Epimorphic regeneration in mice is p53-independent
Epimorphic regeneration in mice is p53-independent
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DOI：
10.4161/cc.9.18.13119
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发表时间：
2010-09-15
期刊：
影响因子：
4.3
通讯作者：
Heber-Katz, E.
中科院分区：
文献类型：
--
作者：
Arthur, L. Matthew;Demarest, Renee M.;Heber-Katz, E.
海绵、水蛇、脊椎动物和火蜥蜴的再生过程最容易被研究。MRL小鼠耳廓贯通孔的闭合提供了一种不寻常的伤口愈合/再生的哺乳动物模型，在这种模型中，胚胎样结构闭合了耳孔，软骨和毛囊被替换。最近的研究，基于广泛的DNA损伤和G(2)/M“停滞”的细胞周期模式，表明p21(Cip1/Waf1)从MRL小鼠的耳朵中缺失，p21缺失的小鼠可以关闭它的耳洞。考虑到控制DNA损伤、细胞周期停滞、细胞凋亡和衰老的p53/p21轴，我们测试了p53在耳洞再生反应中的作用。利用回交小鼠，我们发现MRL小鼠中P53的丢失并没有表现出愈合的减少。此外，还测量了MRL的横截面。在损伤后6周，p53(-/-)小鼠的耳朵显示愈合区域的脂肪细胞和软骨细胞水平增加，而MRL或p21(-/-)小鼠在同一区域仅显示软骨生成，尽管在以后的时间点。此外，我们还研究了其他与细胞周期相关的突变小鼠，以确定p21是如何调控的。我们证明了p16和GADD45基因缺失的小鼠几乎没有愈合能力。有趣的是，在带有双重转化生长因子β/Rag2基因敲除突变的小鼠中，观察到了部分愈合的表型。这些数据表明P53信号在小鼠附件再生中是独立的，并提示p21在这一过程中的作用可能是通过取消转化生长因子β/Smad途径来实现的。
The 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 p21(Cip1/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 cycle-related 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 Tgf beta/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 Tgf beta/Smad pathway.