Control of neuronal synapse specification by a highly dedicated alternative splicing program

Traunmüller, Lisa; Gomez, Andrea M.; Nguyen, Thi-Minh; Scheiffele, Peter

doi:10.1126/science.aaf2397

Cited by 119 publications

(127 citation statements)

References 32 publications

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“…It is unclear whether alternative splicing of other neurexins at SS4 performs a similar trans-synaptic function, as suggested by experiments with SLM2 KO mice. The SLM2 KO caused an increase in SS4 exon inclusion in all neurexins and impaired LTP; this LTP was rescued by expression of Nrxn1-SS4- (Traunmüller et al, 2016), suggesting that Nrxn1-SS4- can rescue a phenotype similar to that caused by the constitutive expression of Nrxn3-SS4+. However, these experiments are indirect, and direct manipulations of SS4 in Nrxn1 and Nrxn2 will be needed to test this question.…”

Section: Neurexins: Form and Functionmentioning

confidence: 97%

“…They are characterized by a central KH-type RNA-binding domain and a C-terminal Sam68 domain, and function broadly in many events of alternative splicing in neuronal and non-neuronal cells (Chawla et al, 2009). Puzzlingly, all STAR-family proteins have been shown to be separately essential for neurexin alternative splicing at SS4 (Iijima et al, 2011 and 2014; Ehrmann et al, 2013; Traunmüller et al, 2016; Danilenko et al, 2017). Of these studies, the best evidence exists for SLM2.…”

Section: Neurexins: Form and Functionmentioning

confidence: 99%

“…Of these studies, the best evidence exists for SLM2. Deletion of SLM2 causes a dramatic loss of SS4- variants for all three neurexins (Ehrmann et al, 2013; Traunmüller et al, 2016). …”

Section: Neurexins: Form and Functionmentioning

confidence: 99%

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Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Südhof

2017

Cell

663

718

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Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, that thereby determines the precise responses of synapses to spike patterns in a neuron and circuit, and that is vulnerable to impairments in neuropsychiatric disorders.

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Section: Neurexins: Form and Functionmentioning

confidence: 97%

Section: Neurexins: Form and Functionmentioning

confidence: 99%

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Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Südhof

2017

Cell

663

718

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“…Alternatively spliced transcripts frequently produce protein isoforms with divergent properties, although the biological significance of the vast majority of these events remains unexplored (Wang et al, 2008; Pan et al, 2008; Keleman et al, 2013; Yang et al, 2016). Many mammalian tissues show cell type and stage specific expression of alternatively spliced transcripts that often fit into biologically coherent pathways (Ule et al, 2005; Fu and Ares, 2014; Yang et al, 2014; Raj and Blencowe, 2015; Bebee et al, 2015; Vuong et al, 2016; Traunmüller et al, 2016; Zhang et al, 2016). The coordinated expression of these splicing-regulatory networks is due in large part to the selective activity of specialized RNA binding proteins that mediate the inclusion or exclusion of alternatively spliced exons based on their recruitment to cis acting elements in target transcripts (Chen and Manley, 2009; Fu and Ares, 2014).…”

Section: Introductionmentioning

confidence: 99%

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

et al. 2017

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Summary Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1). Patient derived iPSCs showed alternative splicing defects that were restored upon repair of an ESRP1 mutant allele. To determine how ESRP1 mutations cause hearing loss we evaluated Esrp1−/− mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in cochlea development and auditory function. Aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.

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“…Studies in animals demonstrate that specific AS programs underlie certain aspects of neuronal development (Li et al, 2014;Gueroussov et al, 2015;Traunmüller et al, 2016). Furthermore, cell cycle progression is accompanied by periodic AS programs and depends on an SR protein kinase in human cells (Dominguez et al, 2016).…”

mentioning

confidence: 99%

Subcellular Compartmentation of Alternatively Spliced Transcripts Defines SERINE/ARGININE-RICH PROTEIN30 Expression

2018

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Alternative splicing (AS) is prevalent in higher eukaryotes, and generation of different AS variants is tightly regulated. Widespread AS occurs in response to altered light conditions and plays a critical role in seedling photomorphogenesis, but despite its frequency and effect on plant development, the functional role of AS remains unknown for most splicing variants. Here, we characterized the light-dependent AS variants of the gene encoding the splicing regulator Ser/Arg-rich protein SR30 in Arabidopsis (Arabidopsis thaliana). We demonstrated that the splicing variant SR30.2, which is predominantly produced in darkness, is enriched within the nucleus and strongly depleted from ribosomes. Light-induced AS from a downstream 39 splice site gives rise to SR30.1, which is exported to the cytosol and translated, coinciding with SR30 protein accumulation upon seedling illumination. Constitutive expression of SR30.1 and SR30.2 fused to fluorescent proteins revealed their identical subcellular localization in the nucleoplasm and nuclear speckles. Furthermore, expression of either variant shifted splicing of a genomic SR30 reporter toward SR30.2, suggesting that an autoregulatory feedback loop affects SR30 splicing. We provide evidence that SR30.2 can be further spliced and, unlike SR30.2, the resulting cassette exon variant SR30.3 is sensitive to nonsense-mediated decay. Our work delivers insight into the complex and compartmentalized RNA processing mechanisms that control the expression of the splicing regulator SR30 in a light-dependent manner.Maturation of eukaryotic mRNAs involves intricate co-and posttranscriptional RNA processing, which has critical functions in regulating gene expression and diversifying the transcriptome. Among several mechanisms, alternative precursor mRNA splicing (AS) in particular generates many transcript variants by removing distinct intronic regions and joining the resulting exons. Deep analysis of transcriptomes via high-throughput RNA sequencing (RNA-seq) has revealed that a major fraction of all intron-containing genes from higher eukaryotes generates AS variants. In humans, more than 95% of multiexon genes display AS (Pan et al., 2008). The prevalence of AS has also been demonstrated for other eukaryotes including plants (Reddy et al., 2013;Staiger and Brown, 2013), with current estimates of ;61% and ;42% of intron-containing genes giving rise to AS variants in the model plants Arabidopsis (Arabidopsis thaliana;Marquez et al., 2012) and Brachypodium distachyon (Mandadi and Scholthof, 2015), respectively.Besides its pivotal role in increasing the coding and regulatory capacity of the transcriptome, AS finetunes gene expression by varying the output ratios of splicing variants. The full extent of AS regulation likely exceeds the current estimates, as the production of many transcript variants can be specifically controlled under certain conditions, such as cell and tissue types, developmental stages, and in response to stresses and other environmental factors (Reddy et al., 2013;Staige...

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Control of neuronal synapse specification by a highly dedicated alternative splicing program

Cited by 119 publications

References 32 publications

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

Subcellular Compartmentation of Alternatively Spliced Transcripts Defines SERINE/ARGININE-RICH PROTEIN30 Expression

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