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.

摘要 集体细胞迁移对正常胚胎发育和器官发生的进程是必不可少的， 是一个受到严格控制的过程，可能涉及两条或更多条信号通路之间的相互作用，以 推动细胞群组向前移动。此外，构建器官模型通常需要选择性的细胞凋亡。 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导致严重的 后果包括发育完全停止、器官功能异常和肿瘤形成。在这 提出的研究计划，我们将利用果蝇胚胎的尾部内脏中胚层(CVM)， 肌肉前体细胞群，经历高度定型的定向运动，作为 集体细胞迁移和存活。作为胚胎发生时间最长的迁移，CVM细胞必须接受输入 通过来自其他细胞的信号信号来导航发育中的胚胎不断变化的环境。 我们之前已经确定了成纤维细胞生长因子信号作为趋化信号和生存信号的重要作用，以及 这种成纤维细胞生长因子受体在迁移细胞亚群中特异表达。然而，丢失成纤维细胞生长因子信号会 没有完全消除集体迁徙，表明存在额外的、迄今尚未确定的特征 暗示。这项研究的目的是为了全面了解时空调节的 引导云服务器定向移动的线索，以及随后不同子集的生存或凋亡 细胞。我们的中心假设是，成纤维细胞生长因子信号与额外的信号线索合作，以便驱动 向前移动和细胞存活，并涉及在每个云服务器队列中定义专门的细胞子集 推动空间组织引领前行。为了验证这一假设，我们将进行以下工作 具体目标：(目标1)调查空间定位的基因在迁移的云服务器集体中的作用 促进细胞迁移；(目标2)研究CVM对PGCs的吸引机制；(AIM 3)调查 骨形态发生蛋白和成纤维细胞生长因子信号在调控CVM细胞迁移和存活中的关系。要完成 为了达到这些目标，我们将采用成熟的遗传学和免疫染色技术的创新组合 凭借优雅的光遗传学和活体成像方法来操纵和可视化迁移细胞，如 以及对细胞死亡程序的时空激活进行量化。我们相信这项研究具有重要意义 因为它不仅展示了一种在新兴的 细胞迁移系统特征不佳，但考虑到大量的功能和疾病 归因于BMP和成纤维细胞生长因子等信号通路，阐明了多个通路之间的相互作用 在遗传上易处理和保守的果蝇模型系统的背景下，有可能识别 更具体的治疗目标。因此，这项研究将对更有影响力的 全面了解集体细胞迁移，以及器官发生的机制 因为细胞迁移和生存计划与正常发育和癌症有关。