A DLG1-ARHGAP31-CDC42 Axis Is Essential for the Intestinal Stem Cell Response to Fluctuating Niche Wnt Signaling

Authors

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

Publication Date

2-2-2023

Journal

Cell Stem Cell

DOI

10.1016/j.stem.2022.12.008

PMID

36640764

PMCID

PMC9922544

PubMedCentral® Posted Date

2-2-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Cell Proliferation, GTPase-Activating Proteins, Intestinal Mucosa, Intestines, Stem Cell Niche, Stem Cells, Wnt Signaling Pathway, stem cells, Wnt, niche, regeneration, Dlg1, Arhgap31, Cdgap, Cdc42, Rac1, organoid, intestine, epithelium, cell death

Abstract

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.

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