Investigating how sequentially acting cues guide long-distance cell migration in vivo within embryos

研究顺序作用线索如何引导胚胎体内的长距离细胞迁移

• 批准号: 10458611
• 负责人: Angelike Stathopoulos
• 金额: $ 35.08万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458611
• 关键词: Anoikis; Apoptosis; Area; Attenuated; Automobile Driving; Biological Assay; Biological Models; Candidate Disease Gene; Cell Communication; Cell Death; Cell Proliferation; Cell Survival; Cells; Chemotactic Factors; Chemotaxis; Chromosome Mapping; Congenital Abnormality; Cues; Data; Defect; Development; Disease; Disseminated Malignant Neoplasm; Distant; Drosophila genus; Embryo; Embryonic Development; Environment; Equilibrium; Exhibits; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Screening; Human; Image; Integral Membrane Protein; Intestines; Invaded; Ligands; Malignant Neoplasms; Mediating; Mesoderm; Mesoderm Cell; Midgut; Modeling; Movement; Muscle; Mutation; Myoblasts; Names; Organ; Organogenesis; Pathologic; Pathway interactions; Pattern; Peptide Hydrolases; Population; Primordium; Process; Regulation; Research; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stereotyping; Structure of primordial sex cell; System; Techniques; Testing; Time; Transcript; Transforming Growth Factor beta; Vertebrates; Visceral; Visceral Myopathies; attenuation; bone morphogenetic protein receptors; cell motility; cell type; cohort; imaging approach; in vivo; innovation; insight; migration; mutant; novel; optogenetics; prevent; programs; spatiotemporal; therapeutic target; tool; tumorigenesis

SUMMARY Collective cell migration is essential to the progression of normal embryonic development and organogenesis, and is a tightly-regulated process that can involve the interplay between two or more signaling pathways to drive forward movement of cell cohorts. Additionally, patterning an organ often requires selective apoptosis and compensatory proliferation of cells. Errors in collective migration and cell death programs can have serious consequences, including complete developmental arrest, abnormal organ function, and tumorigenesis. In this proposed research plan, we will use the Drosophila embryonic caudal visceral mesoderm (CVM), a small population of muscle precursor cells that undergo highly stereotyped directional movement, as a model for collective cell migration and survival. As the longest migration of embryogenesis, CVM cells must receive input via signaling cues from other cells in order to navigate the changing environment of the developing embryo. We have previously determined an important role for FGF signaling as both chemotropic and survival cue, and that FGF receptor is specifically expressed in a subset of migratory cells. However, loss of FGF signaling does not completely ablate collective migration, suggesting the existence of additional, as-of-yet uncharacterized cues. The objective of this study is to gain a comprehensive understanding of the spatiotemporally-regulated cues that guide directional movement of the CVM, and subsequent survival or apoptosis of distinct subsets of cells. Our central hypothesis is that FGF signaling cooperates with additional signaling cues in order to drive forward movement and cell survival, and involves defining specialized subsets of cells within each CVM cohort to promote spatial organization driving forward movement. To test this hypothesis, we will pursue the following specific aims: (AIM 1) Investigate roles for spatially-localized genes within the migrating CVM collective in promoting cell migration; (AIM 2) Investigate mechanism of CVM attraction to PGCs; and (AIM 3) Investigate the relationship between BMP and FGF signaling in regulating CVM cell migration and survival. To accomplish these aims, we will employ an innovative combination of established genetics and immunostaining techniques with elegant optogenetics and in vivo live imaging approaches to manipulate and visualize migratory cells, as well as quantify spatiotemporal activation of the cell death program. We believe this study is significant because it would not only demonstrate a mechanism for signaling cross-talk in an emerging yet poorly-characterized cell migration system, but considering the large number of functions and diseases attributed to signaling pathways such as BMP and FGF, elucidating the interaction between multiple pathways in the context of the genetically-tractable and conserved Drosophila model system has the potential to identify more specific therapeutic targets. Therefore, this study will be impactful by contributing to a more comprehensive understanding of collective cell migration, the mechanisms underlying organogenesis, as well as the cell migration and survival programs implicated in normal development and cancer.

概括 集体细胞迁移对于正常胚胎发育和器官发生的进展至关重要， 并且是一个受到严格调控的过程，可能涉及两个或多个信号通路之间的相互作用 推动细胞群向前运动。此外，器官的图案化通常需要选择性细胞凋亡 以及细胞的代偿性增殖。集体迁移和细胞死亡程序中的错误可能会造成严重的后果 后果，包括发育完全停滞、器官功能异常和肿瘤发生。在这个 提出的研究计划中，我们将使用果蝇胚胎尾部内脏中胚层（CVM），一个小型的 经历高度定型定向运动的肌肉前体细胞群，作为模型 集体细胞迁移和存活。作为胚胎发生过程中最长的迁移过程，CVM细胞必须接受输入 通过来自其他细胞的信号线索来引导发育中胚胎不断变化的环境。 我们之前已经确定 FGF 信号作为趋化性和生存信号的重要作用，并且 FGF 受体在一部分迁移细胞中特异性表达。然而，FGF 信号传导的丧失确实 没有完全消除集体移民，这表明存在额外的、尚未表征的 提示。本研究的目的是全面了解时空调控 指导 CVM 定向运动以及随后不同亚群的存活或凋亡的线索 细胞。我们的中心假设是 FGF 信号与其他信号线索配合以驱动 向前运动和细胞存活，并涉及在每个 CVM 队列中定义专门的细胞子集 促进空间组织推动向前运动。为了检验这个假设，我们将进行以下研究 具体目标：（AIM 1）研究迁移的 CVM 集体中空间定位基因的作用 促进细胞迁移； (AIM 2) 研究CVM对PGC的吸引机制；以及（目标 3）调查 BMP 和 FGF 信号在调节 CVM 细胞迁移和存活中的关系。为了完成 为了实现这些目标，我们将采用现有遗传学和免疫染色技术的创新组合 通过优雅的光遗传学和体内实时成像方法来操纵和可视化迁移细胞， 以及量化细胞死亡程序的时空激活。我们相信这项研究意义重大 因为它不仅展示了一种在新兴的尚未出现的领域中发出串扰信号的机制 细胞迁移系统的特征较差，但考虑到大量的功能和疾病 归因于 BMP 和 FGF 等信号通路，阐明了多个通路之间的相互作用 在遗传上易处理且保守的果蝇模型系统的背景下，有潜力识别 更具体的治疗靶点。因此，这项研究将产生深远的影响，为更多的人做出贡献。 全面了解集体细胞迁移、器官发生的机制以及 因为细胞迁移和生存程序与正常发育和癌症有关。