Noxa is a critical mediator of p53-dependent motor neuron death after nerve injury in adult mouse
Noxa is a critical mediator of p53-dependent motor neuron death after nerve injury in adult mouse
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DOI：
10.1523/jneurosci.4041-04.2005
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发表时间：
2005-02-09
影响因子：
5.3
通讯作者：
Kiyama, H
中科院分区：
文献类型：
--
作者：
Kiryu-Seo, S;Hirayama, T;Kiyama, H
在新生大鼠和小鼠中，轴突切断诱导的运动神经元死亡在一周内发生。然而，成年小鼠(C57BL/6)轴突切断后发生缓慢进行性运动神经元死亡，持续一个多月，而成年大鼠(Wistar)则不发生。在这里，我们证明了P53诱导的只有BH3同源结构域3(BH3)的蛋白Noxa在成年小鼠的轴突切断神经元中表达增强，但在成年大鼠中不表达。在p53基因缺陷的小鼠中，轴突切断后缓慢进行的神经元死亡受到抑制，并伴随着NOXA表达的减少。然而，在p53基因缺陷小鼠的轴突切断后，仍然观察到NoxA表达的轻微反应，这表明P53非依赖性NoxA表达在很小程度上发生。用NOXA缺乏的小鼠来证实NOXA在神经损伤的小鼠运动神经元中表达的后果。在NOXA缺乏的小鼠中，轴突切断诱导的运动神经元死亡受到抑制。此外，在被研究的仅有BH3的蛋白质成员中，Noxa在小鼠的轴突切断后表现出最显著的上调。综上所述，成年小鼠运动神经元死亡主要依赖于P53，NOXA是成年小鼠神经切断后运动神经元死亡的主要执行者，位于P53下游。
Axotomy-induced motor neuron death occurs within a week in the neonatal rat and mouse. However, slowly progressive motor neuron death, which takes more than a month, occurs after axotomy in the adult mouse ( C57BL/ 6) but not in the adult rat ( Wistar). Here we demonstrate that expression of a p53-inducible Bcl-2 homology domain 3 ( BH3)-only protein, Noxa, is enhanced in axotomized neurons of the adult mouse but not in the adult rat. In p53-deficient mice, slowly progressive neuronal death was suppressed and accompanied by reduced Noxa expression after axotomy. However, a minor response of Noxa expression was still observed after axotomy in p53-deficient mice, suggesting that p53-independent Noxa expression occurs to a minor extent. Noxa- deficient mice were used to confirm the consequence of Noxa expression in nerve- injured mouse motor neurons. In Noxa- deficient mice, axotomy-induced motor neuron death was suppressed. Furthermore, among the BH3-only protein members examined, Noxa exhibited the most marked upregulation after axotomy in the mouse. In conclusion, motor neuron death seen in the adult mouse is mainly p53 dependent, and Noxa is a major executor for axotomy- induced motor neuron death in the adult mouse, as a mediator located downstream of p53.