Trans-cellular control of synapse properties by a cell type-specific splicing regulator
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA908743 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22526316_1.fastq.gz | Fastqsanger.gz | |||
| SRR22526316_2.fastq.gz | Fastqsanger.gz | |||
| SRR22526317_1.fastq.gz | Fastqsanger.gz | |||
| SRR22526317_2.fastq.gz | Fastqsanger.gz | |||
| SRR22526318_1.fastq.gz | Fastqsanger.gz |
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Project description:The recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. 'Terminal selector' transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. We find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.
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Project description:Trans-cellular regulation of synaptic properties by neuron-specific alternative splicing
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Project description:The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.
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Project description:Genome-wide mapping of ribosome-associated mRNAs to investigate cell type-specific loss of function of the nuclear RNA binding protein SLM2 in the mouse hippocampus
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Project description:In contrast to canonical cis-splicing, trans-splicing combines exons from two distinct transcripts, yielding chimeric mRNAs. This process is typically suppressed through the tight coupling of pre-mRNA synthesis and splicing, primarily due to the inherent risk of generating chimeric proteins with aberrant or deleterious properties. Nevertheless, trans-splicing permits the creation of a substantially greater diversity of mRNA isoforms that encode variants of a single protein. One compelling example is the mod(mdg4) locus in Drosophila, where all mRNAs, encompassing over 30 isoforms, are exclusively generated via trans-splicing, which integrates common constitutive exons with one of several alternative 3′ variable exons transcribed from independent promoters. This investigation analyzed the roles of the mod(mdg4) gene’s promoter, exons, and introns in trans-splicing. Our methodology involved a previously validated model in the heterogeneous 22A genomic region, augmented by targeted deletions within the fourth intron of the endogenous locus. We determined that the mod(mdg4) promoter only modestly enhances trans-splicing efficiency. Critically, the predominant determinants are multiple, redundant RNA-binding protein motifs concentrated within the proximal 412 bp of the fourth intron. These results collectively support a model wherein trans-splicing is primarily mediated by redundant intronic motifs recognized by spliceosome components.
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Project description:Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3(-/-)) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3(-/-) mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior.
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Project description:How synapses are assembled and specified in brain is incompletely understood. Latrophilin-3, a postsynaptic adhesion-GPCR, mediates Schaffer-collateral synapse formation in the hippocampus but the mechanisms involved remained unclear. Here we show that Latrophilin-3 organizes synapses by a convergent dual-pathway mechanism by which Latrophilin-3 simultaneously activates GaS/cAMP-signaling and recruits phase-separated postsynaptic protein scaffolds. We found that cell type-specific alternative splicing of Latrophilin-3 controls its G protein coupling mode, resulting in Latrophilin-3 variants that predominantly signal via Gas and cAMP or via Gα12/13. A CRISPR-mediated genetic switch of Latrophilin-3 alternative splicing from a GaS- to a Gα12/13-coupled mode impaired synaptic connectivity similar to the overall deletion of Latrophilin-3, suggesting that GaS/cAMP-signaling by Latrophilin-3 splice variants mediates synapse formation. Moreover, GaS- but not Gα12/13-coupled splice variants of Latrophilin-3 recruit phase-transitioned postsynaptic protein scaffolds that are clustered by binding of presynaptic Latrophilin-3 ligands. Strikingly, neuronal activity promotes alternative splicing of the synaptogenic variant of Latrophilin-3, thereby enhancing synaptic connectivity. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways, GaS/cAMP signaling and the phase separation of postsynaptic protein scaffolds.
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Project description:Deep Sequencing of mRNA from Drosophila melanogaster, Drosophila Sechellia, and their F1 hybrid. These data were generated in a study to analyze the extent and specificity of trans-splicing in Drosophila. mRNA-seq libraies were prepared from poly(A)+ RNA prepared from whole F1 hybrids of D. melanogaster and D. sechellia (female 0-3d post eclosion). Separate control libraries were prepared from D. melanogaster and D. sechellia total RNA (mixed before library preparation). The results of this study identified 80 novel trans-splicing events between homologous alleles of the same gene. Keywords: RNA-Seq Keywords: Expression profiling by high throughput sequencing There were 2 total samples in this study. Paired-end mRNA-seq was used to survey trans-splicing in F1 hybrids of D. melanogaster and D. sechellia. A mixed "control" library was used to assess the frequency of false-positive trans-splicing signal resulting from errors in reference genomes, high-throughput sequencing, and RT-PCR amplification based strand-switching.
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