Restoring Ag1, an ancient regeneration gene lost in amniotes, accelerates skin healing in mice

Tissue and organ regeneration is a remarkable ability observed in many animal species, which has been significantly reduced or lost in several vertebrate lineages, partly due to the evolutionary loss of regeneration-associated genes. For example, many genes involved in limb and skin regeneration in anamniotes (fish and amphibians) have been lost in amniotes (reptiles, birds, and mammals) following their transition to terrestrial life. This raises the intriguing question of whether reintroducing such lost genes could partially restore regenerative abilities. Here, we investigated whether the ag1 gene, which plays a key role in regeneration in fish and amphibians and was lost in amniotes, could enhance skin wound healing in mice. We generated transgenic mice with inducible expression of the Xenopus laevis ag1 gene in the skin and compared wound healing dynamics between induced and non-induced groups. Induction of ag1 resulted in approximately 20% faster wound closure. Transcriptomic analysis revealed enhanced activation of multiple pathways involved in wound repair and, notably, the upregulation of a subset of genes typically associated with scarless healing in amphibians and mammalian fetuses. Altogether, our findings demonstrate that a gene lost more than 300 million years ago can still stimulate reparative processes in mammalian tissues, highlighting the potential of ancient gene reactivation to enhance tissue repair in modern vertebrates.