Huntingtin and Celsr3 Orchestrate Spontaneous Long-Distance Spinal Cord Regeneration

Spontaneous spinal cord regeneration, an inherent process observed in various vertebrate and certain mammalian species, remains incompletely understood despite leading to functional recovery. Live-cell imaging of zebrafish spinal cord M-cell axons post laser axotomy reveals a multistep regeneration process. Genetic screening uncovers crucial roles for two evolutionarily conserved genes, celsr3 and huntingtin (htt), in spontaneous spinal cord regeneration.

Htt plays a critical role in initiating a transcriptional injury response in regenerating M-cells, allowing axons to navigate the injury site. Once axons surpass the injury site, celsr3 steps in to accelerate growth rates. Both celsr3 and htt contribute to sustaining long-range axonal growth. However, htt is not essential for regeneration in optic nerve and peripheral motor neurons.

Furthermore, decreasing the distance between the soma and injury site in htt mutant M-cell axons partially restores regeneration, indicating a selective role in long-range CNS axon regeneration.

The findings suggest a transport-based mechanism, as genetic knockdown of htt-associated axonal transport proteins mirrors the regeneration phenotype observed in htt mutants. The results provide compelling evidence for a time and distance-sensitive multistep molecular framework, where celsr3-dependent growth rate modulation and htt-dependent axonal transport drive spontaneous, long-range spinal cord regeneration.