Phylogenetic distribution of appendage regeneration among vertebrates according to the current literature. The blue line indicates lineages containing one or more species capable of appendage regeneration, the orange line those incapables of regeneration, and the black line those in which appendage regeneration has not yet been documented. The dashed yellow line indicates the uncertain presence of appendage regeneration in chondrichthyes and cyclostomes. The arrow indicates the reactivation of the regenerative process in amniotes.

Timeline activation of wound healing, blastema formation and regenerative outgrowth during appendage regeneration in vertebrates. Arrows indicate the duration of each regenerative step in lizard, salamander, and zebrafish. Hpa: hours post-amputation; dpa: days post-amputation.

Comparative anatomy of regenerating appendages in lizard, salamander, and zebrafish. (A) Amputation or autotomy of lizard tail induces the formation of a cone-like shaped blastema, covered by a thick wound epidermis that will form the apical epidermal peg(AEP), whose correspondence to the apical epidermal cap (AEC) found in amphibians and fish is still uncertain. During blastema formation, likely in response to AEP signals, the central canal of the original spinal cord, the ependymal tube, elongates and infiltrates the proliferating tail blastema. (B) After amputation of salamander limb, the wound epidermis quickly covers the stump. Within days, the wound epithelium becomes innervated, thickens, and becomes a specialized AEC. The AEC induces dedifferentiation in the underlying stump tissue and attracts cells, which accumulate below the AEC to form the blastema. Modified from Payzin-Dogru and Whited, 2018. (C) After zebrafish fin amputation, epithelial cells migrate to cover the wound, forming the AEC. Under the AEC, stump tissues dedifferentiate to form the blastema. Within 24 h, blastemal cells segregate into two compartments: the distal blastema, populated by slowly proliferating cells, and the proximal blastema, in which cells rapidly proliferate and differentiate to replace the amputated tissue. Dotted lines indicate the site of amputation/autotomy.

Experiments illustrating the principles of positional memory in salamander limb. (A) Rule of distal transformation. After the creation of a circularized limb, successive amputation induces the creation of two stumps, one with correct polarity and one with reversed polarity. Both stumps regenerate distal elements from the level of amputation, thus duplicating the distal segments already present in the reversed stump. The proximo-distal axis is indicated with a gradient of green (indicating proximal elements) and red (indicating distal elements). (B) Intercalation. Intercalary regeneration (dark red) occurs if a hand is grafted to an upper arm (left), but not if an upper arm segment is grafted to a forearm (right). Adapted from Carlson 2007.

Schematic representation of the molecular signaling regulating the steps of appendage regeneration in vertebrates.