UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
Max-Delbrück-Center for Molecular Medicine, Berlin 13125, Germany.
Development. 2014 Jul;141(14):2780-90. doi: 10.1242/dev.110155.
A central question in development is to define how the equilibrium between cell proliferation and differentiation is temporally and spatially regulated during tissue formation. Here, we address how interactions between cyclin-dependent kinase inhibitors essential for myogenic growth arrest (p21(cip1) and p57(kip2)), the Notch pathway and myogenic regulatory factors (MRFs) orchestrate the proliferation, specification and differentiation of muscle progenitor cells. We first show that cell cycle exit and myogenic differentiation can be uncoupled. In addition, we establish that skeletal muscle progenitor cells require Notch signaling to maintain their cycling status. Using several mouse models combined with ex vivo studies, we demonstrate that Notch signaling is required to repress p21(cip1) and p57(kip2) expression in muscle progenitor cells. Finally, we identify a muscle-specific regulatory element of p57(kip2) directly activated by MRFs in myoblasts but repressed by the Notch targets Hes1/Hey1 in progenitor cells. We propose a molecular mechanism whereby information provided by Hes/Hey downstream of Notch as well as MRF activities are integrated at the level of the p57(kip2) enhancer to regulate the decision between progenitor cell maintenance and muscle differentiation.
在组织形成过程中，细胞增殖和分化之间的平衡如何在时间和空间上得到调节，这是发育中的一个核心问题。在这里，我们研究了细胞周期蛋白依赖性激酶抑制剂（对于肌生成生长抑制至关重要的 p21(cip1) 和 p57(kip2)）、Notch 途径和肌调节因子（MRFs）之间的相互作用如何协调肌肉祖细胞的增殖、特化和分化。我们首先表明细胞周期退出和肌生成分化可以解耦。此外，我们确定骨骼肌祖细胞需要 Notch 信号来维持其循环状态。通过使用几种小鼠模型并结合体外研究，我们证明 Notch 信号对于抑制肌肉祖细胞中的 p21(cip1) 和 p57(kip2) 表达是必需的。最后，我们确定了一个肌肉特异性的 p57(kip2) 调控元件，该元件可被肌源性调节因子（MRFs）在成肌细胞中直接激活，但在祖细胞中被 Notch 靶基因 Hes1/Hey1 抑制。我们提出了一个分子机制，即 Notch 下游的 Hes/Hey 以及 MRF 活性提供的信息在 p57(kip2) 增强子水平上被整合，以调节祖细胞维持和肌肉分化之间的决策。
