The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation
The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation
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DOI：
10.1038/sj.emboj.7600309
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发表时间：
2004-08-04
期刊：
影响因子：
11.4
通讯作者：
Lloyd, AC
中科院分区：
文献类型：
--
作者：
Harrisingh, MC;Perez-Nadales, E;Lloyd, AC
雪旺细胞是一种再生细胞类型。神经损伤后，分化的髓鞘雪旺细胞可以去分化并重新获得增殖潜力。然后这些细胞在修复过程中重新分化。这种行为对于成功的轴突修复很重要，但介导两种分化状态之间切换的信号通路仍不清楚。原代细胞中 Ras/Raf/ERK 级联的持续激活导致细胞周期停滞，并与某些细胞类型的分化有关，在许多情况下起到促进分化的作用。因此，我们研究了它对雪旺细胞分化状态的影响。令人惊讶的是，我们发现 Ras/Raf/ERK 信号传导即使在正常轴突信号传导存在的情况下也能驱动雪旺细胞的去分化。此外，体内神经损伤会导致相关雪旺细胞中持续的 ERK 信号传导。 Ras 信号传导被认为在 1 型神经纤维瘤病患者中施万细胞源性肿瘤的发生中起重要作用。我们的结果表明 Ras 信号传导对雪旺细胞分化状态的影响可能在这些肿瘤的发病机制中很重要。
Schwann cells are a regenerative cell type. Following nerve injury, a differentiated myelinating Schwann cell can dedifferentiate and regain the potential to proliferate. These cells then redifferentiate during the repair process. This behaviour is important for successful axonal repair, but the signalling pathways mediating the switch between the two differentiation states remain unclear. Sustained activation of the Ras/Raf/ERK cascade in primary cells results in a cell cycle arrest and has been implicated in the differentiation of certain cell types, in many cases acting to promote differentiation. We therefore investigated its effects on the differentiation state of Schwann cells. Surprisingly, we found that Ras/Raf/ERK signalling drives the dedifferentiation of Schwann cells even in the presence of normal axonal signalling. Furthermore, nerve wounding in vivo results in sustained ERK signalling in associated Schwann cells. Elevated Ras signalling is thought to be important in the development of Schwann cell-derived tumours in neurofibromatosis type 1 patients. Our results suggest that the effects of Ras signalling on the differentiation state of Schwann cells may be important in the pathogenesis of these tumours.