The capacity for neurons to regrow the axons that connect them is relatively limited. The tissue of large nerves, largely made up of axons, does not readily regenerate; the closer to the central nervous system one comes, the less the capacity for regrowth following injury. This is not the case for all species, and thus – in principle at least – there must be regulatory controls in cellular biochemistry that can be adjusted to encourage lesser degrees of obstructive scarring and greater regrowth of axons. Here, researchers report on one recently discovered way to enhance axon regrowth that works in both peripheral nerves and the spinal cord.
Axon regeneration is limited in the mammalian central nervous system. Neurons must balance stress responses with regenerative demands after axonal injury, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models.
Mechanistic studies reveal that nerve injury induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs.
Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis, and metabolic signalling to control the balance between stress adaptation and axonal repair.
