Toews A D, Griffiths I R, Kyriakides E, Goodrum J F, Eckermann C E, Morell P, Thomson C E
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599.
J Neurosci. 1992 Sep;12(9):3676-87. doi: 10.1523/JNEUROSCI.12-09-03676.1992.
Exposure of developing rats to tellurium results in a highly synchronous segmental demyelination of peripheral nerves with sparing of axons; this demyelination is followed closely by a period of rapid remyelination. Demyelination occurs subsequent to a tellurium-induced block in the synthesis of cholesterol, the major myelin lipid. We utilized the techniques of Northern blotting, in situ hybridization, and immunocytochemistry to examine temporal alterations in Schwann cell gene expression related to demyelination and remyelination. Tellurium-induced demyelination is associated with downregulation of myelin protein expression and a corresponding upregulation of NGF receptor (NGF-R) and glial fibrillary acidic protein (GFAP) expression. Steady-state mRNA levels (expressed on a "per nerve" basis) for P0, the major myelin protein, were decreased by about 50% after 5 d of tellurium exposure, while levels of mRNA for NGF-R and GFAP were markedly increased (about 15-fold). In situ hybridization of teased fibers suggested that the increase in steady-state mRNA levels for NGF-R was primarily associated with demyelinated internodes and not with adjacent unaffected internodes. Although P0 message was almost totally absent from demyelinating internodes, it was also reduced in normal-appearing internodes as well. This suggests that limiting the supply of a required membrane component (cholesterol) may lead to partial downregulation of myelin gene expression in all myelinating Schwann cells. In partially demyelinated internodes, NGF-R and GFAP immunofluorescence appeared largely confined to the demyelinated regions. This suggests specific targeting of these proteins to local areas of the Schwann cell where there is myelin loss. These results demonstrate that demyelination is associated with reversion of the affected Schwann cells to a precursor cell phenotype. Because axons remain intact, our results suggest that these changes in Schwann cell gene expression do not require input from a degenerating axon, but instead may depend on whether concerted synthesis of myelin is occurring.
发育中的大鼠接触碲会导致外周神经高度同步的节段性脱髓鞘，轴突不受影响；这种脱髓鞘之后紧接着是快速的髓鞘再生期。脱髓鞘发生在碲诱导的胆固醇（主要的髓磷脂脂质）合成受阻之后。我们利用Northern印迹、原位杂交和免疫细胞化学技术来检测雪旺细胞基因表达与脱髓鞘和髓鞘再生相关的时间变化。碲诱导的脱髓鞘与髓磷脂蛋白表达下调以及相应的神经生长因子受体（NGF-R）和胶质纤维酸性蛋白（GFAP）表达上调有关。主要髓磷脂蛋白P0的稳态mRNA水平（以“每根神经”为基础表示）在接触碲5天后降低了约50%，而NGF-R和GFAP的mRNA水平则显著增加（约15倍）。对 teased纤维的原位杂交表明，NGF-R稳态mRNA水平的增加主要与脱髓鞘节段相关，而与相邻未受影响的节段无关。尽管脱髓鞘节段几乎完全没有P0信息，但在外观正常的节段中也有所减少。这表明限制所需膜成分（胆固醇）的供应可能导致所有正在形成髓鞘的雪旺细胞中髓磷脂基因表达的部分下调。在部分脱髓鞘节段中，NGF-R和GFAP免疫荧光主要局限于脱髓鞘区域。这表明这些蛋白质特异性地靶向雪旺细胞中存在髓磷脂丢失的局部区域。这些结果表明，脱髓鞘与受影响的雪旺细胞向祖细胞表型的转变有关。由于轴突保持完整，我们的结果表明，雪旺细胞基因表达的这些变化不需要来自退化轴突的输入，而是可能取决于髓磷脂的协同合成是否正在发生。
