Developmental Signalling Laboratory, The Francis Crick Institute, London, UK.
Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, UK.
Dev Cell. 2022 Dec 5;57(23):2604-2622.e5. doi: 10.1016/j.devcel.2022.11.008.
Specification of the germ layers by Nodal signaling has long been regarded as an archetype of how graded morphogens induce different cell fates. However, this deterministic model cannot explain why only a subset of cells at the early zebrafish embryo margin adopt the endodermal fate, whereas their immediate neighbours, experiencing a similar signaling environment, become mesoderm. Combining pharmacology, quantitative imaging and single cell transcriptomics, we demonstrate that sustained Nodal signaling establishes a bipotential progenitor state from which cells can switch to an endodermal fate or differentiate into mesoderm. Switching is a random event, the likelihood of which is modulated by Fgf signaling. This inherently imprecise mechanism nevertheless leads to robust endoderm formation because of buffering at later stages. Thus, in contrast to previous deterministic models of morphogen action, Nodal signaling establishes a temporal window when cells are competent to undergo a stochastic cell fate switch, rather than determining fate itself.
长期以来，Nodal 信号对胚层的特化被认为是形态发生素如何诱导不同细胞命运的典范。然而，这种确定性模型并不能解释为什么只有早期斑马鱼胚胎边缘的一小部分细胞会采用内胚层命运，而它们的紧邻细胞，经历着相似的信号环境，却会成为中胚层。通过药理学、定量成像和单细胞转录组学的结合，我们证明持续的 Nodal 信号从其中可以切换到内胚层命运或分化为中胚层的多能祖细胞状态。转换是一个随机事件，其可能性受到 Fgf 信号的调节。尽管这种固有不精确的机制会导致稳健的内胚层形成，但这是因为在后期阶段进行了缓冲。因此，与形态发生素作用的先前确定性模型相反，Nodal 信号建立了一个时间窗口，在此期间细胞有能力进行随机的细胞命运转换，而不是决定命运本身。
