Unlike human, salamanders can regrow an amputated limb. This regeneration occurs only if there is simultaneous regeneration of the severed nerves. Although we usually think of the nervous system as carrying information between nerve cells and their sensory and motor targets, nerves are also essential for tissue regeneration. When a salamander limb is amputated at any position, from the shoulder to the fingertips, the stump forms a blastema, a mound of stem cells from which regeneration begins. The nerve supply cut by the amputation also regenerates, and this regrowth is required for the proliferation of the blastemal cells. If the nerves are cut at the base of the limb, deeper than the regenerative tissue, the limb stump is permanently denervated, the axons cannot regenerate, and limb regeneration fails.
The nerve dependence of limb regeneration was discovered in 1823 by Tweedy John Todd, an English physician, and analyzed in the 1940s and 1950s by Marcus Singer. Nerves are required for many different sorts of regeneration in both vertebrates and invertebrates (1), perhaps to ensure that the regenerated tissue receives adequate innervation. Singer showed that either sensory or motor nerves could support regeneration and that neither conduction of the nerve impulse nor neurotransmitter release was required. The molecular basis for communication between nerves and regenerating tissue has been unclear, although various growth factors have been proposed as mediators. Our paper now identifies a protein that can rescue the denervated blastema and induce regeneration of the limb.