The Candidate IBD Risk Gene CCNY Is Dispensable for Intestinal Epithelial Homeostasis

Abstract

The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis.

Molecular regulation after mucosal injury and regeneration in ulcerative colitis

“…In addition, intestinal mucosa barrier maintenance and other important functions of other types of IECs are reduced. The roles of Notch and Wnt signaling in maintaining the balance between small intestinal stem cell differentiation and Paneth cell differentiation in the colon may mediate the differentiation of colonic stem cells in individuals with UC, which is not a process that occurs in the normal intestine ( Molinas et al, 2021 ). These results suggest that Wnt and Notch activation and Paneth cells may indirectly participate in the pathology of UC.…”