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

• DOI: 10.1016/j.stem.2022.12.008
• Publication Date: 2023-01-13T15:53:32Z
• Authors: David Castillo-Az...; Tomas Wald; Efren A. Reyes; Aaron Gallagher; Julia Schanin; Stephanie Vlachos; Nathalie Lamarche...; Carolyn Bomidi; Sarah Blutt; Mary K. Estes; Todd Nystul; Ophir D. Klein
• Keywords: Medical Sciences; Biomedical and clinical sciences; Diseases; Regenerative Medicine; Medical and Health Sciences; Mice; Arhgap31; Medical Specialties; Medicine and Health Sciences; 2.1 Biological and endogenous factors; Cdc42; Intestinal Mucosa; Stem Cell Niche; Wnt Signaling Pathway; Biological Phenomena; Cancer; 0303 health sciences; Cell Phenomena; Stem Cells; GTPase-Activating Proteins; Dlg1; Biological Sciences; 3. Good health; Medical Cell Biology; Colo-Rectal Cancer; Intestines; niche; Biological sciences; cell death; Stem Cell Research - Nonembryonic - Non-Human; Rac1; Biotechnology; Cdgap; 570; 1.1 Normal biological development and functioning; organoid; 610; Infectious Disease; Wnt; 03 medical and health sciences; stem cells; Genetics; and Immunity; Animals; intestine; Cell Proliferation; Stem Cell Research; regeneration; Biochemistry and Cell Biology; Digestive Diseases; epithelium; Developmental Biology

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.