The ESRP1-GPR137 axis contributes to intestinal pathogenesis.

Area of Science:

• Molecular Biology
• Gastroenterology
• Oncology

Background:

• Aberrant alternative splicing (AS) is linked to diseases, but its direct role is unclear.
• Epithelial splicing regulator protein 1 (ESRP1) is a key regulator of AS.
• The function of ESRP1 in intestinal homeostasis and disease is not well understood.

Purpose of the Study:

• To investigate the role of ESRP1 in intestinal homeostasis and pathogenesis.
• To elucidate the mechanisms by which ESRP1 influences intestinal barrier integrity and disease development.
• To explore the clinical relevance of ESRP1 in human inflammatory bowel disease (IBD) and colorectal cancer (CRC).

Main Methods:

• Mouse models with reduced ESRP1 function.
• Analysis of intestinal barrier integrity, colitis susceptibility, and colorectal cancer development.
• Investigation of ESRP1-specific GPR137 isoforms and Wnt pathway activation.
• Analysis of human patient biopsies from IBD and CRC cohorts.

Main Results:

• Reduced ESRP1 function in mice impairs intestinal barrier integrity, increases colitis susceptibility, and alters CRC development.
• ESRP1 regulates specific GPR137 isoforms that modulate Wnt pathway activation.
• ESRP1 is downregulated in human IBD biopsies and is an adverse prognostic factor in CRC.
• Altered generation of ESRP1-dependent GPR137 isoforms is observed in CRC, with one isoform predicting patient survival.

Conclusions:

• ESRP1 plays a critical role in maintaining intestinal barrier integrity through regulated alternative splicing.
• Dysregulation of ESRP1 function or expression contributes to intestinal pathologies, including IBD and CRC.
• ESRP1-regulated GPR137 isoforms are key mediators of ESRP1's function in the intestine and have prognostic value in CRC.