Abstract
Production of H
2
O
2
by injured zebrafish skin cells promotes the regeneration of nearby somatosensory axon terminals, thus coordinating wound healing of the skin with sensory reinnervation.
Functional recovery from cutaneous injury requires not only the healing and regeneration of skin cells but also reinnervation of the skin by somatosensory peripheral axon endings. To investigate how sensory axon regeneration and wound healing are coordinated, we amputated the caudal fins of zebrafish larvae and imaged somatosensory axon behavior. Fin amputation strongly promoted the regeneration of nearby sensory axons, an effect that could be mimicked by ablating a few keratinocytes anywhere in the body. Since injury produces the reactive oxygen species hydrogen peroxide (H
2
O
2
) near wounds, we tested whether H
2
O
2
influences cutaneous axon regeneration. Exposure of zebrafish larvae to sublethal levels of exogenous H
2
O
2
promoted growth of severed axons in the absence of keratinocyte injury, and inhibiting H
2
O
2
production blocked the axon growth-promoting effects of fin amputation and keratinocyte ablation. Thus, H
2
O
2
signaling helps coordinate wound healing with peripheral sensory axon reinnervation of the skin.
Touch-sensing neurons project axonal processes that branch extensively within the outer layers of skin to detect touch stimuli. Recovering from skin injuries thus requires not only repair of damaged skin tissue but also regeneration of the sensory axons innervating it. To study whether skin wound healing is coordinated with sensory innervation, we compared the regeneration of severed sensory axons innervating larval zebrafish tail fins with and without concomitant injury to surrounding skin cells. Severed axons regenerated more robustly when nearby skin cells were also damaged, suggesting that wounded skin releases a short-range factor that promotes axon growth. The reactive oxygen species hydrogen peroxide (H
2
O
2
) is known to be produced by injured cells, making it a candidate for mediating this signal. We found that adding exogenous H
2
O
2
improved the regeneration of severed axons. Conversely, blocking H
2
O
2
production prevented the axon growth-promoting effect of skin injury. Thus, H
2
O
2
promotes axon growth after skin damage, helping to ensure that healing skin is properly innervated.
