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

doi:10.7554/eLife.28366

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 BruggmannKathy D. McCoy, Andrew J. Macpherson, Christoph Müller, Bruce Beutler, Philippe Krebs

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Article number	e28366
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.28366
State	Published - Oct 4 2017

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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Mager, L. F., Koelzer, V. H., Stuber, R., Thoo, L., Keller, I., Koeck, I., Langenegger, M., Simillion, C., Pfister, S. P., Faderl, M., Genitsch, V., Tcymbarevich, I., Juillerat, P., Li, X., Xia, Y., Karamitopoulou, E., Lyck, R., Zlobec, I., Hapfelmeier, S., ... Krebs, P. (2017). The ESRP1-GPR137 axis contributes to intestinal pathogenesis. eLife, 6, Article e28366. https://doi.org/10.7554/eLife.28366

Mager, LF, Koelzer, VH, Stuber, R, Thoo, L, Keller, I, Koeck, I, Langenegger, M, Simillion, C, Pfister, SP, Faderl, M, Genitsch, V, Tcymbarevich, I, Juillerat, P, Li, X, Xia, Y, Karamitopoulou, E, Lyck, R, Zlobec, I, Hapfelmeier, S, Bruggmann, R, McCoy, KD, Macpherson, AJ, Müller, C, Beutler, B & Krebs, P 2017, 'The ESRP1-GPR137 axis contributes to intestinal pathogenesis', eLife, vol. 6, e28366. https://doi.org/10.7554/eLife.28366

@article{cffb6d3a42b84485a22753ffdb020217,

title = "The ESRP1-GPR137 axis contributes to intestinal pathogenesis",

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.",

author = "Mager, {Lukas Franz} and Koelzer, {Viktor Hendrik} and Regula Stuber and Lester Thoo and Irene Keller and Ivonne Koeck and Maya Langenegger and Cedric Simillion and Pfister, {Simona P.} and Martin Faderl and Vera Genitsch and Irina Tcymbarevich and Pascal Juillerat and Xiaohong Li and Yu Xia and Eva Karamitopoulou and Ruth Lyck and Inti Zlobec and Siegfried Hapfelmeier and R{\'e}my Bruggmann and McCoy, {Kathy D.} and Macpherson, {Andrew J.} and Christoph M{\"u}ller and Bruce Beutler and Philippe Krebs",

note = "Funding Information: 1Institute of Pathology, University of Bern, Bern, Switzerland; 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; 3Department of BioMedical Research, University of Bern, Bern, Switzerland; 4Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland; 5Institute for Infectious Diseases, University of Bern, Bern, Switzerland; 6Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; 7Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 8Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States; 9Department of Genetics, The Scripps Research Institute, La Jolla, United States; 10Theodor Kocher Institute, University of Bern, Bern, Switzerland Publisher Copyright: {\textcopyright} Mager et al.",

year = "2017",

month = oct,

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doi = "10.7554/eLife.28366",

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T1 - The ESRP1-GPR137 axis contributes to intestinal pathogenesis

AU - Mager, Lukas Franz

AU - Koelzer, Viktor Hendrik

AU - Stuber, Regula

AU - Thoo, Lester

AU - Keller, Irene

AU - Koeck, Ivonne

AU - Langenegger, Maya

AU - Simillion, Cedric

AU - Pfister, Simona P.

AU - Faderl, Martin

AU - Genitsch, Vera

AU - Tcymbarevich, Irina

AU - Juillerat, Pascal

AU - Li, Xiaohong

AU - Xia, Yu

AU - Karamitopoulou, Eva

AU - Lyck, Ruth

AU - Zlobec, Inti

AU - Hapfelmeier, Siegfried

AU - Bruggmann, Rémy

AU - McCoy, Kathy D.

AU - Macpherson, Andrew J.

AU - Müller, Christoph

AU - Beutler, Bruce

AU - Krebs, Philippe

N1 - Funding Information: 1Institute of Pathology, University of Bern, Bern, Switzerland; 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; 3Department of BioMedical Research, University of Bern, Bern, Switzerland; 4Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland; 5Institute for Infectious Diseases, University of Bern, Bern, Switzerland; 6Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; 7Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 8Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United States; 9Department of Genetics, The Scripps Research Institute, La Jolla, United States; 10Theodor Kocher Institute, University of Bern, Bern, Switzerland Publisher Copyright: © Mager et al.

PY - 2017/10/4

Y1 - 2017/10/4

N2 - 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.

AB - 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.

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JO - eLife

JF - eLife

M1 - e28366

ER -

The ESRP1-GPR137 axis contributes to intestinal pathogenesis

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