The gut endoderm: origin, formation and fate

项目总结/摘要 肠道内胚层是呼吸道和消化道的前体组织，以及它们相关的内脏器官。 机关在这个项目中，我们将使用一套最先进的技术来解决基本问题 专注于哺乳动物肠道内胚层细胞谱系定型和组织形态发生的机制， 以及探索构成肠道内胚层的细胞的发育起源和命运， 模型 我们以前的研究为我们理解肿瘤的起源和机制提供了一个范式转变， 肠内胚层的形成。使用命运定位，实时成像和最近的单细胞转录组学 方法，我们证明了小鼠的肠内胚层包含两种不同发育的细胞， 起源;胚胎定形内胚层和胚外内脏内胚层。肠道的双重起源 内胚层挑战了哺乳动物中胚层形成的流行观点， 沿着中胚层和外胚层，仅来源于多能外胚层。我们还发现肠道 内胚层通过一种新的嵌入机制形成，并确定SOX 17作为一个关键的调节剂， 这个过程 该项目的主要目标是利用分子、基因组、胚胎学和成像技术， 调查有关肠道内胚层的起源，形成和命运的基本开放问题， 哺乳动物具体目标1将研究驱动肠道内胚层的动态细胞行为 形态发生特异性目的2将探测SOX 17转录因子驱动转录因子的机制。 肠内胚层细胞命运特化、组织形态发生和胚胎定形细胞之间的通讯 内胚层和胚外内脏内胚层细胞，因为它们形成一致的上皮。具体目标3 将决定胚胎外内脏内胚层细胞的后代是否在整个胚胎发育过程中持续存在， 发育以及它们是否最终有助于成人的内胚层器官。 严格理解正常的肠道内胚层，包括其起源，形成和命运， 支持指导细胞分化成内胚层身份的逻辑努力，产生真正的 用于发育和疾病建模和筛查的内胚层类器官，了解疾病进展 并为这些重要器官系统的衰竭设计新的治疗策略。

PROJECT SUMMARY / ABSTRACT The gut endoderm is the precursor tissue of the respiratory and digestive tracts, and their associated visceral organs. In this project we will use a suite of state-of-the-art technologies to address fundamental questions focused on mechanisms of mammalian gut endoderm cell lineage commitment and tissue morphogenesis, as well as probing the developmental origin and fate of cells that comprise the gut endoderm, using the mouse model. Our previous studies have provided a paradigm-shift in our understanding of the origin and mechanism of formation of the gut endoderm. Using fate mapping, live imaging and more recently single-cell transcriptomic methods, we demonstrated that the gut endoderm of mice comprises cells of two distinct developmental origins; embryonic definitive endoderm, and extra-embryonic visceral endoderm. The dual origin of the gut endoderm challenges the prevailing view of germ layer formation in mammals which posits that endoderm, along with mesoderm and ectoderm, derives solely from pluripotent epiblast. We have also shown that the gut endoderm forms through a novel intercalation mechanism and identified SOX17 as a critical regulator of this process. The broad aim of this project is to use molecular, genomic, embryological and imaging techniques to investigate fundamental open questions pertaining the origin, formation and fate of the gut endoderm in mammals. Specific Aim 1 will investigate the dynamic cellular behaviors driving gut endoderm morphogenesis. Specific Aim 2 will probe the mechanism(s) by which the SOX17 transcription factor drives gut endoderm cell fate specification, tissue morphogenesis and communication between embryonic definitive endoderm and extra-embryonic visceral endoderm cells as they form a congruent epithelium. Specific Aim 3 will determine whether descendants of extra-embryonic visceral endoderm cells persist throughout embryonic development and whether they will ultimately contribute to the endodermal organs of the adult. A rigorous understanding of the normal gut endoderm, encompassing its origin, formation and fate, will underpin logical efforts to direct the differentiation of cells into endoderm identities, generate bona fide endodermal organoids for development and disease modeling and screening, understand disease progression and design new therapeutic strategies for these vital organ systems when they fail.