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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. !

项目总结/摘要理解在转录之间配置相互作用的分子逻辑引导整个生物体发育的因子和信号网络可以说是现代生物学的主要挑战之一，因此，它需要良好的实验系统.哺乳动物的囊胚就是这样一个系统。植入前哺乳动物胚胎发育-从受精卵到囊胚阶段-提供了一个简化和易于处理的模型，用于研究细胞命运的协调特定化和形态发生在整个群体中的单细胞分辨率。的胚泡是哺乳动物普遍的发育阶段，是组织自我发育的范例， organization.植入前胚胎发育涉及两个连续的二元细胞命运决定产生三种细胞谱系：多能外胚层（EPI），几乎所有体细胞的创始人组织，和两个主要的胚外谱系，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。获得深入了解胚泡内细胞命运特化的机制基础，建立在我们以前的研究结果之上，也是R 01资助申请的主题。该项目的首要目标是利用小鼠遗传学和胚胎学方法单细胞分辨率定量方法，以了解多能性胚泡的上胚层（EPI）和原始内胚层（PrE）谱系及时形成，空间通过实时成像EPI和PrE细胞，因为它们出现在ICM群体中，我们将确定驱动ICM内谱系分化的动态细胞行为，具体目标1.为了描绘出驱动这些交替命运的基因调控网络决定，我们将研究NANOG和GATA 6的作用，这两个转录因子位于SPECIFIC AIM 2中网络的顶点。FGF 4是分泌信号，驱动ICM内的谱系分化并促进EPI成熟。具体目标 3我们将观察转导FGF 4信号的细胞，并研究下游信号。在ICM中操作的FGF 4信号级联的组分。因为细胞命运 ICM群体的质量标准仅在细胞分选的同时完成，具体目标4我们将试图确定细胞的位置是否影响其命运选择 !