Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Cell. 2021 May 27;184(11):2825-2842.e22. doi: 10.1016/j.cell.2021.04.004. Epub 2021 Apr 30.
Mouse embryonic development is a canonical model system for studying mammalian cell fate acquisition. Recently, single-cell atlases comprehensively charted embryonic transcriptional landscapes, yet inference of the coordinated dynamics of cells over such atlases remains challenging. Here, we introduce a temporal model for mouse gastrulation, consisting of data from 153 individually sampled embryos spanning 36 h of molecular diversification. Using algorithms and precise timing, we infer differentiation flows and lineage specification dynamics over the embryonic transcriptional manifold. Rapid transcriptional bifurcations characterize the commitment of early specialized node and blood cells. However, for most lineages, we observe combinatorial multi-furcation dynamics rather than hierarchical transcriptional transitions. In the mesoderm, dozens of transcription factors combinatorially regulate multifurcations, as we exemplify using time-matched chimeric embryos of Foxc1/Foxc2 mutants. Our study rejects the notion of differentiation being governed by a series of binary choices, providing an alternative quantitative model for cell fate acquisition.
小鼠胚胎发育是研究哺乳动物细胞命运获得的典型模式系统。最近，单细胞图谱全面描绘了胚胎转录景观，但在这些图谱上推断细胞的协调动力学仍然具有挑战性。在这里，我们引入了一个用于小鼠原肠胚形成的时间模型，该模型由跨越 36 小时分子多样化的 153 个单独采样胚胎的数据组成。使用算法和精确的时间，我们推断出胚胎转录流形上的分化流和谱系指定动力学。快速的转录分支特征是早期特化的节点和血细胞的承诺。然而，对于大多数谱系，我们观察到组合的多分叉动力学，而不是层次转录转变。在中胚层中，数十种转录因子组合调控多分叉，我们使用 Foxc1/Foxc2 突变体的时间匹配嵌合胚胎为例说明了这一点。我们的研究否定了分化由一系列二元选择控制的观点，为细胞命运获得提供了替代的定量模型。
