Nerve roles in blastema induction and pattern formation in limb regeneration

Compared to amniotes, amphibians are widely known to be great healers. Urodele amphibians in particular have tremendous regeneration abilities, and can even regenerate organs, such as the brain, the heart and the limbs. Limb regeneration, in particular, has been investigated since it is representative of their superior regeneration abilities, and the presence of nerves has been examined in detail because they play essential roles in limb regeneration. Without nerves, there is no regeneration. Recent research has succeeded in outlining nerve regulation in the early phases, namely, the blastema induction phase. Based on the results of a few classic studies, it was believed that nerves played minimal roles in the later phases. In the present review, we first summarize the recent insights into the roles of nerves in blastema formation, and in the later stages, pattern formation becomes the focus. Pattern formation in limb regeneration has been interpreted in an intercalary manner. Recent findings point to the participation of nerves in the intercalary regulation of limb regeneration. This may change the current thinking on the effects of nerves on pattern formation in limb regeneration. Although the importance of nerves in amphibian limb regeneration has been recognized, the extent of their importance has remained unclear since the nerve entities were undetermined. This ambiguity was a large obstacle to investigating and comparing regeneration abilities in other species. Recent insights into nerves in limb regeneration may help overcome this obstacle and lead to future advancements.