Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

Bronicki, Lucas; Jasmin, Bernard J.

doi:10.1261/rna.039164.113

Cited by 104 publications

(125 citation statements)

References 212 publications

(324 reference statements)

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“…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: 77%

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: Discussionmentioning

confidence: 77%

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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“…They are about 10 to 15 times bigger than the average Drosophila gene, have several promoters, and, most prominently, have unusually long 3= UTRs (64,65). Complex transcriptional control and extended UTRs are also found in Hu genes, suggesting that elaborate regulation of expression of ELAV/Hu genes is a key feature of their functioning (66).…”

Section: Discussionmentioning

confidence: 99%

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

Zaharieva

Haussmann

Bräuer

et al. 2015

Molecular and Cellular Biology

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bNeuronally coexpressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene-specific regulation is achieved have not been clear. Analysis of mutants in Drosophila ELAV/Hu family proteins ELAV, FNE, and RBP9 and of genetic interactions among them indicates that they have mostly independent roles in neuronal development and function but have converging roles in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9, and human HuR bind ELAV target RNA in vitro with similar affinities. Likewise, all can regulate alternative splicing of ELAV target genes in nonneuronal wing disc cells and substitute for ELAV in eye development upon artificially increased expression; they can also substantially restore ELAV's biological functions when expressed under the control of the elav gene. Furthermore, ELAV-related Sex-lethal can regulate ELAV targets, and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9, providing a maternal fail-safe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing through alteration of their expression levels and subcellular localization but only minimally by altered RNA binding specificity. RNA binding proteins (RBPs) are key regulators of gene expression. Through regulation of alternative splicing and polyadenylation, they expand the proteome and control spatiotemporal expression by affecting mRNA transport, turnover, localization, and translatability (1, 2). In the brain, alternative mRNA processing is particularly abundant and substantially contributes to the complexity of this organ (3, 4). Many RBPs comprise highly related gene families, but they seem to discriminate only marginally between short cognate binding sequences (5). Although redundancy can be evolutionarily stable over extended periods of time (6), it is not clear if highly related RBPs act redundantly in vivo, regulating mostly the same genes in the same biological processes, or if they have diverged such that they regulate genes involved in different biological processes. Detailed analysis of the functions of highly related RBPs in animal models is required to decipher the underlying mechanisms of how highly related RBPs achieve target specificity.ELAV (embryonic-lethal abnormal visual system)/Hu proteins comprise a family of RBPs broadly coexpressed in the nervous system and widely used neuronal markers (7,8). ELAV/Hu proteins are prototype RBPs which harbor three highly conserved RNA recognition motifs (RRMs), whereby the first two RRMs are arranged in tandem and the third RRM is separated by a less conserved hinge region. Humans have four ELAV/Hu protein-encoding genes (HuB, HuC, HuD, and HuR), while Drosophila has three (elav, fne, and Rbp9), which derive from a common ancestor but have duplicated independently in vertebrates ...

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“…22 HuD is a member of neuronal Hu proteins and functions via binding to adenine/uridine-rich elements (AREs) on target mRNAs. 23 Our previous work revealed that the function of HuD is not only target mRNA stabilization but also the translation stimulation of cap-poly(A) mRNA. 24 We also showed that HuD can associate with cap-binding eIF4F complex through the direct interaction with eIF4A and the stimulatory effect of HuD on translation depends on the binding of HuD to eIF4A and poly(A) tail.…”

Section: The Molecular Mechanism Of Translation Repression By Miriscmentioning

confidence: 99%

The molecular mechanism of translational control via the communication between the microRNA pathway and RNA-binding proteins

2015

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Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

Cited by 104 publications

References 212 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

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

The molecular mechanism of translational control via the communication between the microRNA pathway and RNA-binding proteins

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