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ludc web

Anna Wendt

Assistant researcher

ludc web

Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

Author

  • Jon Agraves Juan-Mateu
  • Tatiana H Rech
  • Olatz Villate
  • Esther Lizarraga-Mollinedo
  • Anna Wendt
  • Jean-Valery Turatsinze
  • Leticia A Brondani
  • Tarlliza R Nardelli
  • Tatiane C Nogueira
  • Jonathan Esguerra
  • Maria In Ecircs Alvelos
  • Piero Marchetti
  • Lena Eliasson
  • D Eacutecio L Eizirik

Summary, in English

Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuronal-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain and other human tissues, and identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1 and Rbfox2 were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, while silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

Department/s

  • Diabetes - Islet Cell Exocytosis
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2017-01-11

Language

English

Pages

3466-3480

Publication/Series

Journal of Biological Chemistry

Volume

292

Issue

8

Document type

Journal article

Publisher

ASBMB

Topic

  • Cell and Molecular Biology
  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 1083-351X