The ESRP1-GPR137 axis contributes to intestinal pathogenesis

  1. Lukas Franz Mager
  2. Viktor Koelzer
  3. Regula Stuber
  4. Lester Thoo
  5. Irene Keller
  6. Ivonne Koeck
  7. Maya Langenegger
  8. Cedric Simillion
  9. Simona Pfister
  10. Martin Faderl
  11. Vera Genitsch
  12. Irina Tcymbarevich
  13. Pascal Juillerat
  14. Xiaohong Li
  15. Yu Xia
  16. Eva Karamitopoulou
  17. Ruth Lyck
  18. Inti Zlobec
  19. Siegfried Hapfelmeier
  20. Rémy Bruggmann
  21. Kathy McCoy
  22. Andrew J MacPherson
  23. Christoph Mueller
  24. Bruce Beutler
  25. Philippe Krebs  Is a corresponding author
  1. University of Bern, Switzerland
  2. University Hospital Zurich, Switzerland
  3. University of Texas Southwestern Medical Center, United States
  4. 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

The following data sets were generated
The following previously published data sets were used
    1. The Cancer Genome Atlas Network
    (2012) TCGA-COAD
    Publicly available from the NCI GDC Data Portal (https://portal.gdc.cancer.gov).
    1. The Cancer Genome Atlas Network
    (2012) TCGA-READ
    Publicly available from the NCI GDC Data Portal (https://portal.gdc.cancer.gov).

Article and author information

Author details

  1. Lukas Franz Mager

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  2. Viktor Koelzer

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  3. Regula Stuber

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  4. Lester Thoo

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  5. Irene Keller

    Department of Clinical Research, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  6. Ivonne Koeck

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  7. Maya Langenegger

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  8. Cedric Simillion

    Department of Clinical Research, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  9. Simona Pfister

    Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  10. Martin Faderl

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8807-6146
  11. Vera Genitsch

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  12. Irina Tcymbarevich

    Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  13. Pascal Juillerat

    Department of Gastroenterology, Bern University Hospital, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  14. Xiaohong Li

    Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  15. Yu Xia

    Department of Genetics, The Scripps Research Institute, La Jolla, United States
    Competing interests
    No competing interests declared.
  16. Eva Karamitopoulou

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  17. Ruth Lyck

    Theodor Kocher Institute, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  18. Inti Zlobec

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  19. Siegfried Hapfelmeier

    Institute for Infectious Diseases, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  20. Rémy Bruggmann

    Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4733-7922
  21. Kathy McCoy

    Department of Clinical Research, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
  22. Andrew J MacPherson

    Department of Clinical Research, University of Bern, Bern, Switzerland
    Competing interests
    Andrew J MacPherson, Reviewing editor, eLife.
  23. Christoph Mueller

    Institute of Pathology, University of Bern, Bern, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3921-8678
  24. Bruce Beutler

    Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  25. Philippe Krebs

    Institute of Pathology, University of Bern, Bern, Switzerland
    For correspondence
    philippe.krebs@pathology.unibe.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4918-6654

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

  1. Florian Greten

Publication history

  1. Received: May 4, 2017
  2. Accepted: September 25, 2017
  3. Accepted Manuscript published: October 4, 2017 (version 1)
  4. 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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  1. Lukas Franz Mager
  2. Viktor Koelzer
  3. Regula Stuber
  4. Lester Thoo
  5. Irene Keller
  6. Ivonne Koeck
  7. Maya Langenegger
  8. Cedric Simillion
  9. Simona Pfister
  10. Martin Faderl
  11. Vera Genitsch
  12. Irina Tcymbarevich
  13. Pascal Juillerat
  14. Xiaohong Li
  15. Yu Xia
  16. Eva Karamitopoulou
  17. Ruth Lyck
  18. Inti Zlobec
  19. Siegfried Hapfelmeier
  20. Rémy Bruggmann
  21. Kathy McCoy
  22. Andrew J MacPherson
  23. Christoph Mueller
  24. Bruce Beutler
  25. Philippe Krebs
(2017)
The ESRP1-GPR137 axis contributes to intestinal pathogenesis
eLife 6:e28366.
https://doi.org/10.7554/eLife.28366

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