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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

基本信息

批准号：
10355512
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355512
关键词：
Address Applications Grants Automobile Driving 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 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 gene regulatory network 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

项目摘要

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/摘要理解配置转录之间相互作用的分子逻辑可以说，引导整个生物体发育的因素和信号网络现代生物学的主要挑战之一，因此，它需要良好的实验系统。哺乳动物的胚泡就是这样一个系统。植入前哺乳动物胚胎发育--从受精卵到囊胚 Stage-为研究细胞命运的协调提供了一个简化和易处理的模型在整个种群中以单细胞分辨率指定和形态发生。这个胚泡是哺乳动物普遍存在的发育阶段，也是组织自我调节的典范。组织。植入前胚胎发育涉及两个顺序的二元细胞命运导致三种细胞谱系的决定：多能上皮细胞(EPI)，这是几乎所有体细胞的创始组织，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)。胚泡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。收获洞察胚泡内细胞命运指定的机制基础，基于我们之前的发现，并是这次R01拨款申请的主题。该项目的首要目标是开发小鼠遗传学和胚胎学方法。用单细胞分辨率的定量方法，来理解多能性胚泡的上胚层(EPI)和原始内胚层(PRE)谱系在时间和时间上形成太空。通过对ICM人群中出现的EPI和PRE细胞进行实时成像，我们将确定在ICM内驱动谱系分化的动态细胞行为具体目的1.描绘驱动这些交替命运的基因调控网络决定，我们将研究NANOG和GATA6这两个转录因子的作用定位于特定AIM 2网络的顶端。FGF4是分泌的信号推动ICM内的谱系分化，促进EPI的成熟。在特定目标中 3我们将可视化细胞转导FGF4信号，并研究下游在ICM中运行的FGF4信令级联的组件。因为细胞的命运整个ICM群体的规格只是完全伴随着细胞分类，在具体目标4我们将寻求确定细胞的位置是否影响其命运选择。好了！