Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy.
Development. 2012 Apr;139(7):1359-67. doi: 10.1242/dev.072371. Epub 2012 Feb 22.
Myelination is a complex process that requires coordinated Schwann cell-axon interactions during development and regeneration. Positive and negative regulators of myelination have been recently described, and can belong either to Schwann cells or neurons. Vimentin is a fibrous component present in both Schwann cell and neuron cytoskeleton, the expression of which is timely and spatially regulated during development and regeneration. We now report that vimentin negatively regulates myelination, as loss of vimentin results in peripheral nerve hypermyelination, owing to increased myelin thickness in vivo, in transgenic mice and in vitro in a myelinating co-culture system. We also show that this is due to a neuron-autonomous increase in the levels of axonal neuregulin 1 (NRG1) type III. Accordingly, genetic reduction of NRG1 type III in vimentin-null mice rescues hypermyelination. Finally, we demonstrate that vimentin acts synergistically with TACE, a negative regulator of NRG1 type III activity, as shown by hypermyelination of double Vim/Tace heterozygous mice. Our results reveal a novel role for the intermediate filament vimentin in myelination, and indicate vimentin as a regulator of NRG1 type III function.
髓鞘形成是一个复杂的过程，需要在发育和再生过程中协调施万细胞-轴突相互作用。髓鞘形成的正、负调节剂最近已被描述，它们可以属于施万细胞或神经元。波形蛋白是存在于施万细胞和神经元细胞骨架中的纤维成分，其表达在发育和再生过程中是时间和空间调节的。我们现在报告说，波形蛋白负调节髓鞘形成，因为波形蛋白的缺失导致周围神经过度髓鞘化，这是由于体内、转基因小鼠和体外髓鞘形成共培养系统中髓鞘厚度增加所致。我们还表明，这是由于神经元自主增加了轴突神经调节蛋白 1（NRG1）III 型的水平。因此，在波形蛋白缺失小鼠中降低 NRG1 III 型的遗传水平可挽救过度髓鞘化。最后，我们证明波形蛋白与 TACE 协同作用，TACE 是 NRG1 III 型活性的负调节剂，如双 Vim/Tace 杂合子小鼠的过度髓鞘化所示。我们的研究结果揭示了中间丝波形蛋白在髓鞘形成中的一个新作用，并表明波形蛋白是 NRG1 III 型功能的调节剂。
