Ohno Mikiko, Hiraoka Yoshinori, Matsuoka Tatsuhiko, Tomimoto Hidekazu, Takao Keizo, Miyakawa Tsuyoshi, Oshima Naoko, Kiyonari Hiroshi, Kimura Takeshi, Kita Toru, Nishi Eiichiro
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Nat Neurosci. 2009 Dec;12(12):1506-13. doi: 10.1038/nn.2438.
Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1-/- mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1-/- mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1-/- mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.
轴突成熟和髓鞘形成是建立高效神经元信号网络的重要过程。我们发现，nardilysin（N - 精氨酸二肽基肽酶，也称为Nrd1和NRDc），一种蛋白质胞外域脱落的金属内肽酶增强剂，是这些过程的关键调节因子。Nrd1基因敲除小鼠的脑体积较小，大脑皮层较薄，其中髓鞘化纤维较少，髓鞘较薄，轴突直径较小。我们还发现Nrd1基因敲除小鼠的外周神经系统（PNS）存在髓鞘形成不足的情况。神经元特异性过表达NRDc会诱导髓鞘过度形成，这表明神经元NRDc的水平调节髓鞘厚度。与这些发现一致，Nrd1基因敲除小鼠存在运动活动受损和认知缺陷。此外，NRDc增强了神经调节蛋白1（NRG1）的胞外域脱落，而NRG1是PNS中髓鞘形成的主要调节因子。基于这些数据，我们提出NRDc部分通过调节NRG1的脱落来调节中枢神经系统和外周神经系统中的轴突成熟和髓鞘形成。
