Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo
Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo
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DOI：
10.1016/j.neuron.2004.10.030
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发表时间：
2004-11-18
期刊：
影响因子：
16.2
通讯作者：
Filbin, MT
中科院分区：
文献类型：
--
作者：
Gao, Y;Deng, KW;Filbin, MT
髓鞘抑制剂在防止中枢神经系统损伤后的自发轴突再生中起主要作用。cAMP的升高以转录依赖性方式通过精氨酸酶I（Arg I）的上调和多胺合成的增加克服了这种抑制。在这里，我们表明，cAMP的作用需要激活的转录因子cAMP反应元件结合蛋白（CREB），以克服髓鞘抑制剂;一个显性负CREB废除的效果，和神经元表达的CREB的组成性活性形式不受抑制。cAMP上调Arg 1也需要CREB的激活，并且组成型活性CREB克服抑制的能力被多胺合成抑制剂阻断。最后，在DRG神经元中组成型活性CREB的表达足以促进随后受损的背柱轴突的再生。这些结果表明，CREB在克服髓鞘抑制剂中起着核心作用，因此鼓励体内再生。
Inhibitors in myelin play a major role in preventing spontaneous axonal regeneration after CNS injury. Elevation of cAMP overcomes this inhibition, in a transcription-dependent manner, through the upregulation of Arginase I (Arg I) and increased synthesis of polyamines. Here, we show that the cAMP effect requires activation of the transcription factor cAMP response element binding protein (CREB) to overcome myelin inhibitors; a dominant-negative CREB abolishes the effect, and neurons expressing a constitutively active form of CREB are not inhibited. Activation of CREB is also required for cAMP to upregulate Arg 1, and the ability of constitutively active CREB to overcome inhibition is blocked by an inhibitor of polyamine synthesis. Finally, expression of constitutively active CREB in DRG neurons is sufficient to promote regeneration of subsequently lesioned dorsal column axons. These results indicate that CREB plays a central role in overcoming myelin inhibitors and so encourages regeneration in vivo.