Spinal cord regeneration deploys cell-type specific developmental and non-developmental strategies to restore neuron diversity

A major goal of spinal cord injury research is to develop a path to endogenous regeneration. This approach has been heavily informed by animal models of natural regeneration. An unresolved question is whether these models rebuild the spinal cord exclusively by accessing developmental mechanisms of neuron differentiation. To address this question, we contrasted single-cell gene expression during regeneration with stage-matched controls in the conditionally regenerative frog Xenopus tropicalis. We generated an expanded atlas of neuronal diversity, annotating several previously unidentified neuron classes. From this atlas, we found that the neuron composition of the developing and regenerating spinal cord differ. So do the strategies employed, which favor waves of cell-type specific neurite projection and guidance then proliferative neurogenesis during regeneration. Low levels of early neurogenesis are then compensated by movement of post-mitotic neurons. Our work highlights the contributions of distinct developmental versus regenerative paths to heal post-injury. Some species regenerate after spinal cord injury, but how they do so is unclear. Here they show that Xenopus tropicalis spinal cord regeneration occurs via distinct trajectories from developmental neurogenesis, offering insight into injury repair strategies.