Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell-Axon Interface and in the Initiation of Myelination
Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell-Axon Interface and in the Initiation of Myelination
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DOI：
10.1523/jneurosci.4345-10.2011
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发表时间：
2011-02-23
影响因子：
5.3
通讯作者：
Chan, Jonah R.
中科院分区：
文献类型：
--
作者：
Lewallen, Kathryn A.;Shen, Yun-An A.;Chan, Jonah R.
髓鞘形成依赖于雪旺细胞（SC）和轴突之间复杂的相互作用。最近的证据表明，SC轴突接口代表髓鞘形成必不可少的膜专业化，然而，这种极化顶端域的产生方式仍然是一个谜。细胞粘附分子N-钙粘蛋白在SC-轴突界面富集，并与极性蛋白Par-3共定位。在SC-SC和SC-轴突接触上诱导不对称定位。与DRG神经元共培养的SC中N-钙粘蛋白的敲低破坏了Par-3定位并延迟了髓鞘形成的起始。然而，敲低或过度表达神经元N-钙粘蛋白不影响Par-3或髓鞘形成的分布，这表明SC和轴突N-钙粘蛋白之间的同型相互作用是不是必不可少的周围髓鞘形成的事件。为了进一步研究N-钙粘蛋白的作用，产生并表征了显示N-钙粘蛋白的SC特异性基因消融的小鼠。令人惊讶的是，髓鞘形成仅稍微延迟，并且小鼠是存活的，没有任何可检测到的髓鞘形成缺陷。β-连环蛋白是N-钙粘蛋白的下游效应物，在髓鞘形成的起始时与N-钙粘蛋白共定位和共免疫沉淀。为了确定β-连环蛋白是否介导对N-钙粘蛋白缺失的补偿，产生并表征了β-连环蛋白的SC特异性基因消融。与我们的假设一致，髓鞘形成比单独操纵N-钙粘蛋白时更严重延迟，但髓鞘没有任何缺陷。总之，我们的研究结果表明，N-钙粘蛋白与β-连环蛋白在建立SC极性和髓鞘形成的及时启动中相互作用，但它们是髓鞘形成和成熟的非必需组分。
Myelination is dependent on complex reciprocal interactions between the Schwann cell (SC) and axon. Recent evidence suggests that the SC-axon interface represents a membrane specialization essential for myelination; however, the manner in which this polarized-apical domain is generated remains a mystery. The cell adhesion molecule N-cadherin is enriched at the SC-axon interface and colocalizes with the polarity protein Par-3. The asymmetric localization is induced on SC-SC and SC-axon contact. Knockdown of N-cadherin in SCs cocultured with DRG neurons disrupts Par-3 localization and delays the initiation of myelination. However, knockdown or overexpression of neuronal N-cadherin does not influence the distribution of Par-3 or myelination, suggesting that homotypic interactions between SC and axonal N-cadherin are not essential for the events surrounding myelination. To further investigate the role of N-cadherin, mice displaying SC-specific gene ablation of N-cadherin were generated and characterized. Surprisingly, myelination is only slightly delayed, and mice are viable without any detectable myelination defects. beta-Catenin, a downstream effector of N-cadherin, colocalizes and coimmunoprecipitates with N-cadherin on the initiation of myelination. To determine whether beta-catenin mediates compensation on N-cadherin deletion, SC-specific gene ablation of beta-catenin was generated and characterized. Consistent with our hypothesis, myelination is more severely delayed than when manipulating N-cadherin alone, but without any defect to the myelin sheath. Together, our results suggest that N-cadherin interacts with beta-catenin in establishing SC polarity and the timely initiation of myelination, but they are nonessential components for the formation and maturation of the myelin sheath.