Miyamoto Yuki, Torii Tomohiro, Homma Keiichi, Oizumi Hiroaki, Ohbuchi Katsuya, Mizoguchi Kazushige, Takashima Shou, Yamauchi Junji
Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Laboratory of Molecular Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
Sci Signal. 2022 Jan 25;15(718):eabi5276. doi: 10.1126/scisignal.abi5276.
Mature myelin sheaths insulate axons to increase nerve conduction velocity and protect nerve fibers from stress and physical injury. In the peripheral nervous system, the myelin sheath is produced by Schwann cells. The guanine-nucleotide exchange factor cytohesin-2 activates the protein Arf6 to promote Schwann cell myelination. Here, we investigated the regulation of cytohesin-2 and found that the phosphorylation status of Tyr in cytohesin-2 is central to Schwann cell myelination. Knockin mice with a nonphosphorylatable Y381F mutation in cytohesin-2 exhibited reduced myelin thickness and decreased Arf6 activity in sciatic nerve tissue. In HEK293T cells, cytohesin-2 was dephosphorylated at Tyr by the protein tyrosine phosphatase PTP4A1, whereas phosphorylation at this site was maintained by interaction with the adaptor protein SH2B1. Schwann cell-specific knockdown of PTP4A1 in mice increased cytohesin-2 phosphorylation and myelin thickness. Conversely, Schwann cell-specific loss of SH2B1 resulted in reduced myelin thickness and decreased cytohesin-2 phosphorylation. Thus, a signaling unit centered on cytohesin-2-with SH2B1 as a positive regulator and PTP4A1 as a negative regulator-controls Schwann cell myelination in the peripheral nervous system.
成熟的髓鞘包裹轴突，以提高神经传导速度，并保护神经纤维免受压力和物理损伤。在周围神经系统中，髓鞘由施万细胞产生。鸟嘌呤核苷酸交换因子细胞粘附分子2激活蛋白Arf6以促进施万细胞髓鞘形成。在此，我们研究了细胞粘附分子2的调控机制，发现细胞粘附分子2中酪氨酸的磷酸化状态对施万细胞髓鞘形成至关重要。在细胞粘附分子2中具有不可磷酸化的Y381F突变的敲入小鼠，其坐骨神经组织中的髓鞘厚度降低，Arf6活性下降。在HEK293T细胞中，蛋白酪氨酸磷酸酶PTP4A1使细胞粘附分子2的酪氨酸去磷酸化，而与衔接蛋白SH2B1的相互作用则维持该位点的磷酸化。在小鼠中施万细胞特异性敲低PTP4A1可增加细胞粘附分子2的磷酸化和髓鞘厚度。相反，施万细胞特异性缺失SH2B1会导致髓鞘厚度降低和细胞粘附分子2磷酸化减少。因此，以细胞粘附分子2为中心的信号传导单元——以SH2B1作为正调节因子，PTP4A1作为负调节因子——控制周围神经系统中施万细胞的髓鞘形成。
