Nerves, HO and Shh: Three players in the game of regeneration.

The tight control of reactive oxygen species (ROS) levels is required during regeneration. HO in particular assumes clear signalling functions at different steps in this process. Injured nerves induce high levels of HO through the activation of the Hedgehog (Shh) pathway, providing an environment that promotes cell plasticity, progenitor recruitment and blastema formation. In turn, high HO levels contribute to growing axon attraction. Once re-innervation is completed, nerves subsequently downregulate HO levels to their original state. A similar regulatory loop between HO levels and nerves also exists during development. This suggests that redox signalling is a major actor in cell plasticity.