Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge
Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge
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DOI：
10.1093/brain/awt130
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发表时间：
2013-07-01
期刊：
影响因子：
14.5
通讯作者：
Cabedo, Hugo
中科院分区：
文献类型：
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作者：
Antonio Gomez-Sanchez, Jose;Gomis-Coloma, Clara;Cabedo, Hugo
周围神经中雪旺细胞的数量与轴突长度相吻合。当致瘤刺激诱导不受控制的许旺细胞增殖时，这种关系就丧失了，产生了神经纤维瘤和许旺细胞瘤等肿瘤。在沃勒变性过程中，神经损伤后，雪旺细胞也重新进入细胞周期。在这两种情况下，扩散最终都得到了遏制。我们发现，在神经纤维瘤中，诱导Jmjd 3（含jumonji结构域3，组蛋白赖氨酸脱甲基酶）去除组蛋白-H3的赖氨酸-27上的三甲基基团，并表观遗传激活Ink 4a/Arf-位点，迫使许旺细胞走向复制性衰老。值得注意的是，阻断这种机制允许不受限制的增殖，诱导神经纤维瘤的恶性转化。有趣的是，我们的数据表明，在受损的神经中，许旺细胞表观遗传激活相同的位点来关闭增殖并进入衰老程序。事实上，当这种途径被遗传阻断时，许旺细胞无法退出细胞周期并继续增殖。我们假设Ink 4a/Arf基因座表达为生理反应的一部分，该生理反应防止神经再生期间产生的去分化的雪旺细胞的不受控制的增殖，该反应也被激活以避免在外周神经系统中的致瘤性刺激后过度增殖。
The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration. In both cases proliferation is finally arrested. We show that in neurofibroma, the induction of Jmjd3 (jumonji domain containing 3, histone lysine demethylase) removes trimethyl groups on lysine-27 of histone-H3 and epigenetically activates the Ink4a/Arf-locus, forcing Schwann cells towards replicative senescence. Remarkably, blocking this mechanism allows unrestricted proliferation, inducing malignant transformation of neurofibromas. Interestingly, our data suggest that in injured nerves, Schwann cells epigenetically activate the same locus to switch off proliferation and enter the senescence programme. Indeed, when this pathway is genetically blocked, Schwann cells fail to drop out of the cell cycle and continue to proliferate. We postulate that the Ink4a/Arf-locus is expressed as part of a physiological response that prevents uncontrolled proliferation of the de-differentiated Schwann cell generated during nerve regeneration, a response that is also activated to avoid overproliferation after tumorigenic stimuli in the peripheral nervous system.