NaV-Mediated Sodium Currents Are Necessary For Vertebrate Appendage Regeneration

Abstract

Mammals have a limited ability to regenerate tissues. In contrast, amphibians such as frogs can restore lost developmental structures, including the lens and tail. A detailed understanding of natural regeneration is important for developing therapies for organ repair. Recently, ion transport has been implicated as a regulator of regeneration. While voltage-gated sodium channels play a well-known and important role in propagating action potentials in excitable cells, we have identified a novel role in regeneration for the ion transport function mediated by the voltage-gated sodium channel, NaV1.2. After Xenopus tadpole tail amputation, a regeneration bud (containing progenitors required for regenerative growth) is formed within 1 day at the injury site, and a new tail is re-grown by 7 days. NaV1.2 is expressed early in the bud, and its function is required for regeneration. Inhibition of its activity causes regenerative failure by greatly reducing expression of downstream genes that drive tail outgrowth and patterning, leading to decreased proliferation and altered axonal patterning in the regeneration bud. Significantly, NaV1.2 is not expressed under non-regenerative conditions, suggesting that its activity is a determinant of regenerative ability. Most importantly, pharmacological induction of a brief, transient sodium current into the regeneration bud after tail amputation is sufficient to restore full regeneration of the tail during the refractory period (an endogenous developmental period when regeneration is blocked). Our study demonstrates that sodium transport is a critical mechanism for controlling regeneration, and suggests that short-term modulations of ion transport could represent an exciting new approach to tissue repair in mammals.