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Modulation of insulin secretion by RBFOX2-mediated alternative splicing

Author

Listed:
  • 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)

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.

Suggested Citation

  • Nicole D. Moss & Kristen L. Wells & Alexandra Theis & Yong-Kyung Kim & Aliya F. Spigelman & Xiong Liu & Patrick E. MacDonald & Lori Sussel, 2023. "Modulation of insulin secretion by RBFOX2-mediated alternative splicing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43605-4
    DOI: 10.1038/s41467-023-43605-4
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    References listed on IDEAS

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    1. Julian P. Venables & Laure Lapasset & Gilles Gadea & Philippe Fort & Roscoe Klinck & Manuel Irimia & Emmanuel Vignal & Philippe Thibault & Panagiotis Prinos & Benoit Chabot & Sherif Abou Elela & Pierr, 2013. "MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
    2. Eric L. Nostrand & Peter Freese & Gabriel A. Pratt & Xiaofeng Wang & Xintao Wei & Rui Xiao & Steven M. Blue & Jia-Yu Chen & Neal A. L. Cody & Daniel Dominguez & Sara Olson & Balaji Sundararaman & Liju, 2021. "Author Correction: A large-scale binding and functional map of human RNA-binding proteins," Nature, Nature, vol. 589(7842), pages 5-5, January.
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