Updates and challenges of axon regeneration in the mammalian central nervous system

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.

Keywords: axon regeneration; epigenetic; glaucoma; optic nerve regeneration; reprogramming; spinal cord regeneration; transcription factors.

Figure 1

Representative post-injury CNS neuron in a robustly regenerating state. Acting as the effective driving force of CNS axon regeneration, some pro-growth receptor ligands (growth factors such as CNTF, etc.) coordinate with intracellular retrograde injury-sensing signaling pathways (the Stat3–Socs3 pathway), convergingly activating TFs and/or chromatin regulators to transmit the cellular signals into the cell nucleus. Direct manipulations on these nuclear elements (Sox11-OE, Klf6/7-OE, or p300-OE) could result in similar outcomes. The hub TFs and chromatin regulators may establish specific pro-regeneration chromatin states by influencing both the local accessibility and the distal cis interaction of the whole genome. DNA methylation is represented by '-Me' in the diagram. Histone modifications leading to the closed heterochromatin are represented by red dots, whereas histone modifications leading to the open euchromatin are represented by green dots. Such epigenome eventually results in a pro-regeneration transcriptional program. Meanwhile, the most efficient manipulation should also activate robust ribosomal protein synthesis to translate such pro-regeneration transcriptome into an entity of functional effector proteins, some for the upstream pathways and some for the transcriptional, and other terminal effector proteins transported to the growth cone and functioning to rebuild a penetrating growth cone, which could effectively reextend through the inhibitory environment around the injury site, and guide the axon toward certain temporal pathfinding cues.

Figure 2

Transcriptomic and chromatin state transition existing between developing and mature neurons. The striking contrast in axonal outgrowth ability between robustly projecting neurons and mature neurons with stopped axon growth after synaptogenesis is attributable to the distinct chromatin states—open and closed genome regions and different cis-regulatory folding and TF interaction, which lead to consequential differences in transcriptional programs. Dynamically, the developing young neurons are programmed to transition into mature neurons along with functional alterations. As a therapeutic strategy, the mature neurons (if injured) may be reprogrammed with specific manipulations (Lin28-OE or c-Myc-OE) to re-obtain developing neurons’ characteristics in robust axon outgrowth.