Deletion of claudin‐7 disrupts epithelial cell self‐renewal in mouse colon

Abstract

Tight junctions are one of the physical barriers protecting the body from invasion of intestinal lumen pathogens. Disruption of tight junctions has been reported in a variety of intestinal disorders, such as intestinal bowel disease, necrotizing enterocolitis, and colon rectal cancer. Claudin‐7 is one of the tight junction membrane proteins and is essential in maintaining intestinal epithelial integrity. However, the function of claudin‐7 in colonic epithelial homeostasis remains to be determined. Here we report that claudin‐7 is required for maintaining the balance of intestinal epithelial cell proliferation and differentiation. To dissect the role of claudin‐7 in colonic epithelium, we used our global (gCldn7−/−) and intestinal‐specific (cCldn7−/−) claudin‐7 knockout (KO) mice that are generated recently as our model systems. Using the histological analysis, we found that enterocytes and enteroendocrine cells are significantly reduced in postnatal day 4 gCldn7−/− and 2–4 months old cCldn7−/− mouse colons. Although the absolute number of Goblet cells and tuft cells are reduced in claudin‐7 KO colon, the ratio of Goblet cells or tuft cells versus the total number of epithelial cells remains unchanged. These results are confirmed by qRT‐PCR and Western blotting, suggesting that epithelial cell differentiation was significantly altered after claudin‐7 deletion. In addition, the ki67 and PCNA positive proliferative cells are significantly increased in claudin‐7 KO colons and no longer limited to the basal‐lateral crypt region, where epithelial stem cells and fate‐committed progenitor cells are located. Genome‐wide gene‐expression microarray analysis of Cldn7+/+ and gCldn7−/− colons identified a list of gene expression changes related to cell proliferation and differentiation. Notch and Hippo signaling pathway are suppressed after claudin‐7 deletion. These findings suggest that claudin‐7 may have a novel, unidentified function regulating epithelial cell differentiation and self‐renewal in mouse colon.Support or Funding InformationThis study is supported by the National Institute of Health grant DK103166.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.