The regenerative period of somatosensory nerves is closed by a DCC signaling axis

Tissues and organs have periods of plasticity that close with age. While period closures can lock in tissue architecture and prevent aberrant cellular interactions, they also limit regenerative capacity. These regenerative periods - a timeframe with regeneration capacity - are defined, but the underlying genetic mechanisms that close specific regenerative periods remains critical knowledge that needs expanding. Here, we established zebrafish larvae as a model to study the genetic basis of regenerative period closure. We demonstrated that laser axotomy of the centrally-projecting axons of dorsal root ganglia (DRG) neurons exhibit a robust regenerative period that is closed by 3 days post fertilization (dpf). The closure of the regenerative period corresponds with the rearrangement of glia that express netrin, introducing the idea that changes in the DCC-mediated signaling axis could be a genetic and molecular basis closing the regenerative period. To test this hypothesis, we manipulated dcc, cAMP, and Rac1 in transgenic animals that label axons and the actin cytoskeleton. Combined with genetic epistasis analysis, we show that altering DCC signaling can re-open the regenerative period, allowing severed axons to regrow into the spinal cord. We show that this increased capacity to reinvade the spinal cord is mediated by growth cone invadopodia. Using calcium reporters and behavioral analysis, we demonstrate that re-opening the regenerative period by manipulating the DCC signaling axis restores the sensory circuit and sensory-specific behaviors. By introducing this genetic basis for regenerative period closure, these results reveal an active suppression process that keeps regenerative periods closed and establishes a new model for future dissection of such periods.