Mechanisms driving cell fate specification and morphogenesis in the blastocyst

囊胚中细胞命运规范和形态发生的驱动机制

• 批准号: 10112934
• 负责人: ANNA-KATERINA HADJANTONAKIS
• 金额: $ 48.91万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112934
• 关键词: Address; Applications Grants; Automobile Driving; Biological; Biological Models; Biology; Cell Fate Control; Cell Lineage; Cell Separation; Cells; Cellular Morphology; Cellular biology; Communication; Computational Biology; Congenital Abnormality; Critical Pathways; Data; Defect; Development; Developmental Biology; Embryo; Embryonic Development; Endoderm; Endoderm Cell; Environment; Epiblast; Event; Fibroblast Growth Factor; Foundations; Gene Expression; Generations; Genetic; Genetic Processes; Genotype; Goals; Human; Image; Inner Cell Mass; Light; Logic; Maintenance; Marsupialia; Mechanics; Methods; Modeling; Modernization; Molecular; Morphogenesis; Mus; Mutation Analysis; Organ; Organism; Phase; Population; Positioning Attribute; Pre-implantation Embryo Development; Regulator Genes; Reporter; Resolution; Role; Signal Transduction; Somatic Cell; System; Systems Biology; Therapeutic; Time; Tissues; base; blastocyst; cell behavior; cell fate specification; cell type; cellular transduction; cohort; data analysis pipeline; driving behavior; egg; experimental study; in vivo; innovation; insight; method development; mouse development; mouse genetics; mutant; placental mammal; preimplantation; programs; public health relevance; quantitative imaging; self organization; three dimensional structure; transcription factor; transcriptomics; zygote

PROJECT SUMMARY / ABSTRACT Understanding the molecular logic that configures interactions between the transcription factors and signaling networks that guide the development of an entire organism is arguably one of the major challenges of modern biology, and as such, it needs good experimental systems. The mammalian blastocyst is one such system. Preimplantation mammalian embryo development - from the fertilized egg to the blastocyst stage - offers a simplified and tractable model for investigating the coordination of cell fate specification and morphogenesis at single-cell resolution across a population. The blastocyst is a universal mammalian developmental stage and a paradigm of tissue self- organization. Preimplantation embryo development involves two sequential binary cell fate decisions that give rise to three cell lineages: the pluripotent epiblast (EPI) which is the founder tissue of almost all somatic cells, and two primarily extra-embryonic lineages, the trophectoderm (TE) and primitive endoderm (PrE). The three cell lineages of the blastocyst are defined by their position, developmental potential, and marker expression. Gaining insight into the mechanistic underpinnings of cell fate specification within the blastocyst, builds on our previous findings, and is the subject of this R01 grant application. The overarching goal of this project is to exploit mouse genetic and embryological methods with single-cell resolution quantitative approaches, to understand how the pluripotent epiblast (EPI) and primitive endoderm (PrE) lineages of the blastocyst form in time and space. By live imaging EPI and PrE cells as they emerge within the ICM population, we will determine the dynamic cell behaviors driving lineage divergence within the ICM in SPECIFIC AIM 1. To delineate the gene regulatory network driving these alternate fate decisions, we will investigate the roles of NANOG and GATA6, the two transcription factors positioned at the apex of the network in SPECIFIC AIM 2. FGF4 is the secreted signal driving lineage divergence within the ICM and promoting EPI maturation. In SPECIFIC AIM 3 we will visualize cells transducing the FGF4 signal and investigate downstream components of the FGF4 signaling cascade operating in the ICM. Since cell fate specification across the ICM population is only complete concomitant with cell sorting, in SPECIFIC AIM 4 we will seek to determine whether a cell's position impacts a its fate choice. !

项目摘要 /摘要 了解配置转录之间相互作用的分子逻辑 指导整个生物体发展的因素和信号网络可以说是 现代生物学的主要挑战之一，因此，它需要良好的实验性 系统。哺乳动物胚泡就是这样一种系统。 植入前哺乳动物胚胎发育 - 从受精卵到胚泡 阶段 - 提供了一个简化且可进行的模型，用于研究细胞命运的协调 单细胞分辨率的规格和形态发生。这 胚泡是一个通用的哺乳动物发育阶段，是组织自我的范式 组织。植入前胚胎发育涉及两个顺序二元细胞命运 产生三个细胞谱系的决策：多能层细胞（EPI）是 几乎所有体细胞的创始人组织，两个主要是孔隙外谱系， 滋养剂（TE）和原始内胚层（PRE）。胚泡的三个细胞谱系 由它们的位置，发育潜力和标记表达来定义。获得 深入了解胚泡中细胞命运规范的机械基础， 基于我们以前的发现，并且是此R01赠款应用程序的主题。 该项目的总体目标是利用小鼠遗传和胚胎学方法 使用单细胞分辨率定量方法，以了解多能 胚泡形式的epiblast（EPI）和原始内胚层（PRE）谱系， 空间。 通过实时成像EPI和Pre细胞在ICM种群中出现时，我们将 确定动态细胞行为驱动ICM中驱动谱系差异的动态行为 特定目的1。描绘驱动这些替代命运的基因调节网络 决定，我们将研究Nanog和Gata6的作用，这是两个转录因子 位于特定目标2的网络顶点。FGF4是分泌的信号 在ICM内驱动谱系差异并促进EPI成熟。在特定目标中 3我们将可视化细胞转导FGF4信号并在下游研究 在ICM中运行的FGF4信号级联的组件。由于细胞命运 ICM种群的规格仅与细胞分选完全伴随 特定目的4我们将寻求确定单元的位置是否影响其命运 选择。 呢