Molecular analysis of cell fate specification in mouse gastrulation

从受精卵到成年的胚胎发育是通过从多能祖细胞到终末分化的细胞谱系限制和决定事件的连续步骤实现的。在早期发育过程中，初级胚层外胚层、中胚层和内胚层在分级信号传导分子（如Wnt、TGF β/BMP和FGF）的复杂控制下从共同的祖细胞组织（即外胚层）指定2，3。信号输入在细胞内被解释，并协调分化过程背后的遗传程序和细胞反应。虽然重要的信号分子和相应的途径，以前确定的遗传程序和细胞行为的变化，导致胚层规格的分子细节仍然不明确。我们先前发现了转录因子Eomesodermin（Eomes）在内胚层形成和中胚层细胞层形态发生的早期阶段的关键作用。这项工作计划提出在分子水平上分析Eomes的功能，并将其结果作为切入点，以破译在早期哺乳动物胚胎发生过程中指导原肠胚形成过程的调控网络。将采用小鼠遗传学方法和胚胎干细胞（ES）体外分化研究相结合的方法。预期的发现将对干细胞和祖细胞分化为不同组织类型产生重大影响，并将增强干细胞治疗和再生医学的选择。

Embryonic development from the fertilized egg to adulthood is achieved by successive steps of cell lineage -restriction and -determination events from pluripotent progenitor cells leading up to terminal differentiation. During early development the primary germ layers ectoderm, mesoderm and endoderm are specified from a common progenitor tissue, namely the epiblast, under the complex control of graded signalling molecules, such as Wnts, TGFb/BMPs and FGFs2, 3. Signalling inputs are interpreted intracellulary and orchestrate the genetic program and cellular response underlying the differentiation processes. Whereas the important signalling molecules and corresponding pathways were previously identified, the molecular details of genetic programs and changes in cell behaviour leading to germ layer specification remain ill defined. We previously uncovered the crucial role of the transcription factor Eomesodermin (Eomes) during the early phase of endoderm formation and morphogenesis of the mesoderm cell layer1. This work program proposes to analyse the function of Eomes at the molecular level and to use the results as an entry point to decipher the regulatory network guiding the gastrulation process during early mammalian embryogenesis. A combination of genetic approaches in mouse and in vitro differentiation studies of embryonic stem (ES) cells will be employed. Expected findings will have significant implications for the differentiation of stem and progenitor cells into different tissue types and will enhance the options for stem cell therapy and regenerative medicine.