Lack of p21 expression links cell cycle control and appendage regeneration in mice.
Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue. Certain commonalities, such as blastema formation and basement membrane breakdown at the wound site, suggest that MRL mice may share other features with classical regenerators. As reported here, MRL fibroblast-like cells have a distinct cell-cycle (G2/M accumulation) phenotype and a heightened basal and wound site DNA damage/repair response that is also common to classical regenerators and mammalian embryonic stem cells. Additionally, a neutral and alkaline comet assay displayed a persistent level of intrinsic DNA damage in cells derived from the MRL mouse. Similar to mouse ES cells, the p53-target p21 was not expressed in MRL ear fibroblasts. Because the p53/p21 axis plays a central role in the DNA damage response and cell cycle control, we directly tested the hypothesis that p21 down-regulation could functionally induce a regenerative response in an appendage of an otherwise nonregenerating mouse strain. Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1a(tmi/Tyj)/J p21(-/-) mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.
Cellular and Molecular Oncogenesis and Gene Expression, The Wistar Institute, Philadelphia, PA 19104, USA.
Khamilia
K
Bedelbaeva
Andrew
A
Snyder
Dmitri
D
Gourevitch
Lise
L
Clark
Xiang-Ming
XM
Zhang
John
J
Leferovich
James M
JM
Cheverud
Paul
P
Lieberman
Ellen
E
Heber-Katz
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D005121:Extremities / Q000502:physiology; D005260:Female; D016195:G2 Phase; D066298:In Vitro Techniques; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055550:Protein Stability; D051135:Rad51 Recombinase / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse