The ESRP1-GPR137 axis contributes to intestinal pathogenesis
- University of Bern, Switzerland
- University Hospital Zurich, Switzerland
- University of Texas Southwestern Medical Center, United States
- The Scripps Research Institute, United States
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.
Data availability
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Assessment of transcript isoforms in Esrp1Triaka versus wild-type primary colonic epithelial cellsPublicly available at the EMDataBank (accession no.PRJEB14221).
Article and author information
Author details
Funding
Swiss National Science Foundation (310030_138188)
- Philippe Krebs
Universität Bern (Research Foundation)
- Philippe Krebs
National Institutes of Health (5P01AI070167)
- Bruce Beutler
Boehringer Ingelheim Fonds
- Lukas Franz Mager
Gertrud-Hagmann Foundation for Malignoma Research
- Lukas Franz Mager
National Institutes of Health (5U19A100627)
- Bruce Beutler
Swiss National Science Foundation (314730_163086)
- Philippe Krebs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed in accordance with institutional and federal regulations governing animal care and use and were approved by The Scripps Research Institute (TSRI) Institutional Animal Care and Use Committee (La Jolla, CA, USA) (IACUC protocols 07-0057 and 09-0079) and the Cantonal Veterinary Office of Bern (Switzerland) (protocols BE76-11 and BE130/14).
Human subjects: The use of patient data and samples was approved by the Ethics Committee at the University of Athens, Greece and the Cantonal Ethics Committee of Bern.
Reviewing Editor
- Florian Greten
Publication history
- Received: May 4, 2017
- Accepted: September 25, 2017
- Accepted Manuscript published: October 4, 2017 (version 1)
- Version of Record published: November 1, 2017 (version 2)
Copyright
© 2017, Mager et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The ESRP1-GPR137 axis contributes to intestinal pathogenesis
eLife 6:e28366.
https://doi.org/10.7554/eLife.28366
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