Laboratory of Signal Transduction in Development and Cancer and Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3472-7. doi: 10.1073/pnas.1309342111. Epub 2014 Feb 18.
In the development of the mammalian intestine, Notch and Wnt/β-catenin signals control stem cell maintenance and their differentiation into absorptive and secretory cells. Mechanisms that regulate differentiation of progenitors into the three secretory lineages, goblet, paneth, or enteroendocrine cells, are not fully understood. Using conditional mutagenesis in mice, we observed that Shp2-mediated MAPK signaling determines the choice between paneth and goblet cell fates and also affects stem cells, which express the leucine-rich repeat-containing receptor 5 (Lgr5). Ablation of the tyrosine phosphatase Shp2 in the intestinal epithelium reduced MAPK signaling and led to a reduction of goblet cells while promoting paneth cell development. Conversely, conditional mitogen-activated protein kinase kinase 1 (Mek1) activation rescued the Shp2 phenotype, promoted goblet cell and inhibited paneth cell generation. The Shp2 mutation also expanded Lgr5+ stem cell niches, which could be restricted by activated Mek1 signaling. Changes of Lgr5+ stem cell quantities were accompanied by alterations of paneth cells, indicating that Shp2/MAPK signaling might affect stem cell niches directly or via paneth cells. Remarkably, inhibition of MAPK signaling in intestinal organoids and cultured cells changed the relative abundance of Tcf4 isoforms and by this, promoted Wnt/β-catenin activity. The data thus show that Shp2-mediated MAPK signaling controls the choice between goblet and paneth cell fates by regulating Wnt/β-catenin activity.
在哺乳动物肠道的发育过程中，Notch 和 Wnt/β-catenin 信号控制干细胞的维持及其分化为吸收细胞和分泌细胞。调节前体细胞分化为三种分泌谱系（杯状细胞、潘氏细胞或肠内分泌细胞）的机制尚未完全阐明。我们利用小鼠条件性突变，观察到 Shp2 介导的 MAPK 信号决定了潘氏细胞和杯状细胞命运之间的选择，并且还影响表达富含亮氨酸重复受体 5（Lgr5）的干细胞。肠上皮细胞中 Shp2 酪氨酸磷酸酶的缺失减少了 MAPK 信号，导致杯状细胞减少，而促进潘氏细胞的发育。相反，条件性丝裂原活化蛋白激酶激酶 1（Mek1）的激活挽救了 Shp2 表型，促进了杯状细胞的生成并抑制了潘氏细胞的生成。Shp2 突变还扩大了 Lgr5+干细胞龛，而激活的 Mek1 信号可以限制其范围。Lgr5+干细胞数量的变化伴随着潘氏细胞的改变，表明 Shp2/MAPK 信号可能直接或通过潘氏细胞影响干细胞龛。值得注意的是，在肠类器官和培养细胞中抑制 MAPK 信号改变了 Tcf4 同工型的相对丰度，并通过这种方式促进了 Wnt/β-catenin 活性。因此，数据表明 Shp2 介导的 MAPK 信号通过调节 Wnt/β-catenin 活性来控制杯状细胞和潘氏细胞命运之间的选择。
