The role of p21 in regulating mammalian regeneration

Recently, we published a study demonstrating that a deletion of the gene p21CIP/WAF converts a non-regenerating strain of mouse to one capable of epimorphic regeneration and has provided a unique opportunity to uncover some of the unknowns of this process in mammals. Since p21 is involved intricately in so many cellular processes, it is not clear at this time how deletion of this gene results in such a healing phenotype. This review will discuss our results, how our findings relate to other studies, and speculation as to the role of p21 in regeneration.In 1998, the MRL (Murphy Roths Large) mouse, generated from cross-breeding AKR, C3H, C57BL/6(B6), and LG strains of mice [1], was shown to be able to close ear punches without showing residual signs of injury or scarring [2]. Multiple tissues were perfectly replaced, cartilage re-grew, and hair follicles reappeared. Further-more, this type of perfect multi-tissue healing, known as epimorphic regeneration, occurred with the formation of a blastema-like structure that had been shown to be key to amphibian limb regeneration [3-5]. This phenomenon had earlier been seen in rabbit ear holes [6-8], and furthermore, a blastema-derived structure had also been described during antler re-growth [9]. The amphibian and mammalian ear hole regeneration processes have many features in common, including rapid re-epithelialization of the wound [2], elimination of the basement membrane between the epidermal and dermal tissue layers [10,11], blastema formation, re-growth of cartilage and hair follicles, and scarless healing [2,12,13]. However, the existence of an inbred mouse model allowed this process to be genetically approachable. It was also determined that one of the strains used to generate the MRL mouse, the LG/J mouse, contributed the regeneration phenotype [14].Ear hole closure has lent itself exceedingly well to genetic studies as this is a wound that is easy to access and measure and has proven to be a highly quantitative trai