The ESRP1-GPR137 axis contributes to intestinal pathogenesis
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 homeostasi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/28366 |
| _version_ | 1828375925217034240 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lukas Franz Mager |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:53:38Z |
| format | Article |
| id | doaj.art-46127925fa504c6795248c15aa1ffdf6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:53:38Z |
| publishDate | 2017-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-46127925fa504c6795248c15aa1ffdf62022-12-22T02:05:07ZengeLife Sciences Publications LtdeLife2050-084X2017-10-01610.7554/eLife.28366The ESRP1-GPR137 axis contributes to intestinal pathogenesisLukas Franz Mager0https://orcid.org/0000-0002-7426-2842Viktor Hendrik Koelzer1Regula Stuber2Lester Thoo3Irene Keller4Ivonne Koeck5Maya Langenegger6Cedric Simillion7Simona P Pfister8Martin Faderl9https://orcid.org/0000-0001-8807-6146Vera Genitsch10Irina Tcymbarevich11Pascal Juillerat12Xiaohong Li13Yu Xia14Eva Karamitopoulou15Ruth Lyck16Inti Zlobec17Siegfried Hapfelmeier18Rémy Bruggmann19https://orcid.org/0000-0003-4733-7922Kathy D McCoy20Andrew J Macpherson21Christoph Müller22https://orcid.org/0000-0002-3921-8678Bruce Beutler23Philippe Krebs24https://orcid.org/0000-0003-4918-6654Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Bern, Switzerland; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, SwitzerlandInstitute 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, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Bern, Switzerland; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, SwitzerlandGraduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; Institute for Infectious Diseases, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandDivision of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandCenter for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Genetics, The Scripps Research Institute, La Jolla, United StatesInstitute of Pathology, University of Bern, Bern, SwitzerlandTheodor Kocher Institute, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandInstitute for Infectious Diseases, University of Bern, Bern, SwitzerlandInterfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Bern, SwitzerlandDepartment of BioMedical Research, University of Bern, Bern, Switzerland; Department of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandInstitute of Pathology, University of Bern, Bern, SwitzerlandCenter for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, United StatesInstitute of Pathology, University of Bern, Bern, SwitzerlandAberrant 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.https://elifesciences.org/articles/28366mRNA alternative splicingESRP1GPR137intestinecolon cancerepithelium |
| spellingShingle | 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 The ESRP1-GPR137 axis contributes to intestinal pathogenesis eLife mRNA alternative splicing ESRP1 GPR137 intestine colon cancer epithelium |
| title | The ESRP1-GPR137 axis contributes to intestinal pathogenesis |
| title_full | The ESRP1-GPR137 axis contributes to intestinal pathogenesis |
| title_fullStr | The ESRP1-GPR137 axis contributes to intestinal pathogenesis |
| title_full_unstemmed | The ESRP1-GPR137 axis contributes to intestinal pathogenesis |
| title_short | The ESRP1-GPR137 axis contributes to intestinal pathogenesis |
| title_sort | esrp1 gpr137 axis contributes to intestinal pathogenesis |
| topic | mRNA alternative splicing ESRP1 GPR137 intestine colon cancer epithelium |
| url | https://elifesciences.org/articles/28366 |
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