p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

Abstract

Epithelial-cadherin (E-cadherin) is a master organizer of the epithelial phenotype. Its function is regulated in part by p120-catenin (referred to herein as p120), a cytoplasmic binding partner that directly regulates cadherin stability. As it has been suggested that cadherins have a role in inflammatory bowel disease (IBD), we sought to investigate this further by assessing the effect of p120 deficiency in mouse small intestine and colon. p120 conditional KO mice were superficially normal at birth but declined rapidly and died within 21 days. Cellcell adhesion defects and inflammation led to progressive mucosal erosion and terminal bleeding, similar to what is observed in a dominant-negative cadherin mouse model of IBD. Additionally, selective loss of adherens junctions and accumulation of atypical COX-2-expressing neutrophils in p120-null areas of the colon were observed. To elucidate the mechanism, direct effects of p120 deficiency were assessed in vitro in a polarizing colon cancer cell line. Notably, transepithelial electrical resistance was dramatically reduced, neutrophil binding was increased 30 fold, and levels of COX-2, an enzyme associated with IBD, were markedly increased in neutrophils. Our data suggest that p120 loss disrupts the neonatal intestinal barrier and amplifies neutrophil engagement and that these changes lead to catastrophic inflammation during colonization of the neonatal gut with bacteria and other luminal antigens. Thus, we conclude that p120 has an essential role in barrier function and epithelial homeostasis and survival in the intestine.

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

“…Another mechanism that could relate to the severe epithelial phenotype is the loss of the cadherin/catenin complex and links to the cytoskeleton. For example, p120-catenin KO mice are characterized by disturbed epithelial adhesion, increased inflammation, mucosal erosions, and bloody stools, effects similar to what has been observed in the study by Grill and colleagues [12]. Thus, it will be important to investigate in future studies how colitis and loss of E-cadherin affect catenin functions and the cytoskeleton, which are major factors for controlling epithelial barrier integrity.…”

p120-catenin Is Essential for N-cadherin-mediated Formation of Proper Junctional Structure, thereby Establishing Cell Polarity in Epithelial Cells

“…In contrast to our results, however, Smalley-Freed et al (2010) reported that knockout or knockdown of p120-catenin resulted in the down regulation of E-cadherin and breakage of adherens junction as predicted; but unexpectedly ZO-1 and occludin were still localized at cell-cell contact sites. We do not have a good explanation as to why the tight junction proteins were localized without adherens junction in the experiments, in contrast to the general notion that E-cadherin is required for the localization (Itoh et al, 1993).…”

“…Recently, Smalley-Freed et al (2010) reported knockdown experiments on p120-catenin in cell culture, but the experiments also had the same problem. Meng et al (2008), on the other hand, suggested that p120-catenin-binding proteins participate in cell polarity formation.…”

Neutrophil-Epithelial Interactions

“…117 However, mice with intestinal epithelial loss of P120-catenin have increased intestinal permeability associated with a severe inflammatory phenotype and abnormal intestinal architecture. 118 JAM-A is down-regulated during inflammatory bowel disease and, as highlighted above, its loss is associated with potent effects on epithelial barrier and homeostasis. However, in contrast to the phenotypes observed with claudin-1 and P120-catenin knockout mice, JAM-Aedeficient mice do not get spontaneous colitis despite significantly increased intestinal permeability.…”