Opposing effects of Lrig1 and Lrig3 on EGFR signaling maintain intestinal homeostasis and mitigate the likelihood of colonic neoplasia

ABSTRACT: This study investigates how LRIG1 and LRIG3 exert opposing control over EGFR signaling to maintain intestinal stem-cell (ISC) homeostasis and suppress tumor formation. LRIG1 is an established negative regulator of ERBB/EGFR signaling and tumor suppressor, whereas the function of LRIG3 in the intestine has been less clear. Using conditional mouse models that delete Lrig3 in Lrig1-expressing cells, the authors show that loss of LRIG3 in an LRIG1-null background produces the opposite signaling effect of LRIG1 loss: EGFR/ERBB, ERK, and WNT signaling are markedly reduced. This signaling imbalance causes loss of ISC identity and proliferation, increased cell death and crypt disruption, and a striking shift of stem cells toward immature secretory states, including Paneth/goblet intermediate cells in the small intestine and REG4⁺ deep secretory/goblet cells in the colon; single-cell RNA-seq further reveals reduced stem-cell programs together with activation of injury-responsive reserve/persister stem-cell programs. Importantly, the biological consequence extends to tumorigenesis: whereas Lrig1CreER/+; Apcfl/+ mice develop highly dysplastic distal colonic tumors, deletion of only one Lrig3 allele substantially reduces EGFR/WNT signaling and can abrogate tumor formation. Collectively, the paper proposes that LRIG1 restrains while LRIG3 supports EGFR signaling, and the antagonistic balance between these proteins establishes the signaling range required for ISC maintenance, appropriate lineage differentiation, intestinal crypt homeostasis, and protection against colonic neoplasia.

ORGANISM(S): Mus musculus

PROVIDER: GSE345558 | GEO | 2026/10/01

REPOSITORIES: GEO