内胚层起源及内胚层细胞体内分化的调控机制

The animal body is established during the gastrulation in the early development, through which, the embryonic ectoderm, mesoderm and endoderm are formed and becoming all the cell sources of various organ and tissues. Endoderm cells gives rise to a vast array of highly specialized epithelial cell types that line the respiratory and digestive systems and contribute to associated organs such as thyroid, thymus, lungs, liver, biliary system, and pancreas. Basic studies of endoderm organ formation have proven invaluable for understanding the genetic basis of many human congenital diseases. However, it is still far from clear that how endoderm cells are generated during gastrulation and whether the endoderm is sharing a common progenitor with mesoderm as mesendoderm. It is also unknown about the developmental relationship between visceral endoderm and definitive endoderm. Here, we propose a systematic transcriptome analysis of endoderm formation throughout the gastrulation stages. Using the laser-microdissection-assisted spatial transcriptome analysis approach, we are going to build up a dynamic atlas for endoderm development. We will also compare the endoderm transcriptome with the mesoderm/ectoderm transcriptome data. Meanwhile, the endoderm lineage specification will also be investigated in the single cell level by single cell RNA-seq. The study will also look into the divergence of visceral endoderm and definitive endoderm. Finally, the key regulators will be identified and their biological function will be validated using in vitro and in vivo system. This work will dissect and elucidate the molecular mechanisms underlying endoderm formation and patterning, including the key transcriptonal network, signaling pathway and transcriptome architecture that control endoderm morphogenesis. We study will provide a fundamental basis for endoderm related translational research.

在小鼠胚胎的早期发育过程中，通过原肠运动形成外、中、内三个胚层，并在此期间确立了整个动物个体发育的基本蓝图。内胚层是肺、胰脏、肝以及小肠等内脏器官发育的来源，但内胚层的起源以及体内分化机制一直很不清楚。本项目申请拟在原肠运动早、中、晚各个时期，结合激光显微切割空间转录组分析与单细胞测序技术，建立内胚层发育分化的转录组图谱，并且与中胚层、原条以及内脏内胚层的转录组图谱进行对比，结合体内体外的功能验证实验，回答内胚层是从何处发育而来，是否存在中内胚层的共同发育前体，内胚层与内脏内胚层的分化关系等重要的科学问题，为内胚层以及内胚层相关组织、器官的疾病以及内胚层干细胞的转化医学应用提供指导和坚实的理论依据。

在小鼠胚胎的早期发育过程中，通过原肠运动形成外、中、内三个胚层，并在此期间确立了整个动物个体发育的基本蓝图。内胚层是肺、胰脏、肝以及小肠等内脏器官发育的来源，但内胚层的起源以及体内分化机制一直很不清楚。通过本项目的开展，我们完成了原肠运动时期小鼠胚胎外、中、内三个胚层的空间转录组图谱，解析小鼠原肠期胚胎胚层形成的表观遗传调控规律。结合体内体外的功能验证实验，回答了内胚层是从何处发育而来，是否存在中内胚层的共同发育前体，内胚层与内脏内胚层的分化关系等重要的科学问题，为内胚层以及内胚层相关组织、器官的疾病以及内胚层干细胞的转化医学应用提供指导和坚实的理论依据。