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Bechard, Matthew E.; Chen, Zhengyi; Zhao, Ping; Aramandla, Radhika; Yang, Yilin; Simmons, Alan J.; Washington, M. Kay; Franklin, Jeffery L.; Lau, Ken S.; Coffey, Robert J. (2026).Ìý.ÌýCellular and Molecular Gastroenterology and Hepatology, 20(12), 101873.Ìý

Epidermal growth factor receptor (EGFR) signaling helps regulate the growth and development of intestinal cells, but excessive activity can promote tumor formation. The protein leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) normally limits EGFR signaling, while the role of the related protein LRIG3 is less clear. Using genetically modified mice, researchers examined how loss of LRIG3 affects intestinal cells and colorectal tumor development, particularly when LRIG1 is reduced or absent. Unlike loss of LRIG1, which increased EGFR and Wnt signaling, loss of LRIG3 reduced activity in both pathways and altered the balance between intestinal stem and secretory cells. Removing one copy of LRIG3 in mice with reduced LRIG1 also substantially decreased colon tumor formation. These findings indicate that LRIG1 and LRIG3 have opposing effects that help balance EGFR signaling, maintain normal intestinal function, and influence the development of colon tumors.

Figure 1ÌýLrig1ÌýandÌýLrig3Ìýexpression in mouse and human intestinal tissue.ÌýUMAP analysis indicating cell-type assignments for clusters generated based on canonical (A) mouse and (B) human gene markers, colored by gene expression levels ofÌýLrig1,ÌýLrig3, andÌýLgr5, with corresponding dot plots indicating the mean expression level ofÌýLrig1ÌýandÌýLrig3Ìýin each of the cell types listed. (C) Schematic detailing generation ofÌýLrig3^fl/flÌýmice. To generate theÌýLrig3^flÌýallele, theÌý129 Lrig3ÌýBAC clone was obtained from the Sanger Institute, and BAC recombineering was used to construct a targeting vector that placed LoxP sites 5′ and 3′ of exons 4–12 and a PGK-Neo cassette. Homologous recombination was used to modify the nativeÌýLrig3Ìýlocus in embryonic stem cells, which were injected into blastocyst stage 129 mouse embryos by the Transgenic Mouse/ES Cell Shared Resource at Vanderbilt University. The resulting chimeric mice were bred toÌýFlpEÌýmice to remove the PGK-Neo cassette. SI, small intestine.