近日，美国加州大学旧金山分校Ophir D. Klein及其小组发现，DLG1-ARHGAP31-CDC42轴对于肠道干细胞响应波动的微环境Wnt信号至关重要。该项研究成果于2023年1月13日在线发表在《细胞—干细胞》杂志上。

研究人员报告说，在Wnt信号增加的背景下，肠道干细胞（ISC）存活需要DLG1（Discs large 1）虽然在肠内稳态期间的极性和细胞更新的可分配。RNA测序（RNA-seq）和遗传小鼠模型表明，DLG1调节细胞对经典Wnt配体增加的反应。 这是通过Arhgap31的转录调节（一种失活CDC42的GTP酶激活蛋白）的转录调节，该蛋白是非典型Wnt途径的效应子。这些发现揭示了DLG1-ARHGAP31-CDC42轴，其对于ISC对增加的微环境Wnt信号的响应至关重要。

研究人员表示，维持组织完整性的一个核心因素是干细胞对微环境信号水平变化的反应。在肠道中，ISC依赖于Wnt配体进行自我更新和增殖。WNT信号传导的瞬时增加促进了损伤或炎症性肠道疾病后的再生，而该途径的持续激活可导致结直肠癌。

附：英文原文

Title: A DLG1-ARHGAP31-CDC42 axis is essential for the intestinal stem cell response to fluctuating niche Wnt signaling

Author: David Castillo-Azofeifa, Tomas Wald, Efren A. Reyes, Aaron Gallagher, Julia Schanin, Stephanie Vlachos, Nathalie Lamarche-Vane, Carolyn Bomidi, Sarah Blutt, Mary K. Estes, Todd Nystul, Ophir D. Klein

Issue&Volume: 2023-01-13

Abstract: A central factor in the maintenance of tissue integrity is the response of stem cellsto 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 Wntsignaling promote regeneration after injury or in inflammatory bowel diseases, whereasconstitutive activation of this pathway leads to colorectal cancer. Here, we reportthat 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 responseto increased canonical Wnt ligands. This occurs via the transcriptional regulationof Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonicalWnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential forthe ISC response to increased niche Wnt signaling.

DOI: 10.1016/j.stem.2022.12.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00492-1