Active mechanistic target of rapamycin plays an ancillary rather than essential role in zebrafish CNS axon regeneration
Active mechanistic target of rapamycin plays an ancillary rather than essential role in zebrafish CNS axon regeneration
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DOI：
10.3389/fncel.2015.00251
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发表时间：
2015-07-07
影响因子：
5.3
通讯作者：
Fischer, Dietmar
中科院分区：
文献类型：
--
作者：
Diekmann, Heike;Kalbhen, Pascal;Fischer, Dietmar
哺乳动物中枢神经系统（CNS）内在再生能力的发育性下降与成熟神经元（如视网膜神经节细胞（rgo））中雷帕霉素（mTOR）的机制靶标活性降低有关。虽然mTOR活性在轴突损伤后进一步降低，但维持其损伤前水平，例如通过遗传删除磷酸酶和紧张素同源物（PTEN），可显著促进哺乳动物轴突再生。目前的研究通过分析具有再生能力的斑马鱼对活性mTOR的需求，解决了活性mTOR是否在轴突再生中普遍发挥核心作用的问题。值得注意的是，与哺乳动物相比，斑马鱼视神经损伤后mTOR活动的调节有着根本的不同。在原始RGCs中几乎没有检测到任何活性，而在体内和游离细胞培养中，它在axo切开术后显着增加。短暂爆发后，mTOR活性迅速减弱，这与哺乳动物轴突再生的要求相反。令人惊讶的是，mTOR活性本身并不是轴突生长所必需的，但在体外与细胞因子和PTEN抑制剂诱导的神经突延伸相关。此外，使用雷帕霉素抑制mTOR可显著降低体内轴突再生，并损害视神经损伤后的功能恢复。因此，在斑马鱼的中枢神经系统轴突再生中，轴突切断术诱导的mTOR活性与哺乳动物相似，尽管它在再生能力强的物种中起辅助作用而不是必不可少的作用。
The developmental decrease of the intrinsic regenerative ability of the mammalian central nervous system (CNS) is associated with reduced activity of mechanistic target of rapamycin (mTOR) in mature neurons such as retinal ganglion cells (RGOs). While mTOR activity is further decreased upon axonal injury, maintenance of its pre-injury level, for instance by genetic deletion of the phosphatase and tensin homolog (PTEN), markedly promotes axon regeneration in mammals. The current study now addressed the question whether active mTOR might generally play a central role in axon regeneration by analyzing its requirement in regeneration-competent zebrafish. Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals. Hardly any activity was detected in naive RGCs, whereas it was markedly increased upon axotomy in vivo as well as in dissociated cell cultures. After a short burst, mTOR activity was quickly attenuated, which is contrary to the requirements for axon regeneration in mammals. Surprisingly, mTOR activity was not essential for axonal growth per se, but correlated with cytokine- and PTEN inhibitor induced neurite extension in vitro. Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury. Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.