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The ESRP1-GPR137 axis contributes to intestinal pathogenesis

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Mager Lukas Franz, Koelzer Viktor Hendrik, Stuber Regula, Thoo Lester, Keller Irene, Koeck Ivonne, Langenegger Maya, Simillion Cedric, Pfister Simona P, Faderl Martin, Genitsch Vera, Tcymbarevich Irina, Juillerat Pascal, Li Xiaohong, Xia Yu, Karamitopoulou Eva, Lyck Ruth, Zlobec Inti, Hapfelmeier Siegfried, Bruggmann Rémy, McCoy Kathy D, Macpherson Andrew J, Müller Christoph, Beutler Bruce, et al. ,
Project Molecular dissection of microbe-induced immunopathlogy
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Original article (peer-reviewed)

Journal eLife
Volume (Issue) 6
Page(s) 1
Title of proceedings eLife
DOI 10.7554/elife.28366

Open Access

URL http://doi.org/10.7554/eLife.28366
Type of Open Access Publisher (Gold Open Access)

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.
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