Study On The Function Of Lgr4in The Intestinal Homeostasis And Inflammation

The proliferation and differentiation of epithelial cells in the intestine are tightly regulated by Wnt signaling pathway. Lgr4is one of the newly identified R-Spondinl receptor potentiate Wnt signaling. However, how Lgr4regulates intestinal homeostasis remains elusive. By using an Lgr4gene-trap mouse strain which contains a β-gal reporter driven by endougenous Lgr4promoter we found Lgr4expresses mainly in cypts and predominantly in Paneth cells which constitute the potential niche for Lgr5positive intestinal stem cells (ISCs). Lgr4deficiency resulted in greatly reduced cell number of either Paneth cells or stem cells in the intestine. To explore the physiological role of Lgr4in intestinal inflammation, dextran sulfate sodium (DSS)-induced IBD model was employed. Intestinal inflammation was induced with DSS, followed by a recovery period. Intestinal inflammation symptoms and molecular mechanisms were examined. We found that Lgr4-/-mice exhibited dramatically higher susceptibility and mortality to DSS-induced inflammatory bowel disease (IBD) than WT mice. Mechanisim research determined downregulated Wnt/β-catenin signaling in the intestinal epithelium of Lgr4-/-mice. When Wnt/β-catenin signaling was re-activated by crossing with APCmin/+mice or by treating with a GSK-3β inhibitor, the number of Paneth cells was partially restored and the mortality caused by DSS-induced IBD was strikingly reduced in Lgr4deficient animals. Thus, Lgr4is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through modulation of the Wnt/β-catenin signaling pathway.