Advanced

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

Juan-Mateu, Jon Agraves; Rech, Tatiana H; Villate, Olatz; Lizarraga-Mollinedo, Esther; Wendt, Anna LU ; Turatsinze, Jean-Valery; Brondani, Leticia A; Nardelli, Tarlliza R; Nogueira, Tatiane C and Esguerra, Jonathan LU , et al. (2017) In Journal of Biological Chemistry 292(8). p.3466-3480
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
292
issue
8
pages
3466 - 3480
publisher
ASBMB
external identifiers
  • scopus:85013758218
  • wos:000395538800035
ISSN
1083-351X
DOI
10.1074/jbc.M116.748335
language
English
LU publication?
yes
id
96b1a93d-d98f-4b9b-a6c6-e38eecb542c7
date added to LUP
2017-01-27 15:46:59
date last changed
2018-01-07 11:47:14
@article{96b1a93d-d98f-4b9b-a6c6-e38eecb542c7,
  abstract     = {<p>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.</p>},
  author       = {Juan-Mateu, Jon Agraves and Rech, Tatiana H and Villate, Olatz and Lizarraga-Mollinedo, Esther and Wendt, Anna and Turatsinze, Jean-Valery and Brondani, Leticia A and Nardelli, Tarlliza R and Nogueira, Tatiane C and Esguerra, Jonathan and Alvelos, Maria In Ecircs and Marchetti, Piero and Eliasson, Lena and Eizirik, D Eacutecio L},
  issn         = {1083-351X},
  language     = {eng},
  month        = {01},
  number       = {8},
  pages        = {3466--3480},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival},
  url          = {http://dx.doi.org/10.1074/jbc.M116.748335},
  volume       = {292},
  year         = {2017},
}