Abstract

Axon regeneration in the mammalian central nervous system (CNS) has been a long-standing and highly challenging issue. Successful CNS axon regeneration will benefit many human diseases involving axonal damage, such as spinal cord injury, traumatic brain injury, glaucoma, and neurodegenerative diseases. The current consensus is that the diminished intrinsic regenerative ability in mature CNS neurons and the presence of extrinsic inhibitors blocking axon regrowth are two major barriers for axon regeneration. During the past decade, studies targeting the intrinsic axon growth ability via regulation of gene transcription have produced very promising results in optic nerve and/or spinal cord regeneration. Manipulations of various signaling pathways or the nuclear transcription factors directly have been shown to sufficiently drive CNS axon regrowth. Converging evidence reveals that some pro-regenerative transcriptomic states, which are commonly accomplished by more comprehensive epigenetic regulations, exist to orchestrate the complex tasks of injury sensing and axon regeneration. Moreover, genetic reprogramming achieved via transcriptome and epigenome modifications provides novel mechanisms for enhancing axon regeneration. Recent studies also highlighted the important roles of remodeling neuronal cytoskeleton in overcoming the extrinsic inhibitory cues. However, our knowledge about the cellular and molecular mechanisms by which neurons regulate their intrinsic axon regeneration ability and response to extrinsic inhibitory cues is still fragmented. Here, we provide an update about recent research progress in axon regeneration and discuss major remaining challenges for long-distance axon regeneration and the subsequent functional recovery.

中文翻译：

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哺乳动物中枢神经系统轴突再生的更新和挑战。

摘要

哺乳动物中枢神经系统 (CNS) 的轴突再生一直是一个长期存在且极具挑战性的问题。成功的中枢神经系统轴突再生将有益于许多涉及轴突损伤的人类疾病，例如脊髓损伤、创伤性脑损伤、青光眼和神经退行性疾病。目前的共识是成熟中枢神经系统神经元内在再生能力的减弱和阻碍轴突再生的外在抑制剂的存在是轴突再生的两个主要障碍。在过去十年中，通过调节基因转录来靶向内在轴突生长能力的研究在视神经和/或脊髓再生方面产生了非常有希望的结果。已显示直接操纵各种信号通路或核转录因子足以驱动 CNS 轴突再生。趋同的证据表明，一些促再生转录组状态通常通过更全面的表观遗传调控来完成，以协调损伤感知和轴突再生的复杂任务。此外，通过转录组和表观基因组修饰实现的基因重编程为增强轴突再生提供了新的机制。最近的研究还强调了重塑神经元细胞骨架在克服外在抑制线索中的重要作用。然而，我们对神经元调节其内在轴突再生能力和对外在抑制线索的反应的细胞和分子机制的了解仍然是零散的。这里，