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

• Published in: Cell stem cell 2023-02, Vol.30 (2), p.188-206.e6
• Main Authors: Castillo-Azofeifa, David, Wald, Tomas, Reyes, Efren A., Gallagher, Aaron, Schanin, Julia, Vlachos, Stephanie, Lamarche-Vane, Nathalie, Bomidi, Carolyn, Blutt, Sarah, Estes, Mary K., Nystul, Todd, Klein, Ophir D.
• Format: Article
• Language: English
• Subjects: Animals; Arhgap31; Cdc42; cell death; Cell Proliferation; Dlg1; epithelium; GTPase-Activating Proteins - metabolism; Intestinal Mucosa - metabolism; intestine; Intestines; Mice; organoid; regeneration; Stem Cell Niche; Stem Cells; Wnt; Wnt Signaling Pathway - genetics
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2022.12.008

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. [Display omitted] •Polarity of the mammalian intestinal epithelium is independent of Dlg1•Loss of Dlg1 in ISCs results in cell death under high Wnt conditions•ISCs lacking Dlg1 have impaired cell division and migration•Canonical WNT ligands activate non-canonical Wnt signaling via DLG1-ARHGAP31-CDC42 Throughout an organism’s life, the activity of niche signals fluctuates due to injury, and stem cells need to respond accordingly. Klein and colleagues found that during high Wnt activity observed in intestinal regeneration, niche canonical WNT ligands activate non-canonical Wnt signaling via a DLG1-ARHGAP31-CDC42 axis required for stem cell-driven regeneration.