Epithelial Notch-1: A Central Regulator of Intestinal Homeostasis

Mounting evidence points to paramount importance of Notch-1 signaling in the maintenance of intestinal architecture and barrier function. We have recently shown that epithelial Notch-1 is indispensable in bridging innate and adaptive immunity in the gut and is required for supporting protective epithelial pro-inflammatory responses (Matthern, Laitman et al., Mucosal Immunology 2014). Thus, we hypothesized that intestinal epithelial Notch-1 contributes to mucosal homeostasis and protects against tissue injury during colitis. We have generated colonocyte specific conditional Notch-1 heterozygote mice (CDX2-Notch-1^+/-), as complete deletion of Notch-1 in these cells caused embryonic lethality. We found that CDX2-Notch-1^+/- mice exhibited spontaneous goblet cell hyperplasia and serrated lesions. This phenotype was accompanied with increased colonocyte proliferation and enhanced production of pro-inflammatory mediators in the colon. Moreover, we observed a nuclear redistribution of adherens junction proteins. In experimental models of DSS-induced acute/recovery and chronic colitis, CDX2-Notch-1^+/- mice displayed severe chronic injuries and high susceptibility. Mechanistically, TNFα-stimulated Notch-1 knockdown Caco-2 cells proliferated faster than controls, confirming a defect in epithelial maturation and barrier function. Overall, these results emphasize the key role of Notch-1 signaling in protecting from intestinal inflammation, and exhibit potential for the development of therapeutics targeting Notch-1 signaling in intestinal disorders.