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

项目总结 不同细胞群之间的细胞-细胞通讯，特别是生殖系和体细胞之间的通讯 开发有功能的鸡蛋的关键。果蝇生殖系-胞体相互作用的中心 模型是Notch途径，它在卵子发生过程中的一系列重大事件中发挥关键作用。 确定Notch信号如何调节不同的细胞过程是理解 卵子发生的调控。另一方面，卵巢模型提供了一个很好的平台来发现小说 这条臭名昭著的重要途径的调节机制，在发育、组织中起着至关重要的作用 动态平衡与多种人类疾病的发病机制。尽管经过了多年的研究，仍然有 这一领域有大量的未知数。例如，Notch如何在不同的环境中调节生长 发育或病理背景，细胞周期机制如何反馈调节Notch 途径和环境压力如何影响发育和组织中的信号输出 动态平衡。这项提议旨在利用遗传上易驯化的果蝇来解决这些问题 卵巢模型系统。 拟议的研究是基于一系列先前的发现和初步结果。我们有 研究表明，Notch信号通过将毛囊细胞从有丝分裂周期切换到有丝分裂周期来诱导细胞分化 内复制周期，从而限制细胞的增殖。有趣的是，当结合细胞极性的丧失时 LGL基因，我们发现Notch促进了毛囊细胞上皮的组织生长。我们还发现了那根绳子 CDC25同系物(STG)调节一种活性形式的Notch的核通路，即细胞内的Notch 域(NICD)。此外，我们还发现，毛囊细胞中Notch的过度激活会导致细胞死亡和 生殖系细胞通过吞噬而退化。这些发现为我们提供了进一步 探索生殖系和体细胞发育在正常发育期间和 环境压力，并了解Notch信号如何调节不同种类的植物的生长和存活 生物和病理条件。以下三个具体目标将通过卵巢实现 模型1.以确定Notch如何在不同的遗传背景下调节组织生长。2.确定 CDC25/STRING如何调节NICD核通路以影响Notch信号。以及3.确定如何 毛囊细胞中Notch活性上调可导致生殖细胞死亡。这些目标的成功实现将 有助于更好地理解Notch信号的不同作用和调节机制 发育和组织动态平衡。拟议中的研究结果将有助于设计新的 Notch信号异常相关疾病的治疗策略。

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.