The ESRP1-GPR137 axis contributes to intestinal pathogenesis.

Lukas F Mager ,Martin Faderl,Siegfried Hapfelmeier,Rémy Bruggmann,Regula Stuber,Vera Genitsch,Lester Thoo,Yu Xia,Irene Keller,Bruce Beutler,Irina Tcymbarevich,Pascal Juillerat,Eva Karamitopoulou,Inti Zlobec,Philippe Krebs,Christoph Müller,Maya Langenegger,Ruth Lyck,Xiaohong Li,Ivonne Koeck,S Pfister ,Andrew J Macpherson ,Cédric Simillion ,Kathy D Mccoy ,Viktor H Koelzer

doi:10.7554/elife.28366

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.

Highlights

The single-layered intestinal epithelium provides an important physical barrier that critically contributes to intestinal homeostasis (Peterson and Artis, 2014)
We found that Esrp1Triaka leads to reduced epithelial splicing regulator protein 1 (ESRP1) function causing distinct alterations in the mRNA splicing pattern in colonic intestinal epithelial cells (IECs) of Triaka compared with wild-type (WT) animals
Using this system based on luciferase expression, we found that WT ESRP1 protein led to a 2.4 and 10.9 fold increase of Cd44 variable exon v5 (Cd44v5) and Fgfr2 variable exon IIIb (Fgfr2-IIIb) inclusion, respectively, compared to control

Summary

Introduction

The single-layered intestinal epithelium provides an important physical barrier that critically contributes to intestinal homeostasis (Peterson and Artis, 2014). Dysfunction of intestinal epithelial cells (IECs) leading to increased epithelial permeability is associated with intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC) (Van der Sluis et al, 2006; Schmitz et al, 1999; Grivennikov et al, 2012). IBD is related to polymorphisms in various IBD susceptibility genes (Lees et al, 2011; Van Limbergen et al, 2014), and numerous genetic alterations in key cellular pathways that underlie CRC have been identified (Fearon, 2011).

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