In the central nervous system, oligodendrocyte precursor cells differentiate into oligodendrocytes to wrap their plasma membranes around neuronal axons, generating mature neural networks with myelin sheaths according to spatial and temporal patterns. While myelination is known to be one of the most dynamic cell morphological changes, the overall intrinsic and extrinsic molecular cues controlling myelination remain to be fully clarified. Here, we describe the biphasic roles of Rnd2, an atypical branch of the Rho family GTPase, in oligodendrocyte myelination during development and after maturation in mice. Compared with littermate controls, oligodendrocyte-specific Rnd2 knockout mice exhibit decreased myelin thickness at the onset of myelination but increased myelin thickness in the later period. Larger proportions of Rho kinase and its substrate Mbs, the signaling unit that negatively regulates oligodendrocyte myelination, are phosphorylated at the onset of myelination, while their smaller proportions are phosphorylated in the later period. In addition, we confirm the biphasic role of Rnd2 through experiments with oligodendrocyte-specific Rnd2 transgenic mice. We conclude that Rnd2 positively regulates myelination in the early myelinating period and negatively regulates myelination in the later period. This unique modulator thus plays different roles depending on the myelination period.

在中枢神经系统中，少突胶质细胞前体细胞分化为少突胶质细胞，将它们的质膜包裹在神经元轴突周围，根据时空模式生成具有髓鞘的成熟神经网络。虽然已知髓鞘形成是最具活力的细胞形态变化之一，但控制髓鞘形成的整体内在和外在分子线索仍有待完全阐明。在这里，我们描述了 Rnd2（Rho 家族 GTPase 的非典型分支）在小鼠发育过程中和成熟后少突胶质细胞髓鞘形成中的双相作用。与同窝对照相比，少突胶质细胞特异性 Rnd2 敲除小鼠在髓鞘形成开始时表现出髓鞘厚度降低，但在后期髓鞘厚度增加。较大比例的 Rho 激酶及其底物 Mbs（负调节少突胶质细胞髓鞘形成的信号单元）在髓鞘形成开始时被磷酸化，而它们的较小比例在后期被磷酸化。此外，我们通过少突胶质细胞特异性 Rnd2 转基因小鼠的实验证实了 Rnd2 的双相作用。我们得出结论，Rnd2 在髓鞘形成早期正向调节髓鞘形成，在髓鞘形成后期负向调节髓鞘形成。因此，这种独特的调节剂根据髓鞘形成时期发挥不同的作用。我们通过少突胶质细胞特异性 Rnd2 转基因小鼠的实验证实了 Rnd2 的双相作用。我们得出结论，Rnd2 在髓鞘形成早期正向调节髓鞘形成，在髓鞘形成后期负向调节髓鞘形成。因此，这种独特的调节剂根据髓鞘形成时期发挥不同的作用。我们通过少突胶质细胞特异性 Rnd2 转基因小鼠的实验证实了 Rnd2 的双相作用。我们得出结论，Rnd2 在髓鞘形成早期正向调节髓鞘形成，在髓鞘形成后期负向调节髓鞘形成。因此，这种独特的调节剂根据髓鞘形成时期发挥不同的作用。