Many aquatic vertebrates have a remarkable ability to regenerate limbs and tails after amputation. Previous studies indicate that reactive oxygen species (ROS) signalling initiates regeneration, but the mechanism by which this takes place is poorly understood. Developmental signalling pathways have been shown to have proregenerative roles in many systems. However, whether these are playing roles that are specific to regeneration, or are simply recapitulating their developmental functions is unclear. Here, we analyse zebrafish larval tail regeneration and find evidence that ROS released upon wounding cause repositioning of notochord cells to the damage site. These cells secrete Hedgehog ligands that are required for regeneration. Hedgehog signalling is not required for normal tail development suggesting that it has a regeneration-specific role. Our results provide a model for how ROS initiate tail regeneration, and indicate that developmental signalling pathways can play regenerative functions that are not directly related to their developmental roles.

1 Aquatic vertebrates have a remarkable ability to regenerate limbs and tails after 2 amputation. Previous studies indicate that reactive oxygen species (ROS) signalling 3 initiates regeneration, but the mechanism by which this takes place is poorly 4 understood. Developmental signalling pathways have been shown to have pro-5 regenerative roles in many systems. However, whether these are playing roles that 6 are specific to regeneration, or are simply recapitulating their developmental 7 functions is unclear. We have analysed zebrafish larval tail regeneration and find 8 evidence that ROS released upon wounding cause repositioning of notochord cells to 9 the damage site. These cells secrete Hedgehog ligands which are required for 1 0 regeneration. Hedgehog signalling is not required for normal tail development 1 1 suggesting that it has a regeneration specific role. Our results provide a model for 1 2 how ROS initiate tail regeneration, and indicate that developmental signalling 1 3 pathways can play regenerative functions that are not directly related to their 1 4 developmental roles.