Requirement of Gα(q)/Gα(11) Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis

BACKGROUND & AIMS: Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein–coupled receptors. We herein investigated the role of Gα(q/11)-mediated signaling in intestinal homeostasis. METHODS: Intestinal tissues from control (Gnaq(flox/flox)Gna11(+/+)), Int-G(q) knock-out (KO) (VilCre(+/-)Gnaq(flox/flox)Gna11(+/+)), G(11) KO (Gnaq(flox/flox)Gna11(-/-)), and Int-G(q)/G(11) double knock-out (DKO) (VilCre(+/-)Gnaq(flox/flox)Gna11(-/-)) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gα(q/11)-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gα(q/11) in colon. RESULTS: Paneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear β-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid–Schiff–positive cells, and Muc2-positive cells were unusually observed in the ulcerative region. CONCLUSIONS: The Gα(q/11)-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/β-catenin signaling was reduced significantly in the crypt base in Gα(q)/G(11)-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.