Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity
Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity
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DOI：
10.1073/pnas.1621225114
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发表时间：
2017-07-03
影响因子：
11.1
通讯作者：
Fischer, Dietmar
中科院分区：
文献类型：
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作者：
Leibinger, Marco;Andreadaki, Anastasia;Fischer, Dietmar
GSK 3活性对轴突再生的影响即使没有争议，也常常是不一致的。据报道，GSK 3S/A基因敲入小鼠中持续的GSK 3活性通过增加MAP 1B磷酸化并同时减少微管脱酪氨酸来加速周围神经再生。相反，目前的研究表明，透镜损伤刺激的视神经再生在这些敲入小鼠中显著受损。在增强的GSK 3活性后，视网膜神经节细胞（RGC）轴突中MAP 1B和CRMP 2的磷酸化显著增加，但令人惊讶的是，在坐骨神经中未检测到GSK 3介导的CRMP 2抑制，从而揭示了中枢和外周轴突之间的根本差异。相反，GSK 3 β的遗传或shRNA介导的条件性KO/敲低降低了RGC中CRMP 2的抑制性磷酸化，并改善了视神经再生。因此，GSK 3 β KO介导的神经突生长促进和髓鞘去抑制被CRMP 2抑制消除，并且在组成型活性CRMP 2（CRMP 2 T/A）表达后在WT神经元中被大量模仿。这些结果强调了视神经再生对活性CRMP 2的普遍需求。引人注目的是，CRMP 2 T/A在GSK 3S/A RGCs中的表达进一步促进视神经再生，轴突在3周内到达视交叉。因此，如果CRMP 2同时保持活性，则活性GSK 3也可以显著促进中枢神经中的轴突生长。与外周神经相似，GSK 3介导的MAP 1B磷酸化/激活和微管脱酪氨酸的减少有助于这种作用。总的来说，这些发现调和了关于GSK 3介导的轴突再生的相互矛盾的数据。此外，通常拮抗性靶向的GSK 3底物的互补调节的概念提供了一种治疗上适用的方法来增强受损CNS中的再生结果。
Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3S/A knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice. Phosphorylation of MAP1B and CRMP2 was expectedly increased in retinal ganglion cell (RGC) axons upon enhanced GSK3 activity, but, surprisingly, no GSK3-mediated CRMP2 inhibition was detected in sciatic nerves, thus revealing a fundamental difference between central and peripheral axons. Conversely, genetic or shRNA-mediated conditional KO/knock-down of GSK3 beta reduced inhibitory phosphorylation of CRMP2 in RGCs and improved optic nerve regeneration. Accordingly, GSK3 beta KO-mediated neurite growth promotion and myelin disinhibition were abrogated by CRMP2 inhibition and largely mimicked in WT neurons upon expression of constitutively active CRMP2 (CRMP2T/A). These results underscore the prevalent requirement of active CRMP2 for optic nerve regeneration. Strikingly, expression of CRMP2T/A in GSK3S/A RGCs further boosted optic nerve regeneration, with axons reaching the optic chiasm within 3 wk. Thus, active GSK3 can also markedly promote axonal growth in central nerves if CRMP2 concurrently remains active. Similar to peripheral nerves, GSK3-mediated MAP1B phosphorylation/activation and the reduction of microtubule detyrosination contributed to this effect. Overall, these findings reconcile conflicting data on GSK3-mediated axon regeneration. In addition, the concept of complementary modulation of normally antagonistically targeted GSK3 substrates offers a therapeutically applicable approach to potentiate the regenerative outcome in the injured CNS.