Somatic stem cells in the Drosophila ovary

果蝇卵巢中的成体干细胞

• 批准号: 8692183
• 负责人: DANIEL D KALDERON
• 金额: $ 10.89万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692183
• 关键词: Actins; Adhesions; Adult; Affect; Behavior; Biological Assay; Biological Models; Cancer Etiology; Cancerous; Cell Adhesion; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Proliferation; Cell model; Cell physiology; Cell-Cell Adhesion; Cells; Complement; Coupled; Cyclin E; Cyst; DNA Replication Factor; DNA biosynthesis; Daughter; Development; Drosophila genome; Drosophila genus; Environment; Equilibrium; Erinaceidae; Extracellular Matrix; Future; Genetic Screening; Genotype; Growth; Individual; Induced Mutation; Investigation; Lead; Longevity; Malignant Neoplasms; Measures; Medicine; Methods; Mitochondria; Modeling; Molecular Genetics; Mutation; Nature; Oncogenic; Ovarian Follicle; Ovary; Pathway interactions; Physiological; Positioning Attribute; Proliferating; Property; Quality Control; Reagent; Regenerative Medicine; Regulation; Role; Scheme; Signal Pathway; Signal Transduction; Spatial Distribution; Stem cells; Stress; Supporting Cell; System; Testing; Tissues; cell behavior; cell type; combat; egg; extracellular; genetic analysis; human stem cells; in vivo; infancy; insight; interest; mutant; public health relevance; regenerative therapy; research study; response; screening; self-renewal; stem cell biology; stem cell niche

DESCRIPTION (provided by applicant): Stem cells self-renew and produce daughters that generally proliferate before differentiating into a variety of cell types. These properties allow a single stem cell to produce sufficient progeny to maintain adult tissues. However, stem cell proliferation must be strictly limited according to need and must occur only in an environment that allows stem cell progeny to develop appropriately. Hence, stem cells are normally supported only in restricted, appropriately positioned micro-environments, termed niches. Most stem cell niches are hard to access or define. The Drosophila ovary, in which germline and somatic stem cell progeny collaborate to produce eggs, provides an exception that also affords the critical attribute of extensive and rapid investigation using molecular genetics. Here, somatic follicle stem cells (FSCs) in Drosophila ovaries will be used to ascertain the mechanisms by which a niche regulates stem cell behavior. Many types of stem cell niche interactions are found in nature, so insights gained from FSCs will undoubtedly both complement and strengthen those derived from other model stem cells. Particularly interesting aspects of the FSC model are regulation by multiple signaling pathways, competition between stem cells for niche positions and extensive regulation of niche adhesion. FSC dynamics and the impact of specific mutations also provide an excellent model for the retention and immortalization of pre-cancerous mutations that arise in stem cells. Execution of the first genetic screen for stem cell function in vivo, coupled with extensive testing of the role of signaling pathways on FSCs has provided key reagents, methods and hypotheses concerning stem cell function. This proposal aims to determine how individual signaling pathways affect FSCs and how multiple pathways are integrated, particularly to regulate niche adhesion. A very successful genetic screen will be extended to include more of the Drosophila genome and key mutations identified will be used to understand the fundamental circuits affecting FSC biology. This includes testing specific hypotheses that quality control uses enhanced checkpoint responses to DNA replication stress and co-ordinated regulation of the cell cycle and niche retention. FSC mutations that induce ectopic FSC duplication or displacement of neighboring FSCs provide critical reagents and impetus for understanding how stem cells compete for limited niche positions. New competition assays, FSC mutants derived from screens and signaling pathway studies will be supplemented by a new selection scheme to isolate mutations conferring enhanced competition in order to decipher both principles and players. Collectively, these studies should provide a pioneering, open-ended approach to building a comprehensive framework for the regulatory circuits that control stem cell behavior.

描述（由申请人提供）：干细胞自我更新并产生女儿，这些女儿通常在区分各种细胞类型之前扩散。这些特性允许单个干细胞产生足够的后代以维持成年组织。但是，必须严格根据需要严格限制干细胞增殖，并且必须仅发生在使干细胞后代适当发展的环境中。因此，通常仅在限制，适当定位的微环境（称为利基）中支持干细胞。大多数干细胞壁ni不难访问或定义。果蝇卵巢，其中种系和体细胞后代合作产生卵，提供了一个例外，还提供了使用分子遗传学进行广泛和快速研究的关键属性。 在这里，果蝇卵巢中的体细胞干细胞（FSC）将用于确定利基市场调节干细胞行为的机制。在自然界中发现了许多类型的干细胞小众相互作用，因此从FSC中获得的见解无疑会补充并增强从其他模型干细胞中得出的见解。 FSC模型的特别有趣的方面是通过多个信号通路，干细胞之间的竞争和小众粘附的广泛调节。 FSC动力学和特定突变的影响也为干细胞中出现的癌前突变的保留和永生化提供了一个极好的模型。 在体内的第一个遗传筛选执行，加上信号通路对FSC的作用的广泛测试，提供了有关干细胞功能的关键试剂，方法和假设。该建议旨在确定单个信号通路如何影响FSC以及如何整合多个途径，尤其是调节小众粘附。将扩展一个非常成功的遗传筛查，以包括更多的果蝇基因组，并且确定的关键突变将用于了解影响FSC生物学的基本电路。这包括测试特定的假设，即质量控制使用增强的检查点对DNA复制应力的响应以及对细胞周期和利基保留的协调调节。诱导异位FSC重复或相邻FSC的位移的FSC突变提供了关键的试剂和动力，以了解干细胞如何竞争有限的小裂位置。新的竞争分析，从屏幕衍生而来的FSC突变体和信号通路研究将由新的选择方案补充，以隔离突变，以赋予增强的竞争，以破译原理和参与者。总的来说，这些研究应提供开创性的开放式方法，以为控制干细胞行为的调节电路建立综合框架。