NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord

Leggere, Janelle C; Saito, Yuhki; Darnell, Robert B.; Tessier‐Lavigne, Marc; Junge, Harald J.; Chen, Zhe

doi:10.7554/elife.14264

Cited by 57 publications

(72 citation statements)

References 79 publications

(127 reference statements)

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“…S2H). A similar neuronal/glial marker ratio between Nova2-KO and the wildtype mice is consistent with our previous reports that loss of Nova2 does not affect neuronal differentiation (Leggere et al, 2016; Saito et al, 2016). In contrast, a decrease in both the pan-neuron/astrocyte marker ratio and the excitatory neuron/astrocyte marker ratio suggests a possible decrease in the number of excitatory neurons in Ptbp2-KO mice, which is consistent with a known role of Ptbp2 in neuronal maturation (Li et al, 2014; Licatalosi et al, 2012).…”

Section: Resultssupporting

confidence: 92%

cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation

Hwang

Saito

Park

et al. 2017

Neuron

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Alternative polyadenylation (APA) is increasingly recognized to regulate gene expression across different cell-types, but obtaining APA maps from individual cell-types typically requires prior purification, a stressful procedure that can itself alter cellular states. Here, we describe a new platform, cTag-PAPERCLIP, that generates APA profiles from single cell populations in intact tissues; cTag-PAPERCLIP requires no tissue dissociation and preserves transcripts in native states. Applying cTag-PAPERCLIP to profile four major cell-types in the mouse brain revealed common APA preferences between excitatory and inhibitory neurons distinct from astrocytes and microglia, regulated in part by neuron-specific RNA-binding proteins NOVA2 and PTBP2. We further identified a role of APA in switching Araf protein isoforms during microglia activation, impacting production of downstream inflammatory cytokines. Our results demonstrate the broad applicability of cTag-PAPERCLIP and a previously undiscovered role of APA in contributing to protein diversity between different cell-types and cellular states within the brain.

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Section: Resultssupporting

confidence: 92%

cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation

Hwang

Saito

Park

et al. 2017

Neuron

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“…Nova, a neuron-specific KH-type RNA binding protein, was identified as a target of a human paraneoplastic neurological disorder (Buckanovich et al, 1993; Buckanovich et al, 1996). However, subsequent studies found mNova functions include development of motor and cortical neurons and long-term synaptic potentiation (Leggere et al, 2016; Ule and Darnell, 2006; Yano et al, 2010). In Drosophila , pasilla was identified as a regulator of salivary gland development (Seshaiah et al, 2001) and reported to be required for activity-dependent alternative splicing of mRNA encoding voltage-gated sodium channel DmNa (V) (Lin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Regulated Intron Removal Integrates Motivational State and Experience

Gill

Park

McGinnis

et al. 2017

Cell

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Myriad experiences produce transient memory, yet, contingent on the internal state of the organism and the saliency of the experience, only some memories persist over time. How experience and internal state influence the duration of memory at the molecular level remains unknown. A self-assembled aggregated state of Drosophila Orb2A protein is required specifically for long-lasting memory. We report that in the adult fly brain the mRNA encoding Orb2A protein exists in an unspliced non-protein-coding form. The convergence of experience and internal drive transiently increases the spliced protein-coding Orb2A mRNA. A screen indentified pasilla, the fly orthologue of mammalian Nova-1/2, as a mediator of Orb2A mRNA processing. A single nucleotide substitution in the intronic region that reduces Pasilla binding and intron removal selectively impairs long-term memory. We posit that pasilla-mediated processing of unspliced Orb2A mRNA integrates experience and internal state to control Orb2A protein abundance and long-term memory formation.

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“…Nova proteins have been extensively studied in brain where they regulate splicing networks involved in survival, migration, synaptic function, and axon guidance (45)(46)(47)(48). We have previously shown that Nova1 controls beta cell function and survival by regulating genes involved in exocytosis, apoptosis, insulin receptor signaling, splicing, and transcription (27).…”

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

confidence: 99%

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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NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord

Cited by 57 publications

References 79 publications

cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation

cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation

Regulated Intron Removal Integrates Motivational State and Experience

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

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