Modulation of insulin secretion by RBFOX2-mediated alternative splicing

Nicole D. Moss, Kristen L. Wells, Alexandra Theis, Yong-Kyung Kim, Aliya F. Spigelman, Xiong Liu, Patrick E. MacDonald and Lori Sussel ()
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Nicole D. Moss: University of Colorado Anschutz Medical Campus
Kristen L. Wells: University of Colorado Anschutz Medical Campus
Alexandra Theis: University of Colorado Anschutz Medical Campus
Yong-Kyung Kim: University of Colorado Anschutz Medical Campus
Aliya F. Spigelman: University of Alberta
Xiong Liu: University of Alberta
Patrick E. MacDonald: University of Alberta
Lori Sussel: University of Colorado Anschutz Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.

Date: 2023
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DOI: 10.1038/s41467-023-43605-4

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