Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milan, Italy 20132.
Hunter James Kelly Research Institute.
J Neurosci. 2018 May 2;38(18):4275-4287. doi: 10.1523/JNEUROSCI.0201-18.2018. Epub 2018 Apr 2.
Schwann cell differentiation and myelination in the PNS are the result of fine-tuning of positive and negative transcriptional regulators. As myelination starts, negative regulators are downregulated, whereas positive ones are upregulated. Fully differentiated Schwann cells maintain an extraordinary plasticity and can transdifferentiate into "repair" Schwann cells after nerve injury. Reactivation of negative regulators of myelination is essential to generate repair Schwann cells. Negative regulators have also been implicated in demyelinating neuropathies, although their role in disease remains elusive. Here, we used a mouse model of Charcot-Marie-Tooth neuropathy type 1B (CMT1B), the P0S63del mouse characterized by ER stress and the activation of the unfolded protein response, to show that adult Schwann cells are in a partial differentiation state because they overexpress transcription factors that are normally expressed only before myelination. We provide evidence that two of these factors, Sox2 and Id2, act as negative regulators of myelination However, their sustained expression in neuropathy is protective because ablation of Sox2 or/and Id2 from S63del mice of both sexes results in worsening of the dysmyelinating phenotype. This is accompanied by increased levels of mutant P0 expression and exacerbation of ER stress, suggesting that limited differentiation may represent a novel adaptive mechanism through which Schwann cells counter the toxic effect of a mutant terminal differentiation protein. In many neuropathies, Schwann cells express high levels of early differentiation genes, but the significance of these altered expression remained unclear. Because many of these factors may act as negative regulators of myelination, it was suggested that their misexpression could contribute to dysmyelination. Here, we show that the transcription factors Sox2 and Id2 act as negative regulators of myelination , but that their sustained expression in Charcot-Marie-Tooth type 1B (CMT1B) represents an adaptive response activated by the Schwann cells to reduce mutant protein toxicity and prevent demyelination.
施万细胞在周围神经系统中的分化和髓鞘形成是正、负转录调控因子精细调控的结果。髓鞘形成开始时，负调控因子下调，而正调控因子上调。完全分化的施万细胞保持着非凡的可塑性，在神经损伤后可以转分化为“修复”施万细胞。髓鞘形成的负调控因子的重新激活对于产生修复施万细胞是至关重要的。负调控因子也与脱髓鞘神经病变有关，尽管它们在疾病中的作用仍不清楚。在这里，我们使用 1B 型腓骨肌萎缩症（CMT1B）的小鼠模型，即 P0S63del 小鼠，其特征是内质网应激和未折叠蛋白反应的激活，表明成年施万细胞处于部分分化状态，因为它们过度表达正常仅在髓鞘形成前表达的转录因子。我们提供的证据表明，这两个因子，Sox2 和 Id2，作为髓鞘形成的负调控因子起作用。然而，它们在神经病变中的持续表达是保护性的，因为从 S63del 雌雄小鼠中敲除 Sox2 或/和 Id2 会导致脱髓鞘表型恶化。这伴随着突变 P0 表达水平的增加和内质网应激的加剧，表明有限的分化可能是施万细胞对抗突变终末分化蛋白毒性的一种新的适应性机制。在许多神经病变中，施万细胞表达高水平的早期分化基因，但这些改变的表达意义仍不清楚。由于许多这些因子可能作为髓鞘形成的负调控因子起作用，因此有人提出它们的异常表达可能导致脱髓鞘。在这里，我们表明转录因子 Sox2 和 Id2 作为髓鞘形成的负调控因子起作用，但它们在 1B 型腓骨肌萎缩症（CMT1B）中的持续表达代表了施万细胞激活的一种适应性反应，以降低突变蛋白毒性并防止脱髓鞘。
