The ESRP1-GPR137 axis contributes to intestinal pathogenesis.

Mager, Lukas Franz; Kölzer, Viktor Hendrik; Stuber Roos, Regula; Thoo Sin Lang, Lester; Keller, Irene; Köck, Ivonne; Langenegger, Maya; Simillion, Cedric; Pfister, Simona P; Faderl, Martin Richard; Genitsch Gratwohl, Vera; Tcymbarevich, Irina; Juillerat, Pascal; Li, Xiaohong; Xia, Yu; Karamitopoulou, Evanthia; Lyck, Ruth; Zlobec, Inti; Hapfelmeier, Siegfried Hektor; Bruggmann, Rémy; ... (2017). The ESRP1-GPR137 axis contributes to intestinal pathogenesis. eLife, 6 eLife Sciences Publications 10.7554/eLife.28366

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Kölzer, Viktor; Stuber Roos, Regula; Thoo Sin Lang, Lester; Köck, Ivonne; Faderl, Martin Richard; Genitsch Gratwohl, Vera; Karamitopoulou, Evanthia; Lyck, Ruth; Zlobec, Inti; Hapfelmeier, Siegfried Hektor; Müller, Christoph and Krebs, Philippe

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2050-084X

Publisher:

eLife Sciences Publications

Language:

English

Submitter:

Christa Hagert

Date Deposited:

24 Nov 2017 17:11

Last Modified:

04 Jul 2018 15:15

Publisher DOI:

10.7554/eLife.28366

PubMed ID:

28975893

Uncontrolled Keywords:

ESRP1 GPR137 cancer biology cell biology colon cancer epithelium human intestine mRNA alternative splicing mouse

BORIS DOI:

10.7892/boris.106971

URI:

https://boris.unibe.ch/id/eprint/106971

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