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子细胞，这些子细胞通常在分化成各种细胞类型之前增殖。这些特性允许单个干细胞产生足够的后代以维持成体组织。然而，干细胞增殖必须根据需要严格限制，并且必须仅在允许干细胞后代适当发育的环境中发生。因此，干细胞通常只在有限的、适当定位的微环境中得到支持，称为小生境。大多数干细胞龛很难进入或定义。果蝇卵巢，其中生殖系和体干细胞后代合作产生卵子，提供了一个例外，也提供了广泛和快速的调查，使用分子遗传学的关键属性。 在这里，果蝇卵巢中的体细胞滤泡干细胞（FSC）将被用来确定一个小生境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生态位相互作用，因此从FSC获得的见解无疑将补充和加强来自其他模型干细胞的见解。FSC模型特别有趣的方面是多个信号通路的调节、干细胞之间对生态位位置的竞争和生态位粘附的广泛调节。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很好的模型。 体内干细胞功能的第一次遗传筛选的执行，加上对FSC信号通路作用的广泛测试，提供了关于干细胞功能的关键试剂、方法和假设。该提案旨在确定单个信号通路如何影响FSC以及多个通路如何整合，特别是调节生态位粘附。一个非常成功的遗传筛选将扩大到包括更多的果蝇基因组和关键突变确定将用于了解影响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复制应激的反应以及细胞周期和生态位保留的协调调节。诱导异位FSC复制或邻近FSC置换的FSC突变为理解干细胞如何竞争有限的小生境位置提供了关键的试剂和动力。新的竞争试验，FSC突变体来源于屏幕和信号通路的研究将补充一个新的选择方案，以隔离突变赋予增强竞争，以破译双方的原则和球员。总的来说，这些研究应该提供一个开创性的，开放式的方法来建立一个全面的框架，控制干细胞行为的调节电路。