Dominant-negative β1 integrin mice have region-specific myelin defects accompanied by alterations in NL4PK activity
Dominant-negative β1 integrin mice have region-specific myelin defects accompanied by alterations in NL4PK activity
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DOI：
10.1002/glia.20343
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发表时间：
2006-06-01
期刊：
影响因子：
6.2
通讯作者：
Kothary, R
中科院分区：
文献类型：
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作者：
Lee, KK;De Repentigny, Y;Kothary, R
最近的研究表明，β1整合素在少突胶质细胞体外成熟过程中具有重要作用。由于整合素亚单位零突变对胚胎和围产期的致命性，体内类似的研究一直很困难。在这里，我们已经建立了在蛋白脂蛋白(PLP)启动子的控制下过表达全长β1整合素或表达显性负的β1整合素Delta C(缺少C末端尾巴)的转基因小鼠模型。我们证明，这些转基因主要在中枢神经系统组织中表达，更具特异性地在少突胶质细胞中表达。进一步的分析表明，显性阴性的β1整合素Delta C转基因小鼠，而不是全长的β1整合素小鼠，在脊髓和视神经中有低髓鞘轴突。此外，在β1整合素Delta C小鼠中，脊髓和视神经中的无髓鞘轴突数量显著增加。相比之下，这些小鼠的胼胝体并没有表现出类似的髓鞘缺陷。为了评估重新髓鞘形成是否会影响到胼胝体，对小鼠进行了铜酮诱导的脱髓鞘实验。有趣的是，显性阴性的小鼠从这种侮辱中恢复过来的方式与野生型小鼠相似。已重新髓鞘的胼胝体内的轴突具有正常的g-比率；然而，与野生型小鼠相比，有髓轴突的实际百分比显著降低。我们还表明，在显性阴性的β1整合素Delta C小鼠中观察到的缺陷伴随着MAP-K信号通路的中断。我们的工作强调了β1整合素介导的信号在体内中枢神经系统髓鞘形成中的重要性。(C)2006年Wiley-Liss，Inc.
Recent studies have demonstrated the importance of beta 1 integrin in oligodendrocyte maturation in vitro. Similar studies in vivo have been difficult due to the embryonic and perinatal lethality of null mutations in integrin subunits. Here, we have generated transgenic mouse models that overexpress full length beta 1 integrin or express a dominant-negative beta 1 integrin Delta C (lacking the C-terminal tail) under the control of the proteolipid protein (PLP) promoter. We demonstrate that these transgenes are expressed predominantly in CNS tissues and more specifically in oligodendrocytes. Further analysis reveals that the dominant-negative beta 1 integrin Delta C transgenic mice, but not the full length beta 1 integrin mice, have hypomyelinated axons in spinal cords and optic nerves. In addition, there is a significant increase in the number of unmyelinated axons within the spinal cords and optic nerves of the beta 1 integrin Delta C mice. In contrast, the corpus callosum from these mice did not show similar myelin defects. To assess if remyelination would be affected in the corpus callosum, mice were subjected to a cuprizone-induced demyelination. Interestingly, the dominant-negative mice recovered from this insult in a manner similar to the wild type littermates. Axons within the corpus callosum that were remyelinated had normal g-ratios; however, the actual percentage of myelinated axons was significantly reduced compared with wild type mice. We also show that the defects observed in the dominant-negative beta 1 integrin Delta C mice are accompanied by disruption of the MAP-kinase signaling pathway. Our work highlights the importance of beta 1 integrin-mediated signaling in CNS myelination in vivo. (c) 2006 Wiley-Liss, Inc.