Carenini S, Montag D, Schachner M, Martini R
Department of Neurobiology, Swiss Federal Institute of Technology, Hönggerberg, Zürich, Switzerland.
Glia. 1999 Sep;27(3):203-12.
Peripheral nerves of P0-deficient mice display a severe dysmyelinating phenotype, confirming the view that P0 mediates myelin formation and compaction. In addition to the compromised myelin organization, an elevated expression of several cell recognition molecules was described in the axon-Schwann cell units of P0-deficient mice. The present study was performed to focus on the subcellular localization and functional roles of two of these up-regulated molecules, the neural cell adhesion molecule (N-CAM) and the myelin-associated glycoprotein (MAG). We show by postembedding immunoelectron microscopy that in peripheral nerves of P0-deficient mice both molecules are expressed in noncompacted myelin-like regions. In addition, N-CAM, but not MAG, is detected in partially compacted myelin. By the generation of P0/N-CAM- and P0/MAG-deficient double mutants, we investigated the roles of the dysregulated molecules in P0-deficient mice. In 4-week-old double mutants, the dysmyelinating phenotype of the axon-Schwann cell units was very similar to that seen in the P0-deficient single mutants, suggesting that neither N-CAM nor MAG are responsible for the poor myelin compaction in P0-deficient mice. However, the noncompacted turns surrounding the abnormally compacted regions were significantly reduced in number in P0/MAG mutants as compared to P0 or N-CAM/P0 mice. During formation of myelin sheaths, absence of N-CAM resulted in a transient retardation of Schwann cell spiralling in P0-deficient mice, whereas absence of MAG impaired Schwann cell spiralling for a more extended time period. Our findings demonstrate for the first time that MAG and also N-CAM can play significant roles during myelin formation in the peripheral nervous system. Because these functional roles are detectable only in the absence of P0, our results confirm the view that myelin-related molecules can play distinct, but also partially overlapping roles.
P0基因缺陷小鼠的外周神经表现出严重的脱髓鞘表型，这证实了P0介导髓鞘形成和紧密化的观点。除了髓鞘结构受损外，P0基因缺陷小鼠的轴突-施万细胞单元中几种细胞识别分子的表达也有所升高。本研究旨在关注其中两种上调分子——神经细胞黏附分子（N-CAM）和髓鞘相关糖蛋白（MAG）的亚细胞定位和功能作用。我们通过包埋后免疫电子显微镜显示，在P0基因缺陷小鼠的外周神经中，这两种分子都在非紧密化的髓鞘样区域表达。此外，在部分紧密化的髓鞘中检测到了N-CAM，但未检测到MAG。通过构建P0/N-CAM和P0/MAG基因双缺陷突变体，我们研究了这些失调分子在P0基因缺陷小鼠中的作用。在4周龄的双突变体中，轴突-施万细胞单元的脱髓鞘表型与P0基因缺陷单突变体中所见的非常相似，这表明N-CAM和MAG都不是P0基因缺陷小鼠中髓鞘紧密化不良的原因。然而，与P0或N-CAM/P0小鼠相比，P0/MAG突变体中异常紧密化区域周围的非紧密化转折数量显著减少。在髓鞘形成过程中，N-CAM的缺失导致P0基因缺陷小鼠中施万细胞螺旋化出现短暂延迟，而MAG的缺失则在更长时间内损害施万细胞螺旋化。我们的研究首次表明，MAG以及N-CAM在外周神经系统髓鞘形成过程中可发挥重要作用。由于这些功能作用仅在P0缺失时才可检测到，我们的结果证实了髓鞘相关分子可发挥不同但也部分重叠作用的观点。
