Inhibition of Ras extracellular-signal-regulated kinase (ERK) mediated signaling promotes ciliary neurotrophic factor (CNTF) expression in Schwann cells
Inhibition of Ras extracellular-signal-regulated kinase (ERK) mediated signaling promotes ciliary neurotrophic factor (CNTF) expression in Schwann cells
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DOI：
10.1046/j.1471-4159.2001.00286.x
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发表时间：
2001-04-01
影响因子：
4.7
通讯作者：
Kiyama, H
中科院分区：
文献类型：
--
作者：
Abe, K;Namikawa, K;Kiyama, H
睫状体神经营养因子（CNTF）可预防损伤性运动神经元死亡。然而，同样明显的是，在神经再生过程中，雪旺细胞中CNTF的表达受到抑制。在本报告中，我们利用小鼠雪旺细胞系IMS32和小鼠坐骨神经探讨了CNTF在损伤神经中表达下调的机制。在IMS32细胞中，通过腺病毒载体介导的显性活性MEK1表达激活Ras细胞外信号调节激酶（ERK）途径不会改变CNTF表达的基础水平，而通过腺病毒载体抑制Ras-ERK途径导致CNTF表达显著增加。小鼠坐骨神经切开术前后也有明显的负相关。在坐骨神经切开后，磷酸化的ERK明显升高；相反，CNTF的表达明显降低。这些发现表明，在雪旺细胞中，ERK的失活状态对CNTF的表达至关重要，神经损伤后ERK的激活对CNTF的表达有重要影响。这可以很好地解释为什么CNTF在周围神经系统的静止雪旺细胞中高表达，以及为什么CNTF在增殖信号明显活跃的axoized神经或培养雪旺细胞中含量不丰富。
Ciliary neurotrophic factor (CNTF) can prevent injury-induced motor neuron death. However, it is also evident that expression of CNTF in Schwann cells is suppressed during nerve regeneration. In this report, we have addressed the mechanism underlying the down-regulation of CNTF expression in injured nerves using a mouse Schwann cell line IMS32 and mouse sciatic nerve. In IMS32 cells, activation of the Ras extracellular-signal-regulated kinase (ERK) pathway by adenoviral vector-mediated expression of dominant active MEK1 did not alter a basal level of CNTF expression, whereas inhibition of the Ras-ERK pathway by using adenoviral vectors resulted in a marked increase in CNTF expression. This inverse relation between before and after axotomy was also observed in mouse sciatic nerve. In the axotomized sciatic nerve, the phosphorylated ERK was markedly increased; in contrast, the expression of CNTF was markedly decreased. These findings suggest that an inactive state of ERK is crucial for the CNTF expression in Schwann cells, and that activation of ERK following nerve injury critically influences the expression of CNTF. This might well explain why CNTF is highly expressed in quiescent Schwann cells in the peripheral nervous system, and also why CNTF is not abundant in axotomized nerves or cultured Schwann cells in which the proliferation signal is obviously active.