Stem Cells and Development, Department of Developmental Biology, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, 75105 Paris, France.
Development. 2012 Dec;139(24):4536-48. doi: 10.1242/dev.084756. Epub 2012 Nov 7.
During organogenesis, a continuum of founder stem cells produces temporally distinct progeny until development is complete. Similarly, in skeletal myogenesis, phenotypically and functionally distinct myoblasts and differentiated cells are generated during development. How this occurs in muscle and other tissues in vertebrates remains largely unclear. We showed previously that committed cells are required for maintaining muscle stem cells. Here we show that active Notch signalling specifies a subpopulation of myogenic cells with high Pax7 expression. By genetically modulating Notch activity, we demonstrate that activated Notch (NICD) blocks terminal differentiation in an Rbpj-dependent manner that is sufficient to sustain stem/progenitor cells throughout embryogenesis, despite the absence of committed progeny. Although arrested in lineage progression, NICD-expressing cells of embryonic origin progressively mature and adopt characteristics of foetal myogenic cells, including expression of the foetal myogenesis regulator Nfix. siRNA-mediated silencing of NICD promotes the temporally appropriate foetal myogenic fate in spite of expression of markers for multiple cell types. We uncover a differential effect of Notch, whereby high Notch activity is associated with stem/progenitor cell expansion in the mouse embryo, yet it promotes reversible cell cycle exit in the foetus and the appearance of an adult muscle stem cell state. We propose that active Notch signalling is sufficient to sustain an upstream population of muscle founder stem cells while suppressing differentiation. Significantly, Notch does not override other signals that promote temporal myogenic cell fates during ontology where spatiotemporal developmental cues produce distinct phenotypic classes of myoblasts.
在器官发生过程中，创始干细胞连续产生具有时间差异的后代，直到发育完成。同样，在骨骼肌肉发生过程中，表型和功能不同的成肌细胞和分化细胞也会产生。在脊椎动物的肌肉和其他组织中，这种情况是如何发生的仍然很大程度上不清楚。我们之前曾表明，定型细胞对于维持肌肉干细胞是必需的。在这里，我们表明活跃的 Notch 信号指定了具有高 Pax7 表达的成肌细胞亚群。通过遗传调节 Notch 活性，我们证明激活的 Notch（NICD）以依赖 Rbpj 的方式阻止终末分化，足以维持干细胞/祖细胞在整个胚胎发生过程中，尽管缺乏定型的后代。尽管在谱系进展中被阻止，但源自胚胎的 NICD 表达细胞逐渐成熟并采用胎儿成肌细胞的特征，包括胎儿成肌调节因子 Nfix 的表达。尽管表达了多种细胞类型的标志物，NICD 的 siRNA 介导的沉默促进了暂时适当的胎儿成肌命运。我们揭示了 Notch 的差异效应，即高 Notch 活性与小鼠胚胎中的干细胞/祖细胞扩张相关，但它促进了胎儿中可逆的细胞周期退出，并出现了成年肌肉干细胞状态。我们提出，活跃的 Notch 信号足以维持肌肉创始干细胞的上游群体，同时抑制分化。重要的是，Notch 不会覆盖其他信号，这些信号在本体论中促进了具有时间差异的成肌细胞命运，其中时空发育线索产生了不同表型类别的成肌细胞。
