Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves.
Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves.
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DOI：
10.1016/j.bbrc.2015.03.113
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发表时间：
2015-05
影响因子：
3.1
通讯作者：
Tomohiro Torii;N. Ohno;Y. Miyamoto;K. Kawahara;Y. Saitoh;Kazuaki Nakamura;S. Takashima;H. Sakagami;A. Tanoue;J. Yamauchi
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文献类型：
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作者：
Tomohiro Torii;N. Ohno;Y. Miyamoto;K. Kawahara;Y. Saitoh;Kazuaki Nakamura;S. Takashima;H. Sakagami;A. Tanoue;J. Yamauchi
在外周神经系统（PNS）发育过程中，雪旺细胞分化形成髓鞘隔离神经元轴突，增加神经传导速度。雪旺细胞在形成多层成熟髓鞘的过程中，经历了动态的形态学变化。虽然已知生长因子和细胞粘附配体等细胞外分子调节髓鞘形成过程，但髓鞘形成的细胞内分子机制尚不清楚。在这项研究中，我们制造了雪旺细胞特异性条件敲除小鼠，用于细胞素-2，一种特异性激活Arf6的鸟嘌呤核苷酸交换因子（GEF）。Arf6是ras样蛋白家族的一员，参与包括细胞形态改变在内的多种细胞功能。细胞hesin-2敲除小鼠表现出Arf6活性下降和坐骨神经髓鞘厚度减少，髓鞘蛋白0 （MPZ）表达水平下降，髓鞘蛋白0是主要的髓鞘标记蛋白。这些结果与用泛细胞分裂素抑制剂SecinH3处理雪旺细胞神经元培养物的实验结果一致。另一方面，在敲除小鼠和对照组中，ki67阳性细胞的数量是相当的，这表明cytohesin-2对细胞数量没有积极的影响。因此，雪旺细胞的髓鞘形成需要通过胞嘧啶-2的信号传导，并且胞嘧啶-2被添加到已知的PNS髓鞘形成的分子列表中。
In postnatal development of the peripheral nervous system (PNS), Schwann cells differentiate to insulate neuronal axons with myelin sheaths, increasing the nerve conduction velocity. To produce the mature myelin sheath with its multiple layers, Schwann cells undergo dynamic morphological changes. While extracellular molecules such as growth factors and cell adhesion ligands are known to regulate the myelination process, the intracellular molecular mechanism underlying myelination remains unclear. In this study, we have produced Schwann cell-specific conditional knockout mice for cytohesin-2, a guanine-nucleotide exchange factor (GEF) specifically activating Arf6. Arf6, a member of the Ras-like protein family, participates in various cellular functions including cell morphological changes. Cytohesin-2 knockout mice exhibit decreased Arf6 activity and reduced myelin thickness in the sciatic nerves, with decreased expression levels of myelin protein zero (MPZ), the major myelin marker protein. These results are consistent with those of experiments in which Schwann cell-neuronal cultures were treated with pan-cytohesin inhibitor SecinH3. On the other hand, the numbers of Ki67-positive cells in knockout mice and controls are comparable, indicating that cytohesin-2 does not have a positive effect on cell numbers. Thus, signaling through cytohesin-2 is required for myelination by Schwann cells, and cytohesin-2 is added to the list of molecules known to underlie PNS myelination.