Wu W, Toma J G, Chan H, Smith R, Miller F D
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Canada.
Dev Biol. 1994 Jun;163(2):423-39. doi: 10.1006/dbio.1994.1159.
Following nerve injury, Schwann cells distal to the site of injury down-regulate genes associated with myelination. We hypothesized that at least some of these alterations were due to the loss of ongoing axon:Schwann cell homeostatic signals, as opposed to loss of physical contact and/or inflammatory responses. To directly test this hypothesis, we perturbed axonal physiology by selectively blocking fast axonal transport via locally cooling the sciatic nerve to 5-8 degrees C (a cold block). Immunostaining with the monoclonal antibody ED1, which recognizes mononuclear phagocytic cells, demonstrated that macrophages did not invade the cold-blocked nerve, indicating the lack of an inflammatory response. Morphological studies demonstrated that the nerve distal to the cold block showed no signs of Wallerian degeneration, with maintenance of normal axon and myelin profiles, and confirmed the absence of invading macrophages. Thus, any effects of a cold-block treatment were not likely due to inflammatory responses or to loss of physical contact between axons and Schwann cells. To determine whether this treatment affected Schwann cell phenotype, we examined expression of the major myelin protein P0, and p75 NGF receptor, both of which are regulated as a function of axon:Schwann cell interactions. Levels of p75 NGF receptor mRNA were unaffected by the cold block, while p75 NGF receptor protein levels were increased in the region of the nerve immediately adjacent to the cold block, presumably reflecting protein accumulation as a consequence of the block to fast axonal transport. In contrast, levels of P0 mRNA were decreased in the distal nerve in a fashion that indicated modulation of Schwann cell phenotype as a function of local axonal microenvironment. These data therefore suggest that P0 and p75 NGF receptor are regulated as a function of two different aspects of Schwann cell:axon communication. Furthermore, these data demonstrate that the presence of axon:Schwann cell contact alone is insufficient to maintain Po gene expression and indicate that at least some myelin-specific Schwann cell responses are dependent upon ongoing biochemical signals generated by the axon and maintained by fast axonal transport.
神经损伤后，损伤部位远端的施万细胞会下调与髓鞘形成相关的基因。我们推测，这些改变中至少有一些是由于轴突与施万细胞之间持续的稳态信号丧失所致，而非物理接触的丧失和/或炎症反应。为了直接验证这一假设，我们通过将坐骨神经局部冷却至5-8摄氏度（冷阻断）来选择性阻断快速轴突运输，从而扰乱轴突生理功能。用识别单核吞噬细胞的单克隆抗体ED1进行免疫染色表明，巨噬细胞未侵入冷阻断的神经，这表明不存在炎症反应。形态学研究表明，冷阻断远端的神经没有沃勒变性的迹象，轴突和髓鞘轮廓保持正常，并证实没有巨噬细胞侵入。因此，冷阻断治疗的任何效果不太可能是由于炎症反应或轴突与施万细胞之间物理接触的丧失。为了确定这种治疗是否影响施万细胞表型，我们检测了主要髓鞘蛋白P0和p75神经生长因子受体的表达，这两者均受轴突与施万细胞相互作用的调节。冷阻断对p75神经生长因子受体mRNA水平没有影响，而在紧邻冷阻断的神经区域，p75神经生长因子受体蛋白水平升高，这可能反映了由于快速轴突运输受阻导致的蛋白积累。相反，远端神经中P0 mRNA水平降低，表明施万细胞表型根据局部轴突微环境进行了调节。因此，这些数据表明，P0和p75神经生长因子受体受施万细胞与轴突通讯的两个不同方面的调节。此外，这些数据表明，仅轴突与施万细胞接触的存在不足以维持P0基因表达，并表明至少一些髓鞘特异性施万细胞反应依赖于轴突产生并由快速轴突运输维持的持续生化信号。
