F.M. Kirby Neurobiology Center, Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature. 2011 Nov 6;480(7377):372-5. doi: 10.1038/nature10594.
A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either phosphatase and tensin homologue (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signalling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around 2 weeks after the crush injury. Here we show that, remarkably, simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as key for sustaining long-distance axon regeneration in adult CNS, a crucial step towards functional recovery.
在成人中枢神经系统（CNS）中进行神经修复面临的一个巨大挑战是，再生轴突通常需要长距离才能重新连接到其靶标。因此，持续的轴突再生能力对于实现功能恢复至关重要。尽管在成年视网膜神经节细胞（RGC）中单独删除磷酸酶和张力蛋白同源物（PTEN），一种哺乳动物雷帕霉素靶蛋白（mTOR）的负调节剂，或细胞因子信号转导抑制因子 3（SOCS3），一种 Janus 激酶/信号转导和转录激活因子（JAK/STAT）途径的负调节剂，都能促进显著的视神经再生，但这种再生在挤压损伤后约 2 周就逐渐减少。在这里，我们发现，令人惊讶的是，同时删除 PTEN 和 SOCS3 可以实现强大而持续的轴突再生。我们进一步表明，PTEN 和 SOCS3 调节两个独立的通路，它们协同作用以促进增强的轴突再生。基因表达分析表明，双重缺失不仅导致许多与生长相关基因的诱导，而且还允许 RGC 在损伤后维持一系列基因的表达处于生理水平。我们的结果揭示了 mTOR 和 STAT3 通路的同时激活是维持成年中枢神经系统长距离轴突再生的关键，这是功能恢复的关键步骤。
