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P020 Regulation of intestinal epithelial homeostasis by the IBD risk gene CCNY

S. Heil1, A. Molinas1, S. Koch*1

1Linköping University, Clinical and Experimental Medicine, Linköping, Sweden

Background

CCNY, encoding Cyclin Y, has previously been identified as a putative risk gene in Crohn’s disease and ulcerative colitis; however, the function of CCNY in the gut is unknown. We have shown that Cyclin Y is a critical activator of the Wnt/β-catenin signalling pathway, which controls stemness and proliferation in intestinal epithelia. We thus investigated whether CCNY regulates epithelial homeostasis and wound repair in the gut.

Methods

To address the role of CCNY in intestinal epithelia, we used a RNA interference based loss-of-function approach in model cell lines. In addition, we generated transgenic mice with deletion of Ccny specifically in intestinal epithelial cells. These animals were subjected to the dextran sulphate sodium model of intestinal injury and repair, which mimics human inflammatory bowel diseases. We studied Wnt pathway activity in these models using reporter assays and pathway-specific antibodies, as well as functional in vitro assays. In addition, we determined colitis progression and epithelial homeostasis in mice using an established disease activity index and histopathological analyses.

Results

In contrast to non-intestinal epithelia, loss-of-function of CCNY did not reduce Wnt signalling activity in model intestinal cell lines. Accordingly, CCNY depletion did not impair epithelial proliferation or stemness in vitro. Moreover, markers of Wnt activity and cell proliferation were unchanged in Ccny mutant mice, and we observed no changes in disease activity during acute intestinal inflammation.

Conclusion

Our results thus far suggest that IBD risk gene CCNY is dispensable for intestinal epithelial homeostasis. The apparent uncoupling of Cyclin Y from Wnt signalling in the gut is the subject of ongoing investigation in our lab. In addition, we continue to investigate the possible contribution of CCNY to epithelial regeneration following colitis.