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. !

项目概要/摘要 了解配置转录之间相互作用的分子逻辑 指导整个有机体发育的因素和信号网络可以说是 现代生物学的主要挑战之一，因此需要良好的实验 系统。哺乳动物囊胚就是这样的系统之一。 植入前哺乳动物胚胎发育 - 从受精卵到囊胚 stage - 提供一个简化且易于处理的模型来研究细胞命运的协调 群体中单细胞分辨率的规范和形态发生。这 囊胚是哺乳动物普遍的发育阶段，也是组织自我发育的范例 组织。植入前胚胎发育涉及两个连续的二元细胞命运 产生三种细胞谱系的决定：多能外胚层（EPI） 几乎所有体细胞的创始人组织，以及两个主要的胚胎外谱系， 滋养外胚层 (TE) 和原始内胚层 (PrE)。囊胚的三种细胞谱系 由它们的位置、发育潜力和标记表达来定义。获得 深入了解囊胚内细胞命运规范的机制基础， 建立在我们之前的发现之上，并且是 R01 拨款申请的主题。 该项目的总体目标是利用小鼠遗传和胚胎学方法 通过单细胞分辨率定量方法，了解多能性如何 囊胚形成的外胚层 (EPI) 和原始内胚层 (PrE) 谱系及时 空间。 通过对 ICM 群体中出现的 EPI 和 PrE 细胞进行实时成像，我们将 确定驱动 ICM 内谱系分歧的动态细胞行为 具体目标 1. 描绘驱动这些交替命运的基因调控网络 决定时，我们将研究 NANOG 和 GATA6 这两个转录因子的作用 位于 SPECIFIC AIM 2 网络的顶端。FGF4 是分泌信号 推动 ICM 内的谱系分歧并促进 EPI 成熟。在具体目标中 3 我们将可视化转导 FGF4 信号的细胞并研究下游 ICM 中运行的 FGF4 信号级联的组成部分。既然细胞命运 ICM 群体的规范只有在细胞分选时才能完成， 具体目标 4 我们将寻求确定细胞的位置是否影响其命运 选择。 ！