Hunter James Kelly Research Institute, University at Buffalo, Buffalo, NY, USA.
Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Hum Mol Genet. 2019 Apr 15;28(8):1260-1273. doi: 10.1093/hmg/ddy420.
Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.
髓鞘厚度精确调节，对于有髓轴突中动作电位的快速传播至关重要。在周围神经系统中，来自轴突蛋白神经调节蛋白 1 型 III（NRG1 型 III）的外在信号调节许旺细胞的命运和髓鞘形成。在这里，我们询问在先天性少突胶质细胞髓鞘营养不良（CHN）模型中调节神经元中 NRG1 型 III 的水平是否会恢复髓鞘形成。我们使用 CHN 的小鼠模型，通过早期过表达 NRG1 型 III 改善了髓鞘缺陷。令人惊讶的是，这种改善与 Egr2 或必需髓鞘基因的上调无关。相反，我们观察到 MAPK/ERK 的激活和其他髓鞘基因，如外周髓鞘蛋白 2 和少突胶质细胞髓鞘糖蛋白。我们还证实，MAPK/ERK 在许旺细胞中的永久激活对髓鞘形成有不利影响。我们的研究结果表明，在 CHN 模型中，调节轴突-神经胶质 NRG1 型 III 信号具有有益作用，并改善了发育过程中的髓鞘缺陷。
