Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch.

Abstract

Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching on <i>Aldh1a2</i> or RA supplementation reactivated regeneration. Evolutionary inactivation of multiple <i>Aldh1a2-linked</i> regulatory elements accounted for the deficient <i>Aldh1a2</i> expression upon injury in mice and rats. Furthermore, the activation of <i>Aldh1a2</i> by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.