维持组织完整性的一个中心因素是干细胞对基质信号水平变化的反应。在肠道中，肠干细胞（ISCs）依赖Wnt配体进行自我更新和增殖。Wnt信号的短暂增加促进了损伤后或在炎症性肠病中的再生，而该途径的构成性活化则导致结肠癌。在这里，我们报告Discs large 1（Dlg1），尽管在肠道稳态期间细胞极性和轮换中是可以省略的，但在Wnt信号增加背景下，它是ISC的生存所必需的。RNA测序和基因突变的鼠模型表明，DLG1通过转录调节Arhgap31，一种使CDC42失活的GTP酶激活蛋白，调节细胞对增加的典型Wnt配体的反应。这些发现揭示了一个对于ISC对增加的基质Wnt信号反应至关重要的DLG1-ARHGAP31-CDC42轴。版权所有©2022 Elsevier Inc.。保留所有权利。

A central factor in the maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1), although dispensable for polarity and cellular turnover during intestinal homeostasis, is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNA-seq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt ligands. This occurs via the transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to increased niche Wnt signaling.Copyright © 2022 Elsevier Inc. All rights reserved.