Epimorphic regeneration in mice is p53-independent

Abstract

T he process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G 2 /M "arrest," showed that p21Cip1/Waf1 was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53 -/-mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21 -/-mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cyclerelated mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgfβ/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgfβ/Smad pathway.

Tumor suppressors: enhancers or suppressors of regeneration?

“…The p21 gene does not appear to exist in planaria (Pearson and Sánchez Alvarado, 2010) but is present in zebrafish (Langheinrich et al, 2002). p21 has been implicated in suppression of epimorphic regenerative capacity in a mouse ear hole model , whereas deficiency of p53 had no apparent effect (Arthur et al, 2010). Although the existence of p21 in zebrafish demonstrates that potent regeneration can occur in organsisms that contain this gene, it is possible that differences in regulation of p21 expression, e.g.…”

The Role of TGFβ Signaling in Wound Epithelialization

“…64 These findings again highlight the variability of the in vivo data resulting from the broad spectrum of TGFb1 functions in wound healing, regeneration, and inflammation. 39 Another recently described wild-type model of mammalian regeneration is the African spiny mice, Acomys, with the extraordinary ability to regenerate skin along with complete wound closure of the through-and-through ear hole punch.…”

“…64 These double mutants can overcome the lethal inflammatory response in TGFb1-null mice due to complete lack of mature B and T lymphocytes caused by Rag2 abrogation. Interestingly, even though improved wound closure was observed in TGFb1…”

Increased levels of p21(CIP1/WAF1) correlate with decreased chondrogenic differentiation potential in synovial membrane progenitor cells.

“…In contrast, increasing p21 expression levels induces differentiation, limiting self-renewal and function of adult progenitor cells (Nishimura et al, 2005). Furthermore, p53 (which regulates p21) appears to have a limited role in regeneration as p53 knockout mice demonstrate baseline regenerative capacity (Arthur et al, 2010). While it has been clearly demonstrated that MRL and p21 knockout mice demonstrate increased regenerative capacity, it remains unknown which cell population(s) are responsible for this observation.…”