Arf6 mediates Schwann cell differentiation and myelination.
Arf6 mediates Schwann cell differentiation and myelination.
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DOI：
10.1016/j.bbrc.2015.08.038
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发表时间：
2015-09
影响因子：
3.1
通讯作者：
Tomohiro Torii;Y. Miyamoto;Masahiro Yamamoto;Katsuya Ohbuchi;H. Tsumura;K. Kawahara;A. Tanoue;H. Sakagami;J. Yamauchi
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文献类型：
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作者：
Tomohiro Torii;Y. Miyamoto;Masahiro Yamamoto;Katsuya Ohbuchi;H. Tsumura;K. Kawahara;A. Tanoue;H. Sakagami;J. Yamauchi
在周围神经系统(PNS)的发育过程中，雪旺细胞包裹神经元轴突，成为帮助轴突功能的髓鞘。虽然控制雪旺细胞和外周神经元之间髓鞘形成过程的细胞间信号已经被很好地研究，但这些信号在雪旺细胞中的转导仍然是难以捉摸的。在这里，我们展示了Arf6，一个小GTPase家族的Arf蛋白，参与促进髓鞘形成过程。在原代雪旺细胞中，用小干扰(Si)RNA敲除Arf6可显著降低二丁基环腺苷诱导的髓鞘标志物蛋白的表达，表明Arf6在分化样表型改变中起作用。为了获得活体证据，我们培育了靶向Arf6的雪旺细胞的小发夹(Sh)RNA转基因小鼠。与对照组相比，转基因小鼠的髓鞘厚度降低，这与转基因小鼠来源的雪旺细胞和神经元培养系统中观察到的髓鞘形成缺陷一致。转基因小鼠还表现出与髓鞘形成相关的信号分子，如Akt激酶级联蛋白的磷酸化水平降低，以及髓鞘标记蛋白的下调。这些结果表明，雪旺细胞髓鞘形成需要通过Arf6进行信号传递，从而将Arf6添加到参与髓鞘形成过程的细胞内信号分子名单中。
During development of the peripheral nervous system (PNS), Schwann cells wrap neuronal axons, becoming the myelin sheaths that help axonal functions. While the intercellular signals controlling the myelination process between Schwann cells and peripheral neurons are well studied, the transduction of these signals in Schwann cells still remains elusive. Here, we show that Arf6, an Arf protein of the small GTPase family, is involved in promoting the myelination process. Knockdown of Arf6 with the small-interfering (si)RNA in primary Schwann cells markedly decreases dibutyl-cyclic AMP-induced myelin marker protein expression, indicating that Arf6 plays a role in differentiation-like phenotypic changes. To obtainin vivoevidence, we generated small-hairpin (sh)RNA transgenic mice targeting Arf6 for Schwann cells. Transgenic mice exhibited reduced myelin thickness compared to littermate controls, consistent with the defective myelin formation observed in the transgenic mouse-derived Schwann cell and neuronal culture system. Transgenic mice also exhibited decreased phosphorylation of myelination-related signaling molecules such as Akt kinase cascade proteins as well as downregulation of myelin marker proteins. These results suggest that signaling through Arf6 is required for Schwann cell myelination, adding Arf6 to the list of intracellular signaling molecules involved in the myelination process.