Overexpression of Sox11 Promotes Corticospinal Tract Regeneration after Spinal Injury While Interfering with Functional Recovery
Overexpression of Sox11 Promotes Corticospinal Tract Regeneration after Spinal Injury While Interfering with Functional Recovery
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DOI：
10.1523/jneurosci.2832-14.2015
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发表时间：
2015-02-18
影响因子：
5.3
通讯作者：
Blackmore, Murray G.
中科院分区：
文献类型：
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作者：
Wang, Zimei;Reynolds, Ashley;Blackmore, Murray G.
斑马鱼的胚胎神经元、外周神经元和中枢神经系统神经元通过启动促再生转录程序对轴突损伤作出反应，该程序使轴突能够延伸、定位适当的靶点，并最终有助于行为恢复。相反，许多长距离投射神经元在成年哺乳动物中枢神经系统，特别是皮质脊髓束（CST）神经元，显示出低得多的再生能力。为了促进CNS修复，一个长期的目标是激活损伤的CNS神经元通常缺失的促再生机制。Sox11是一种转录因子，其表达在许多类型的再生神经元中是常见的，但尚不清楚Sox11的次优表达是否导致成年哺乳动物CNS的低再生能力。在这里，我们表明，在成年小鼠背根神经节神经元（DRG）和CST神经元不能上调Sox11脊髓轴突损伤后。此外，在急性和慢性损伤范例中，Sox11的强制病毒表达减少DRG轴突的轴突死亡，并促进CST发芽和再生轴突生长。然而，在前肢灵活性的测试中，Sox11在皮层的过度表达导致了适度但一致的行为障碍。这些数据确定Sox11作为一个关键的转录因子，可以赋予中枢神经系统神经元先天再生能力的提高。结果还表明轴突生长和行为结果之间的意外分离，突出了需要额外的策略来优化刺激神经元的功能输出。
Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons.