DOI：10.1038/nature15382 作者：Jeffrey L. Wrana
摘要 : Hippo 通道(在发育过程中影响细胞命运的决定和组织生长)被发现是成年个体组织再生的一个重要调控因子。
Hippo 通道(在发育过程中影响细胞命运的决定和组织生长)被发现是成年个体组织再生的一个重要调控因子。小肠上皮的经常性自我更新是由小肠干细胞中的Wnt信号通道控制的，但小肠受伤后怎样再生却一直不清楚。Jeffrey Wrana及同事发现，第二个信号通道Hippo是小肠上皮在接受电离辐射后的恢复所需的。Hippo的构成成分Yap会阻滞小肠干细胞向Paneth细胞的分化，以通过第三个通道Egfr的激发来促进一个“存活和自我更新再生程序”。这一由Yap驱动的再生通道还被发现参与肿瘤发生。
The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5+ intestinal stem cells (ISCs)1. However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5+ ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap-deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the ApcMin mouse model of colon cancer, and that Yap-driven expansion of Apc−/−organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivoYap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5+ ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation.
来源： Nature 浏览次数：0