The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain

Gehman, Lauren; Stoilov, Peter; Maguire, Jamie; Damianov, Andrey; Lin, Chia-Ho; Shiue, Lily; Ares, Manuel; Módy, István; Black, Douglas L.

doi:10.1038/ng.841

Cited by 299 publications

(403 citation statements)

References 48 publications

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“…The similar phenotype observed for Rbfox1 and Rbfox2 KD suggests that both RBPs regulate overlapping sets of transcripts in beta cells. This is in agreement with previous studies showing that Rbfox proteins bind to the same UGCAUG motif due to the presence of a common RNA binding domain (28,32,62). Functional analysis of the role of Rbfox proteins in beta cells (present data) indicates that Rbfox depletion increases the insulin secretory capacity by affecting actin depolymerization kinetics following glucose stimulation.…”

Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 82%

“…Our data analysis identified a cluster of RBPs that are expressed in both brain and in human islets. This cluster includes members of the Elavl, Nova, and Rbfox families, which have been implicated in neuronal physiology and disease (28,(31)(32)(33)(34)(35). We found that Elavl4 and Nova2 are required for beta cell survival, and their depletion leads to activation of the intrinsic pathway of apoptosis.…”

Section: Discussionmentioning

confidence: 84%

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

Juan-Mateu

Rech

Villate

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinPancreatic 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-␤H1 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.Insulin-secreting pancreatic beta cells share many phenotypic traits with neurons. Similarities range from an analogous physiology and function to similar development and gene expression (1). Beta cells release insulin using a similar exocytotic machinery as used by neurons to release neurotransmitters. Indeed, insulin is stored and secreted using scaffolding proteins and synaptic-like vesicles similar to neuronal cells (2-4), and like neurons, beta cells are able to generate action potentials in response to different stimuli (5). Despite having different embryonic origins (6, 7), global gene expression and active chromatin marks of beta cells are closer to neural tissues than to any other tissue, including other pancreatic cells (8). Neurons are phylogenetically older than beta cells, and in some primitive organisms neurons express insulin and regulate circulating glucose levels (9, 10). Taken together, these findings suggest that beta cells have evolved into specialized insulinsecretory cells by adopting, at least in part, neuronal transcription programs (1). Supporting this hypothesis, both neurons and beta cells lose the expression of the transcriptional repressor element-1 silencing transcription factor (REST) 5 during differentiation (11). REST is expressed in most non-neuronal cells and acts as a master negative regula...

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Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 84%

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

Juan-Mateu

Rech

Villate

et al. 2017

Journal of Biological Chemistry

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“…Mutations or deletions in RBFOX1 and RBFOX3 are found in epilepsy patients (Bhalla et al 2004;Lal et al 2013a,b), whereas copy-number variations in RBFOX1 are associated with autism spectrum disorders and spinocerebellar ataxias (Bill et al 2013;Weyn-Vanhentenryck et al 2014). Mouse models with Rbfox KO or KD show extensive defects in neuronal and muscle physiology, suggesting that these proteins play key roles in normal development (Gehman et al 2011(Gehman et al , 2012. A role for RBFOX2 in cancer has also been proposed.…”

Section: Rbfox2-rna Binding Protein Fox-2 Homologmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

227

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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“…6C; Supplemental Table S4). The GO term enrichment profile for PQBP1's AS targets is specific compared with high-throughput studies on other proteins in neurons, especially RNA splicing, chromatin modification, dendrite development-related functions, and ARF signal transduction (Ule et al 2005;Gehman et al 2011;Charizanis et al 2012). Bcl-x AS is not conserved from humans to mice and was not identified as a target in this analysis.…”

Section: Coupling Of Neuron Projection and Pqbp1 Functionmentioning

confidence: 99%

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

et al. 2013

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Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders.

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The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain

Cited by 299 publications

References 48 publications

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

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

Splicing-factor alterations in cancers

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

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