Functional Regeneration of the Sensory Root via Axonal Invasion

Regeneration following spinal root avulsion is broadly unsuccessful despite the regenerative capacity of other PNS-located nerves. By combining focal laser lesioning to model root avulsion in zebrafish, time-lapse imaging, and transgenesis, we identify that regenerating DRG neurons fail to recapitulate developmental paradigms of actin-based invasion after injury. We demonstrate that inducing actin reorganization into invasive components via pharmacological and genetic approaches in the regenerating axon can rescue sensory axon spinal cord entry. Cell-autonomous induction of invasion components using constitutively active Src induces DRG axon regeneration, suggesting an intrinsic mechanism can be activated to drive regeneration. Furthermore, analyses of neuronal activity and animal behavior show restoration of sensory circuit activity and behavior upon stimulating axons to re-enter the spinal cord via invasion. Altogether, our data identify induction of invasive components as sufficient for functional sensory root regeneration after injury. [Display omitted] •Visualization of regenerating nerves in zebrafish model of avulsion-like injuries•Regenerating DRG sensory axons do not invade back into the spinal cord•Stabilization of invasion components induces regeneration•Regenerated axons restore neural circuits and behavior by 1–2 days after injury Dorsal root ganglion (DRG) sensory axons are unable to regenerate into the spinal cord after injury. Nichols and Smith demonstrate in zebrafish that injured DRG axons do not initiate actin-based invasion components during re-entry into the spinal cord. Pharmacological and cell-autonomous genetic manipulations that promote actin-mediated cell invasion to restore sensory behavior.