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

Andrea Molinas,Stefan Koch,Stéphanie Heil

doi:10.3390/cells10092330

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.

Highlights

Inflammatory bowel disease (IBD) is a common disorder that involves chronic, recurring inflammation of the intestinal epithelium with a considerable impact on the patients’ quality of life
Whereas expression levels of CCNY, CCNYL1, and CDK16 were broadly comparable across all cell types, the average level of CDK14 was more than an order of magnitude lower in colon cancer cells compared to any other tissue included in this analysis (Supplemental Figure S1d)
Because CCNY has been implicated in IBD pathogenesis [3,4,5], and our analyses supported a role in intestinal epithelial stem cells, we investigated the function of cyclin Y in intestinal epithelial cell (IEC) in vivo

Summary

Introduction

Inflammatory bowel disease (IBD) is a common disorder that involves chronic, recurring inflammation of the intestinal epithelium with a considerable impact on the patients’ quality of life. Several single nucleotide polymorphisms identified in these studies have been mapped to the CCNY gene encoding the cell cycle regulator cyclin Y [3,4,5,6,7], whose biological functions are incompletely understood. Ccny-deficient mice display altered lipid metabolism and lower body weight, while double knock-out mice for Ccny, and its less ubiquitously expressed homolog Ccnyl (cyclin Y-like 1), are embryonic lethal [8,9,10]. These observations suggest that cyclin Y is essential for normal development and physiology

Methods

Results

Conclusion