eLife (Oct 2017)
The ESRP1-GPR137 axis contributes to intestinal pathogenesis
- Lukas Franz Mager,
- Viktor Hendrik Koelzer,
- Regula Stuber,
- Lester Thoo,
- Irene Keller,
- Ivonne Koeck,
- Maya Langenegger,
- Cedric Simillion,
- Simona P Pfister,
- Martin Faderl,
- Vera Genitsch,
- Irina Tcymbarevich,
- Pascal Juillerat,
- Xiaohong Li,
- Yu Xia,
- Eva Karamitopoulou,
- Ruth Lyck,
- Inti Zlobec,
- Siegfried Hapfelmeier,
- Rémy Bruggmann,
- Kathy D McCoy,
- Andrew J Macpherson,
- Christoph Müller,
- Bruce Beutler,
- Philippe Krebs
Affiliations
- Lukas Franz Mager
- ORCiD
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
- Viktor Hendrik Koelzer
- Institute of Pathology, University of Bern, Bern, Switzerland
- Regula Stuber
- Institute of Pathology, University of Bern, Bern, Switzerland
- Lester Thoo
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
- Irene Keller
- Department of BioMedical Research, University of Bern, Bern, Switzerland; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
- Ivonne Koeck
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; Department of BioMedical Research, University of Bern, Bern, Switzerland
- Maya Langenegger
- Institute of Pathology, University of Bern, Bern, Switzerland
- Cedric Simillion
- Department of BioMedical Research, University of Bern, Bern, Switzerland; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
- Simona P Pfister
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- Martin Faderl
- ORCiD
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
- Vera Genitsch
- Institute of Pathology, University of Bern, Bern, Switzerland
- Irina Tcymbarevich
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Pascal Juillerat
- Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Xiaohong Li
- Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Yu Xia
- Department of Genetics, The Scripps Research Institute, La Jolla, United States
- Eva Karamitopoulou
- Institute of Pathology, University of Bern, Bern, Switzerland
- Ruth Lyck
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
- Inti Zlobec
- Institute of Pathology, University of Bern, Bern, Switzerland
- Siegfried Hapfelmeier
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- Rémy Bruggmann
- ORCiD
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
- Kathy D McCoy
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Andrew J Macpherson
- Department of BioMedical Research, University of Bern, Bern, Switzerland; Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Christoph Müller
- ORCiD
- Institute of Pathology, University of Bern, Bern, Switzerland
- Bruce Beutler
- Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
- Philippe Krebs
- ORCiD
- Institute of Pathology, University of Bern, Bern, Switzerland
- DOI
- https://doi.org/10.7554/eLife.28366
- Journal volume & issue
-
Vol. 6
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