The ESRP1-GPR137 axis contributes to intestinal pathogenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28975893.
- Also identified by DOI 10.7554/eLife.28366 and PMC identifier 5665647.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Gpr137</i> isoforms differently activating the Wnt pathway. In humans, <i>ESRP1</i> is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of <i>ESRP1-</i>dependent <i>GPR137</i> isoforms is altered in CRC and expression of a specific <i>GPR137</i> 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.
Medical subject headings
- Alternative Splicing
- Colorectal Neoplasms
- Inflammatory Bowel Diseases
- RNA-Binding Proteins
- Receptors, G-Protein-Coupled