title: Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival.
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 neuron-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 we 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, whereas 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.
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium. Electronic address: mjuanmat@ulb.ac.be.
authors.forename: Jonàs
authors.initials: J
authors.lastname: Juan-Mateu
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Tatiana H
authors.initials: TH
authors.lastname: Rech
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Olatz
authors.initials: O
authors.lastname: Villate
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Esther
authors.initials: E
authors.lastname: Lizarraga-Mollinedo
authors.affiliation: Lund University Diabetes Center, Unit of Islets Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, SE 205 02 Malmö, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wendt
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Jean-Valery
authors.initials: JV
authors.lastname: Turatsinze
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Letícia A
authors.initials: LA
authors.lastname: Brondani
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Tarlliza R
authors.initials: TR
authors.lastname: Nardelli
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Nogueira
authors.affiliation: Lund University Diabetes Center, Unit of Islets Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, SE 205 02 Malmö, Sweden.
authors.forename: Jonathan L S
authors.initials: JLS
authors.lastname: Esguerra
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Maria Inês
authors.initials: MI
authors.lastname: Alvelos
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Lund University Diabetes Center, Unit of Islets Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, SE 205 02 Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium; Welbio, Université Libre de Bruxelles, 808 Route de Lennik, CP618, 1070 Brussels, Belgium. Electronic address: deizirik@ulb.ac.be.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D000067779:ELAV-Like Protein 4 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D000067779:ELAV-Like Protein 4; D007328:Insulin; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D005947:Glucose
keywords: alternative splicing; apoptosis; autoimmunity; beta cell (B-cell); diabetes; insulin secretion