Ileal Crohn’s disease exhibits reduced activity of phospholipase C-β3 (PLC-β3)-dependent Wnt/b-catenin signaling pathway [microarray]. Ileal Crohn’s disease exhibits reduced activity of phospholipase C-β3 (PLC-β3)-dependent Wnt/b-catenin signaling pathway [microarray]

Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-β3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/β-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease. Overall design: To gain insight into the molecular mechanisms by which Plcb3 deficiency increases DSS susceptibility, gene expression in isolated small intestinal IECs, whole jejunum or whole ileum from WT, Plcb3_KO, Plcb3_Flox or Plcb3_deltaIEC mice with or without 3% DSS treatment was analyzed using DNA microarray.