The ability to regenerate amputated or injured tissues and organs is a fascinating property shared by several invertebrates and, interestingly, some vertebrates. The mechanism of evolutionary loss of regeneration in mammals is not understood, yet from the biomedical and clinical point of view, it would be very beneficial to be able, at least partially, to restore that capability. The current availability of new experimental tools, facilitating the comparative study of models with high regenerative ability, provides a powerful instrument to unveil what is needed for a successful regen-eration. The present review provides an updated overview of multiple aspects of appendage regeneration in three vertebrates: lizard, salamander, and zebrafish. The deep investigation of this process points to common mechanisms, including the relevance of Wnt/β-catenin and FGF signaling for the restoration of a functional appendage. We discuss the formation and cellular origin of the blastema and the identification of epigenetic and cellular changes and molecular pathways shared by vertebrates capable of regeneration. Understanding the similarities, being aware of the differences of the processes, during lizard, salamander, and zebrafish regeneration can provide a useful guide for supporting effective regenerative strategies in mammals.
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