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Trans-cellular control of synapse properties by a cell type-specific splicing regulator

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE220062 | GEO | 2022/12/08

REPOSITORIES: GEO

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SAM68-specific splicing is required for proper selection of alternative 3'UTR isoforms in the nervous system

Project description:Neuronal alternative splicing is dynamically regulated in a spatiotemporal fashion. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs governed by STARs remains unclear. We deciphered the alternative splicing programs of SAM68 and SLM1 proteins using transcriptomics. We reveal that SAM68 and SLM1 encode distinct alternative splicing programs; SAM68 preferentially controls alternative last exon (ALE) splicing. Interleukin 1-receptor accessory protein (Il1rap) is a novel target for SAM68. The usage of Il1rap ALEs results in mainly two variants encoding two functionally different isoforms, a membrane-bound (mIL1RAcP) and a soluble (sIL1RAcP) type. The brain exclusively expresses mIL1RAcP. SAM68 knockout results in remarkable conversion into sIL1RAcP in the brain, which significantly disturbs IL1RAcP neuronal function. Thus, we uncover the critical role of proper neuronal isoform selection through ALE choice by the SAM68-specific splicing program.

2019-12-29 | GSE110258 | GEO

Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition

Project description:Diversification of cell adhesion molecules by alternative splicing is proposed to underlie molecular codes for neuronal wiring. Transcriptomic approaches mapped detailed cell type-specific mRNA splicing programs. However, it has been hard to probe synapse-specific localization and function of the resulting protein splice isoforms, or “proteoforms”, in vivo. We here apply a proteoform-centric workflow in mice to test synapse-specific functions of splice isoforms of the synaptic adhesion molecule Neurexin-3 (NRXN3). We uncover a major proteoform, NRXN3 AS5, that is highly expressed in GABAergic interneurons and dendrite-targeting GABAergic terminals. NRXN3 AS5 abundance significantly diverges from the distribution of the Nrxn3 mRNA and is gated by translation-repressive elements. Nrxn3 AS5 isoform deletion results in selective impairment of dendrite-targeting interneuron synapses in the dentate gyrus without affecting somatic inhibition or glutamatergic perforant-path synapses. This work establishes cell- and synapse-specific functions of a specific neurexin proteoform and highlights the importance of alternative splicing regulation for synapse specification.

2022-02-11 | PXD031379 | Pride

Identification of PTPD meA splicing variants

Project description:Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic cell-adhesion molecules that orchestrate multifarious synaptic adhesion pathways. Extensive alternative splicing of LAR-RPTP mRNAs, similar to neurexins, may produce innumerable LAR-RPTP isoforms that act as regulatory codes for determining the identify and strength of specific synapse signaling. However, no direct evidence for the hypothesis exists, apart from the role of LAR-RPTP splice variants in specifying region-specific, cell type-specific and neural circuit-specific properties in vivo. Here, using deep RNA sequencing (RNA-seq), we targeted Ptprs, Ptprd, and Ptprf mRNAs in diverse cell types across adult mouse brain areas. In addition to identifying novel alternatively spliced exons of Ptprd, we found pronounced cell-type-specific patterns of two microexons, meA and meB, in brain Ptprd mRNAs. Quantitative targeted proteomics uncovered profiles of LAR-RPTP proteoforms containing or lacking meA that are in line with RNA-seq results. Moreover, diverse neural circuits targeting the same neuronal popluations were dictated by the expression of different Ptprd variants characterized by distinct inclusion patterns of meA and/or meB. Remarkably, fear-related learning induced upregulation of Ptprd meA+ variants in hippocampal memory-activated dentate gyrus neurons. Furthermore, conditional ablation of Ptprd meA+ variants at presynaptic loci of distinct hippocampal circuits resulted in impairment of distinct modes of synaptic transmission and different cognitive tasks. Our data provide the first evidence of cell-type- and/or circuit-specific expression patterns and physiological functions of LAR-RPTP microexons that are dynamically regulated and likely to dictate diverse synaptic properties. In particular, we propose Ptprd splicing as a key mechanism that mediates activity-dependent neural circuit specification

2023-05-08 | MSV000091879 | MassIVE

Mus musculus

Project description:Cell type-specific alternative splicing during mammalian neuronal differentiation

| PRJNA380202 | ENA

Control of Neuronal Synapse Specification by a Highly Dedicated Alternative Splicing program

Project description:The RNA binding protein SLM2 represents a major functional determinant of neuronal function by directing the splice isoform identity of synaptic recognition receptors.

2016-05-12 | GSE79902 | GEO

Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development

Project description:The paralog RNA binding proteins (RBPs) Sam68 and SLM2 are co-expressed in the cerebral cortex and display very similar splicing activity. However, their relative function(s) in this context is unknown. By performing a time-course analysis, we found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that are sensitive to concomitant ablation of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and the development of a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that maintenance of the Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program while ensuring a robust redundant mechanism that supports proper cortical development.

2024-02-12 | GSE229749 | GEO

The dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons [seCLIP-Seq]

Project description:Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, and adaptation of neuronal circuits. RNA metabolism has emerged as a key regulatory node of neural development and nervous system pathologies. To uncover novel cell-type-specific RNA regulators, we systematically investigated expression of RNA recognition motif-containing proteins in the mouse neocortex. Surprisingly, we found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed in cortical parvalbumin interneurons and mitral cells of the olfactory bulb. Genome-wide mapping of RBM20 target mRNAs revealed that neuronal RBM20 binds distal intronic regions. Loss of neuronal RBM20 has only modest impact on alternative splice isoforms but results in a significant reduction in an array of mature mRNAs in the neuronal cytoplasm. This phenotype is particularly pronounced for genes with long introns that encode synaptic proteins. We hypothesize that RBM20 ensures fidelity of pre-mRNA splicing by suppressing non-productive splicing events in long neuronal genes. This work highlights a common requirement of two excitable cell types, cardiomyocytes and neurons, for RBM20-dependent transcriptome regulation.

2023-12-16 | GSE250098 | GEO

The dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons [Ribo-TRAP RNA-seq]

2023-12-16 | GSE250096 | GEO

Definition of germ cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

Project description:Alternative splicing is critical for development. However, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-specific RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes likely arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Collectively, our results thus uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.

2022-02-01 | MSV000088762 | MassIVE

Data for Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

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.

2023-10-19 | GSE240791 | GEO

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