Modeling epithelial stem cell competition in a dynamic drosophila ovarian niche

动态果蝇卵巢生态位中上皮干细胞竞争的建模

• 批准号: 9903025
• 负责人: Todd Nystul
• 金额: $ 8.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903025
• 关键词: Address; Affect; Aging; Biochemistry; Cell Differentiation process; Cell Lineage; Cells; Cellular Morphology; Cellular biology; Collection; Data; Disease; Drosophila genus; Environment; Epidermal Growth Factor Receptor; Epithelial; Failure; Family; Fostering; Foundations; Gene Expression; Gene Expression Profile; Genetic; Goals; Grant; Health; Homeostasis; Knowledge; Literature; Malignant Neoplasms; Mammals; Mediating; Memory; Mission; Modeling; Molecular; Oogenesis; Ovarian; Phenotype; Physiological; Physiology; Population; Process; Public Health; Publishing; Regenerative Medicine; Regulation; Repression; Research; Signal Transduction; Specific qualifier value; Starvation; Stem cells; Stress; Study models; Techniques; Time; Tissues; United States National Institutes of Health; Work; autocrine; base; daughter cell; feeding; improved; innovation; insight; mutant; novel; parent grant; preservation; progenitor; response; segregation; self-renewal; stem cell biology; stem cell fate specification; stem cell niche; tool; transcription factor

R01 GRANT ABSTRACT This proposal outlines a strategy for identifying the mechanisms that allow for precise specification of the stem cell fate within a dynamic tissue environment and for elucidating the mechanism of competition for stem cell niche occupancy. Accomplishing the aims in this proposal will be an important milestone toward the long-term goal of building a detailed model of epithelial stem cell regulation in order to develop regenerative medicine- based therapies and understand how the process fails in disease states such as cancer. The follicle stem cells (FSCs) have many features in common with mammalian epithelial progenitors and will likely be an excellent model for epithelial stem cell biology. Like several other types of epithelial stem cells in Drosophila and mammals, FSCs are stably maintained by a non-dedicated population of niche cells and depend on Wnt/wg and EGFR signals for self-renewal. In addition, FSCs produce daughter cells that differentiate over the course of several divisions but also retain the capacity to compete with resident stem cells for niche occupancy, much like transit amplifying cells in mammalian epithelial stem cell lineages. However, the precise mechanisms that govern these fundamental features of epithelial stem cell biology remain poorly understood. Based on published studies and significant preliminary data, the central hypothesis of the proposal is that FSC self-renewal is established by localized autocrine and juxtacrine signaling within the niche, and that a cellular memory of these niche signals preserves the ability of newly produced daughter cells to participate in niche competition. A corollary to this hypothesis is the idea that the genetic basis for niche competition is dependent on the relative capacity of a stem cell and a potential replacement cell for self-renewal or differentiation. The specific aims, which will provide complementary approaches to addressing these hypotheses, are: (1) determine how essential niche signals interact to precisely specify FSCs within a dynamic tissue; (2) identify the molecular switch that regulates the segregation of FSC and daughter cell fates; and (3) elucidate the mechanism of FSC niche competition. Newly developed tools and the finding that wg and EGFR are specific FSC niche signals make it possible to achieve the first aim. The second aim will be use biochemistry and cell biology techniques, and will build from the thorough understanding of Six-family transcription factors and groucho-mediated repression provided by the literature. The third aim will combine the detailed knowledge of FSC niche function provided by previous work and the first two aims with a new collection of hypercompetition mutants to obtain a comprehensive understanding of how niche competition is regulated. This project is significant because it will provide detailed mechanistic insight into the function of epithelial stem cell niches. It is an innovative departure from previous studies that focuses on building a comprehensive model of the FSC niche and on understanding novel concepts, the dynamic niche and niche competition. Ultimately, it will provide a detailed understanding of the conserved mechanisms that regulate epithelial stem cells.

R 01赠款摘要 该提案概述了一项战略，以确定机制，允许精确规格的茎 动态组织环境中的细胞命运和阐明干细胞竞争机制 利基占有率。实现这一建议中的目标将是实现长期目标的一个重要里程碑。 目标是建立上皮干细胞调控的详细模型，以发展再生医学- 并了解该过程如何在癌症等疾病状态下失败。卵泡干细胞 FSC与哺乳动物上皮祖细胞具有许多共同的特征，并且可能是一种极好的细胞分化因子。 上皮干细胞生物学模型。与果蝇中的其他几种上皮干细胞一样， 在哺乳动物中，FSC由非专用的小生境细胞群稳定维持，并依赖于Wnt/wg 和EGFR信号进行自我更新。此外，FSC产生的子细胞在整个过程中分化， 但也保留了与常驻干细胞竞争利基占用的能力， 就像哺乳动物上皮干细胞谱系中的转运放大细胞一样。然而， 上皮干细胞生物学的这些基本特征仍然知之甚少。 根据已发表的研究和重要的初步数据，该提案的中心假设是， 自我更新是通过小生境内的局部自分泌和外分泌信号建立的， 这些小生境信号的记忆保持了新产生的子细胞参与小生境的能力 竞争这一假说的一个推论是，生态位竞争的遗传基础是依赖于 取决于干细胞和潜在替代细胞自我更新或分化的相对能力。的 为解决这些假设提供补充办法的具体目标是：（1） 确定必要的小生境信号如何相互作用以精确地指定动态组织内的FSC;（2）识别 调节FSC和子细胞命运分离的分子开关;以及（3）阐明 FSC生态位竞争机制。新开发的工具以及wg和EGFR具有特异性的发现 FSC小生境信号使实现第一个目标成为可能。第二个目标是利用生物化学和细胞 生物学技术，并将建立在深入了解六个家庭的转录因子， 由文献提供的groucho介导的抑制。第三个目标是将联合收割机的详细知识 FSC生态位函数提供了以前的工作和前两个目的与一个新的收集超竞争 突变体，以获得如何调节生态位竞争的全面理解。 该项目是重要的，因为它将提供详细的机制洞察上皮干的功能， 细胞龛这是一个创新的出发点，从以往的研究，重点是建立一个全面的模型 的FSC生态位和理解新的概念，动态生态位和生态位竞争。最终 将提供一个详细的了解保守的机制，调节上皮干细胞。

项目成果

EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.

• DOI: 10.7554/elife.04437
• 发表时间: 2014-12-01
• 期刊: eLife
• 影响因子: 7.7
• 作者: Castanieto A;Johnston MJ;Nystul TG
• 通讯作者: Nystul TG

Enhancer-trap flippase lines for clonal analysis in the Drosophila ovary.

• DOI: 10.1534/g3.114.010710
• 发表时间: 2014-07-14
• 期刊: G3 (Bethesda, Md.)
• 作者: Huang P;Sahai-Hernandez P;Bohm RA;Welch WP;Zhang B;Nystul T
• 通讯作者: Nystul T

Signal transduction in the early Drosophila follicle stem cell lineage.

• DOI: 10.1016/j.cois.2019.11.005
• 发表时间: 2020-01
• 期刊: Current opinion in insect science
• 影响因子: 5.3
• 作者: Katja Rust;T. Nystul

A Pak-regulated cell intercalation event leading to a novel radial cell polarity is involved in positioning of the follicle stem cell niche in the Drosophila ovary.

Pak 调节的细胞嵌入事件导致新的径向细胞极性，参与果蝇卵巢中卵泡干细胞生态位的定位。

• DOI: 10.1242/dev.111039
• 发表时间: 2015
• 期刊: Development (Cambridge, England)
• 作者: Vlachos,Stephanie;Jangam,Sharayu;Conder,Ryan;Chou,Michael;Nystul,Todd;Harden,Nicholas
• 通讯作者: Harden,Nicholas