Jiang Liangxia, Tian Jie, Yang Jun, Luo Ronggang, Zhang Yongjin, Shao Chihao, Guo Bing, Wu Xiaoming, Dan Juhua, Luo Ying
Department of Pathophysiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China.
Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, China.
Cell Death Discov. 2024 Sep 28;10(1):413. doi: 10.1038/s41420-024-02192-z.
The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, however, how this balance is maintained and how the Wnt-Notch pathways are connected with cell cycle regulation is still not clear. By analyzing the molecular alterations in mouse model with accelerated aging phenotypes due to loss of p21 function in a Werner syndrome background, we observed that Wnt3 and β-Catenin were down-regulated, while Notch1 and Hes1 were up-regulated. This disruption in Wnt-Notch signaling was accompanied by the loss of intestinal stem cell compartment, increase in Bmi1 positive cells, loss of Olfm4/Lgr5 positive cells, and reduced secretory Paneth cells and goblet cells in the intestinal crypts of p21TKO mice. BrdU incorporation, cleaved caspase 3, and Tunel assay results revealed the fast turnover of intestinal epithelia, which may result in abnormal stem cell mobilization and exhaustion of the stem cell reservoir in the intestinal crypts. We further identified shift of DREAM complex towards MMB complex due to the loss of p21 as the cause for faster turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which linked the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the DREAM pathway, as well as the imbalance of Wnt-Notch pathway. In summary, our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.
已知Wnt-Notch的相互作用和平衡调节对于细胞命运决定和组织再生至关重要，然而，这种平衡是如何维持的以及Wnt-Notch信号通路如何与细胞周期调节相联系仍不清楚。通过分析在Werner综合征背景下由于p21功能丧失而具有加速衰老表型的小鼠模型中的分子改变，我们观察到Wnt3和β-连环蛋白下调，而Notch1和Hes1上调。Wnt-Notch信号的这种破坏伴随着肠道干细胞区室的丧失、Bmi1阳性细胞的增加、Olfm4/Lgr5阳性细胞的丧失以及p21TKO小鼠肠道隐窝中分泌性潘氏细胞和杯状细胞的减少。BrdU掺入、裂解的半胱天冬酶3和Tunel分析结果显示肠道上皮细胞周转迅速，这可能导致干细胞异常动员和肠道隐窝中干细胞储备的耗尽。我们进一步确定，由于p21的丧失导致DREAM复合物向MMB复合物的转变是肠道上皮细胞周转加快的原因。重要的是，我们确定E2F1是Notch1的转录调节因子，它将p21-DREAM/MMB/Rb-E2F1通路与Wnt-Notch通路联系起来。p21的过表达挽救了DREAM通路以及Wnt-Notch通路的失衡。总之，我们的数据确定p21是维持肠道干细胞顺序动员、增殖和稳态的重要因素。
