Stem Cells & Development, Department of Developmental Biology, Institut Pasteur, CNRS URA 2578, Paris, France.
Stem Cells. 2012 Feb;30(2):243-52. doi: 10.1002/stem.775.
Notch signaling plays a key role in virtually all tissues and organs in metazoans; however, limited examples are available for the regulatory role of this pathway in adult quiescent stem cells. We performed a temporal and ontological assessment of effectors of the Notch pathway that indicated highest activity in freshly isolated satellite cells and, unexpectedly, a sharp decline before the first mitosis, and subsequently in proliferating, satellite cell-derived myoblasts. Using genetic tools to conditionally abrogate canonical Notch signaling during homeostasis, we demonstrate that satellite cells differentiate spontaneously and contribute to myofibers, thereby resulting in a severe depletion of the stem cell pool. Furthermore, whereas loss of Rbpj function provokes some satellite cells to proliferate before fusing, strikingly, the majority of mutant cells terminally differentiate unusually from the quiescent state, without passing through S-phase. This study establishes Notch signaling pathway as the first regulator of cellular quiescence in adult muscle stem cells.
Notch 信号通路在后生动物的几乎所有组织和器官中都发挥着关键作用；然而，关于该途径在成年静止干细胞中的调控作用的例子有限。我们对 Notch 通路的效应物进行了时间和本体评估，结果表明该通路在新分离的卫星细胞中活性最高，出乎意料的是，在第一次有丝分裂之前急剧下降，随后在增殖的卫星细胞衍生的成肌细胞中下降。我们使用遗传工具在体内条件性消除经典 Notch 信号，证明卫星细胞会自发分化并有助于肌纤维形成，从而导致干细胞池严重耗竭。此外，虽然 Rbpj 功能丧失会促使一些卫星细胞在融合前增殖，但令人惊讶的是，大多数突变细胞会从不稳定的静止状态异常地终末分化，而不会经历 S 期。这项研究确立了 Notch 信号通路作为成年肌肉干细胞中细胞静止的第一个调节因子。
