A Key Role for E-cadherin in Intestinal Homeostasis and Paneth Cell Maturation

Abstract

BackgroundE-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease.Methods and FindingsTo genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen.ConclusionThese results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells.

253 TSC2/mTORC1 Signaling Controls Paneth and Goblet Cell Differentiation in the Intestinal Epithelium

“…The effects of TSC2 inactivation on Paneth cells have also been determined by IHC staining for MMP7, another Paneth cell marker. 26 Consistent with the decreased lysozyme staining, decreased staining of MMP7 was also found in TSC2-mutant mice (Supplementary Figure 6). In addition, decreased enteroendocrine cell numbers were found in TSC2-mutant TG mice as assessed by chromogranin A staining (Supplementary Figure 7).…”

E-cadherin Is Important for the Maintenance of Intestinal Epithelial Homeostasis Under Basal and Inflammatory Conditions

“…Intestinal-specific deletion of the floxed CDH1 gene using Villin-Cre mice was associated with death within 24 h after birth [8]. Targeted E-cadherin deletion was induced in adult mice using a tamoxifen-induced deletion that was associated with bloody diarrhea with death attributed to epithelial shedding [9]. These data highlight the importance of E-cadherin for intestinal epithelial homeostasis even under basal conditions.…”

The mucosal barrier at a glance

“…In mice, functional disruption of E-cadherin through chimeric expression of a dominant-negative N-cadherin mutant that lacks an extracellular domain leads to aberrant epithelial differentiation, an active inflammatory response, crypt hyperproliferation and epithelial dysplasia (Hermiston and Gordon, 1995a,b). Tissue-specific E-cadherin knockout within the intestinal epithelium results in loss of both adherens junctions and desmosomes as well as deficiencies in the numbers of Paneth and goblet cells (Bondow et al, 2012;Schneider et al, 2010). Similar changes occur after deletion of other adherens junction components, such as p120 and afadin Ikeda et al, 1999;Smalley-Freed et al, 2010;Tanaka-Okamoto et al, 2011).…”