Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Department of Biomedicine, University Hospital Basel, Basel 4031, Switzerland.
Neuron. 2019 Jan 16;101(2):224-231.e5. doi: 10.1016/j.neuron.2018.11.032. Epub 2018 Dec 11.
The initiation of axoglial contact is considered a prerequisite for myelination, yet the role cell adhesion molecules (CAMs) play in mediating such interactions remains unclear. To examine the function of axoglial CAMs, we tested whether enhanced CAM-mediated adhesion between OLs and neurons could affect myelination. Here we show that increased expression of a membrane-bound extracellular domain of Cadm4 (Cadm4dCT) in cultured oligodendrocytes results in the production of numerous axoglial contact sites that fail to elongate and generate mature myelin. Transgenic mice expressing Cadm4dCT were hypomyelinated and exhibit multiple myelin abnormalities, including myelination of neuronal somata. These abnormalities depend on specific neuron-glial interaction as they were not observed when these OLs were cultured alone, on nanofibers, or on neurons isolated from mice lacking the axonal receptors of Cadm4. Our results demonstrate that tightly regulated axon-glia adhesion is essential for proper myelin targeting and subsequent membrane wrapping and lateral extension.
轴突与神经胶质细胞的接触起始被认为是髓鞘形成的前提条件，但细胞黏附分子 (CAMs) 在介导这种相互作用中的作用仍不清楚。为了研究轴突与神经胶质细胞 CAM 的功能，我们测试了增强 OLs 和神经元之间的 CAM 介导的黏附是否会影响髓鞘形成。在这里，我们表明，培养的少突胶质细胞中 Cadm4 的膜结合细胞外结构域（Cadm4dCT）表达增加，导致产生许多未能延长和产生成熟髓鞘的轴突与神经胶质接触位点。表达 Cadm4dCT 的转基因小鼠表现出髓鞘减少和多种髓鞘异常，包括神经元胞体的髓鞘形成。这些异常取决于特定的神经元-神经胶质相互作用，因为当这些 OLs 单独培养、在纳米纤维上培养或在缺乏 Cadm4 轴突受体的神经元中培养时，没有观察到这些异常。我们的结果表明，紧密调节的轴突-神经胶质黏附对于正确的髓鞘靶向以及随后的膜包裹和侧向延伸是必不可少的。
