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Elife. 2017 Oct 4;6. pii: e28366. doi: 10.7554/eLife.28366.

The ESRP1-GPR137 axis contributes to intestinal pathogenesis.

Author information

1
Institute of Pathology, University of Bern, Bern, Switzerland.
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
3
Department of BioMedical Research, University of Bern, Bern, Switzerland.
4
Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
5
Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
6
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
7
Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
8
Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States.
9
Department of Genetics, The Scripps Research Institute, La Jolla, United States.
10
Theodor Kocher Institute, University of Bern, Bern, Switzerland.

Abstract

Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific Gpr137 isoforms differently activating the Wnt pathway. In humans, ESRP1 is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of ESRP1-dependent GPR137 isoforms is altered in CRC and expression of a specific GPR137 isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology.

KEYWORDS:

ESRP1; GPR137; cancer biology; cell biology; colon cancer; epithelium; human; intestine; mRNA alternative splicing; mouse

PMID:
28975893
PMCID:
PMC5665647
DOI:
10.7554/eLife.28366
[Indexed for MEDLINE]
Free PMC Article

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