plays critical roles in a series of major events during oogenesis. Determining how Notch signaling regulates diverse cellular processes is fundamental to the understanding the regulation of oogenesis. On the other hand, the ovarian model offers an excellent platform to uncover novel regulatory mechanisms of this notoriously important pathway, with roles crucial in development, tissue homeostasis and pathogenesis of a multitude of human diseases. Despite many years of studies, there are still a significant number of unknowns in the field. For example, how Notch regulates growth in different developmental or pathological contexts, how the cell cycle machinery feeds back to modulate the Notch pathway and how environmental stresses impact the signaling output during development and tissue homeostasis. This proposal aims to address these questions using the genetically tractable Drosophila ovarian model system. The proposed studies are based on a series of previous findings and preliminary results. We have shown that Notch signaling induces cell differentiation by switching the follicle cells from the mitotic cycle to an endoreplication cycle, thus restricting cell proliferation. Interestingly, when combined with a loss of cell polarity gene lgl, we found that Notch promotes tissue growth in the follicle cell epithelium. We also found that String (Stg), a Cdc25 homolog, regulates the nuclear access of an active form of Notch, the Notch intracellular domain (NICD). Furthermore, we found that hyperactivation of Notch in follicle cells causes cell death and degeneration of germline cells through phagocytosis. These findings provide us the opportunity to further explore how germline and somatic development are coordinated during normal development and under environmental stresses, and to understand how Notch signaling regulates growth and survival in various biological and pathological conditions. The following three specific aims will be addressed using the ovarian model.1. To determine how Notch regulates tissue growth in different genetic backgrounds. 2. To determine how Cdc25/String regulates NICD nuclear access to impact Notch signaling. And 3. To determine how upregulated Notch activity in follicle cells induces germline cell death. Successful completion of these aims will lead to improved understanding of the diverse effects and regulatory mechanisms of Notch signaling during development and tissue homeostasis. The findings from the proposed studies will help designing new therapeutic strategies for diseases related to aberrant Notch signaling.