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

果蝇卵巢模型中的Notch信号传导和种系-体细胞相互作用

• 批准号: 10467652
• 负责人: Wu-Min Deng
• 金额: $ 31.81万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467652
• 关键词: Address; Back; Biological; Biological Models; Biological Process; Cell Communication; Cell Cycle; Cell Death; Cell Differentiation process; Cell Polarity; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Clonal Expansion; Development; Disease; Drosophila genus; Ensure; Environmental Risk Factor; Epithelial Cells; Event; Feedback; Feeds; Genes; Genetic; Growth; Homeostasis; Homologous Gene; MAPK8 gene; Mitotic; Mitotic Cell Cycle; Modeling; Molecular; Notch Signaling Pathway; Nuclear; Oocytes; Oogenesis; Output; Ovarian; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Phagocytes; Phagocytosis; Physiological; Play; Regimen; Regulation; Role; Series; Signal Transduction; Somatic Cell; System; Temperature; Testing; Tissues; Tumor Suppressor Proteins; Up-Regulation; base; cell growth; design; egg; environmental stressor; human disease; improved; neuronal cell body; notch protein; novel; novel therapeutic intervention; programs

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.

项目摘要 不同细胞组之间的细胞电池通信，尤其是种系和体细胞之间 功能性鸡蛋发展的关键。在果蝇的种系瘤相互作用的中心 模型是Notch途径，该途径在卵子发生过程中在一系列重大事件中起着关键作用。 确定Notch信号如何调节各种细胞过程是对理解的基础 卵子发生的调节。另一方面，卵巢模型提供了一个出色的平台来揭示小说 这一臭名昭著的重要途径的调节机制，在发育中至关重要的角色，组织 多种人类疾病的稳态和发病机理。尽管有多年的研究，但仍有 该领域中有大量未知数。例如，Notch如何调节不同的增长 发育或病理环境，细胞周期机械如何反馈以调节缺口 途径以及环境应力如何影响发育和组织期间信号输出 稳态。该提案旨在使用遗传上的果蝇解决这些问题 卵巢模型系统。 拟议的研究基于一系列以前的发现和初步结果。我们有 表明Notch信号传导通过将卵泡细胞从有丝分裂循环切换到一个 内核周期，从而限制了细胞增殖。有趣的是，当结合细胞极性丧失时 Gene LGL，我们发现Notch促进了卵泡细胞上皮的组织生长。我们还发现那个字符串 （STG），一种CDC25同源物，调节了凹槽内的活性形式的核通道 域（NICD）。此外，我们发现卵泡细胞中缺口过度激活会导致细胞死亡和 生殖细胞通过吞噬作用的变性。这些发现为我们提供了进一步的机会 探索在正常发展期间及以下的种系和躯体发育如何协调 环境压力，并了解Notch信号如何调节各种的生长和生存 生物学和病理状况。以下三个特定目标将使用卵巢解决 型号1。确定Notch如何调节不同遗传背景的组织生长。 2。确定 CDC25/字符串如何调节NICD核访问撞击置换信号。和3。确定如何 卵泡细胞中的Notch活性上调会诱导种系细胞死亡。这些目标的成功完成将 导致人们对凹口信号的各种效果和调节机制的了解得到改善 发展和组织稳态。拟议研究的发现将有助于设计新的 与异常缺口信号有关的疾病的治疗策略。