In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration
In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration
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DOI：
10.1073/pnas.1015239108
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发表时间：
2011-04-12
影响因子：
11.1
通讯作者：
Kerschensteiner, Martin
中科院分区：
文献类型：
--
作者：
Bareyre, Florence M.;Garzorz, Natalie;Kerschensteiner, Martin
在周围神经系统（PNS）中，受损的轴突可以成功再生，而中枢神经系统中的轴突则无法再生。在背根神经节 (DRG) 的神经元中，分支延伸至 PNS 和 CNS，只有 PNS 损伤而不是 CNS 损伤诱导轴突生长。这种差异性生长反应在体内是如何调节的尚不完全清楚。在这里，我们将体内延时荧光显微镜与小鼠基因操作相结合，揭示转录因子 STAT3 如何调节轴突再生。我们发现，STAT3-floxed 小鼠的 DRG 神经元中选择性删除 STAT3 会损害神经切断后外周 DRG 分支的再生。此外，病毒基因转移诱导的 STAT3 过度表达使背柱损伤后中央 DRG 分支的生长和侧枝发芽增加了 400% 以上。值得注意的是，对单个荧光标记的 PNS 和 CNS 轴突进行重复体内成像表明，STAT3 选择性地调节轴突生长的起始，但不调节其后期的持续生长。因此，通过 STAT3，我们确定了轴突生长的阶段特异性调节剂。激活 STAT3 可能提供“快速启动”再生的机会，从而启动受损脊髓中的轴突，以应用改善轴突伸长的补充疗法。
In the peripheral nervous system (PNS), damaged axons regenerate successfully, whereas axons in the CNS fail to regrow. In neurons of the dorsal root ganglia (DRG), which extend branches to both the PNS and CNS, only a PNS lesion but not a CNS lesion induces axonal growth. How this differential growth response is regulated in vivo is only incompletely understood. Here, we combine in vivo time-lapse fluorescence microscopy with genetic manipulations in mice to reveal how the transcription factor STAT3 regulates axonal regeneration. We show that selective deletion of STAT3 in DRG neurons of STAT3-floxed mice impairs regeneration of peripheral DRG branches after a nerve cut. Further, overexpression of STAT3 induced by viral gene transfer increases outgrowth and collateral sprouting of central DRG branches after a dorsal column lesion by more than 400%. Notably, repetitive in vivo imaging of individual fluorescently labeled PNS and CNS axons reveals that STAT3 selectively regulates initiation but not later perpetuation of axonal growth. With STAT3, we thus identify a phase-specific regulator of axonal outgrowth. Activating STAT3 might provide an opportunity to "jumpstart" regeneration, and thus prime axons in the injured spinal cord for application of complementary therapies that improve axonal elongation.