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Modulation of insulin secretion by RBFOX2-mediated alternative splicing
Nicole D Moss1, Kristen L Wells1, Alexandra Theis1
1Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nature Communications
|November 25, 2023
Summary
RNA-binding protein RBFOX2 regulates insulin secretion by controlling alternative splicing of key exocytosis genes. Its mutation impairs blood glucose homeostasis, revealing a new mechanism in pancreatic beta cells.
Area of Science:
- Molecular Biology
- Endocrinology
- Diabetes Research
Background:
- Insulin secretion is crucial for blood glucose homeostasis but its fine-tuning regulation is not fully understood.
- Dysregulation of RNA-binding proteins (RBPs) and mRNA splicing are implicated in diabetes onset.
Purpose of the Study:
- To investigate the role of the RBP RBFOX2 in regulating insulin secretion.
- To determine if RBFOX2 impacts alternative splicing of genes involved in insulin granule exocytosis.
Main Methods:
- Conditional mutation of the Rbfox2 gene in mouse pancreatic beta cells.
- Analysis of insulin secretion, blood glucose levels, and mRNA splicing patterns.
- Examination of insulin granule docking and SNARE complex component splicing.
Main Results:
- Conditional mutation of Rbfox2 led to decreased insulin secretion and impaired glucose homeostasis in mice.
- RBFOX2 regulates alternative splicing of genes essential for insulin granule docking and exocytosis, including SNARE complex components.
- Splicing defects in SNARE complex genes were observed in Rbfox2-mutant mice.
Conclusions:
- RBFOX2 is a critical regulator of insulin secretion through alternative splicing.
- RBFOX2-mediated splicing defects contribute to impaired insulin secretion and glucose dysregulation.
- This study identifies a novel mechanism for modulating insulin secretion in pancreatic beta cells.
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