Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear Paxillin Modulates Alternative Splicing Programs in Neurons during Sensitive Periods of Brain Development

ABSTRACT: During sensitive postnatal periods, brain neural circuits undergo significant refinement coincident with widespread neuronal alternative splicing events in which hundreds of genes alter their splice site selection to generate isoforms essential for synaptic plasticity. Here, we reveal that neuronal activity-dependent serine119 phosphorylation of paxillin (p-paxillin S119) acts as a molecular switch in the nucleus to modulate alternative splicing during this period. We report that following NMDA receptor activation, nuclear p-paxillin S119 is recruited to nuclear speckles, where it interacts with U2AFs and splicing factors. Neuronal paxillin expression is required for timely alternative splicing of synaptic factors, including Snap25. Consequently, young mice lacking paxillin S119 phosphorylation exhibit significantly reduced levels of Snap25-5b isoforms, impaired presynaptic function at hippocampal Schaffer collateral-CA1 synapses, and deficits in short-term learning and memory. These findings support the idea that nuclear p-paxillin S119 is a critical mediator of alternative splicing programs in postnatal neurons during a sensitive period essential for neural plasticity.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Pei-Lin Cheng

LAB HEAD: Pei-Lin, Cheng

PROVIDER: PXD060131 | Pride | 2025-08-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	1_220606.raw	Raw
	2_220606.raw	Raw
	3_220606.raw	Raw
	Cyto_2_230328.raw	Raw
	Nuc_1_230328.raw	Raw

Items per page:

1 - 5 of 9

Similar Datasets

Nuclear Paxillin Modulates Alternative Splicing Programs in Neurons during Sensitive Periods of Brain Development

Project description:During sensitive postnatal periods, brain neural circuits undergo significant refinement coincident with widespread neuronal alternative splicing events in which hundreds of genes alter their splice site selection to generate isoforms essential for synaptic plasticity. Here, we reveal that neuronal activity-dependent serine119 phosphorylation of paxillin (p-paxillin S119) acts as a molecular switch in the nucleus to modulate alternative splicing during this period. We report that following NMDA receptor activation, nuclear p-paxillin S119 is recruited to nuclear speckles, where it interacts with U2AFs and splicing factors. Neuronal paxillin expression is required for timely alternative splicing of synaptic factors, including Snap25. Consequently, young mice lacking paxillin S119 phosphorylation exhibit significantly reduced levels of Snap25-5b isoforms, impaired presynaptic function at hippocampal Schaffer collateral-CA1 synapses, and deficits in short-term learning and memory. These findings support the idea that nuclear p-paxillin S119 is a critical mediator of alternative splicing programs in postnatal neurons during a sensitive period essential for neural plasticity.

2025-08-07 | GSE288599 | GEO

Nuclear Paxillin Modulates Alternative Splicing Programs in Neurons during Sensitive Periods of Brain Development

Project description:Nuclear Paxillin Modulates Alternative Splicing Programs in Neurons during Sensitive Periods of Brain Development

| PRJNA1218668 | ENA

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development. In order to find some LSD1+8a regulated genes at differentiated SH-SY5Y cell lines, we infected SH-SY5Y with control or LSD1+8a shRNA, then induced differentiation with RA and BDNF, (Retinoic acid (RA) (Sigma) was added at a final concentration of 10 μM the next day after plating. After 4 days, the cells were washed three times with PBS and incubated with 50 ng/mL of Brain Derived Neural Factor (BDNF) (Millipore) in serum-free medium for 3 days), we extracted RNA from BDNF induced SH-SY5Y cells for expression analysis.Duplicates were included for Affymetrix Human transcriptome version 2 array.

2015-06-05 | E-GEOD-63097 | biostudies-arrayexpress

Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain [HITS-CLIP]

Project description:Two polypyrimidine tract RNA-binding proteins (PTBs), one near-ubiquitously expressed (Ptbp1) and another highly tissue-restricted (Ptbp2), regulate RNA in interrelated but incompletely understood ways. Ptbp1, a splicing regulator, is replaced in the brain and differentiated neuronal cell lines by Ptbp2. To define the roles of Ptbp2 in the nervous system, we generated two independent Ptbp2-null strains, unexpectedly revealing that Ptbp2 is expressed in neuronal progenitors and is essential for postnatal survival. A HITS-CLIP (high-throughput sequencing crosslinking immunoprecipitation)-generated map of reproducible Ptbp2–RNA interactions in the developing mouse neocortex, combined with results from splicing-sensitive microarrays, demonstrated that the major action of Ptbp2 is to inhibit adult-specific alternative exons by binding pyrimidine-rich sequences upstream of and/or within them. These regulated exons are present in mRNAs encoding proteins associated with control of cell fate, proliferation, and the actin cytoskeleton, suggesting a role for Ptbp2 in neurogenesis. Indeed, neuronal progenitors in the Ptbp2-null brain exhibited an aberrant polarity and were associated with regions of premature neurogenesis and reduced progenitor pools. Thus, Ptbp2 inhibition of a discrete set of adult neuronal exons underlies early brain development prior to neuronal differentiation and is essential for postnatal survival. Eight Ptbp2 HITS-CLIP libraries generated from mouse embryonic brain (four libraries from each of two biologic replicates).

2013-05-31 | E-GEOD-47564 | biostudies-arrayexpress

RNA-seq analysis of AS-NMD targets in developing mouse neurons

Project description:The functional coupling between alternative pre-mRNA splicing (AS) and the mRNA quality control mechanism called nonsense-mediated decay (NMD) has been shown to modulate the expression of numerous genes. Previous studies have identified several examples of this regulation in developing neurons. However, the systems-level effects of AS-NMD in this context have been poorly understood. To this end, we performed a longitudinal analysis of gene expression in mouse embryonic stem cells undergoing induced neuronal differentiation, as well as primary neural cells. To improve the detection of NMD-sensitive splice forms, some of the samples were treated with the translation inhibitor cycloheximide or separated into nuclear and cytoplasmic fractions. Our analyses uncovered hundreds of AS-NMD events with significant potential to regulate their host genes. Notably, these events were significantly overrepresented in developmentally downregulated genes. Particularly strong enrichment was detected for alternative cassette exons that trigger NMD upon their inclusion into mature mRNA. Overall, this study extends our understanding of the molecular mechanisms underlying neuronal differentiation and highlights the importance of post-transcriptional regulation gene expression in orchestrating this intricate process.

2024-05-29 | E-MTAB-13134 | biostudies-arrayexpress

Neuronal-specific Deficiency of the Splicing Factor Tra2b Causes p21-mediated Apoptosis in Neurogenic Areas of the Developing Mouse Brain

Project description:Alternative splicing (AS) increases the informational content of the genome and is more prevalent in the brain than in any other tissue. The splicing factor Tra2b (Sfrs10) can modulate splicing inclusion of exons by specifically detecting GAA-rich binding motifs and its absence causes early embryonic lethality in mice. TRA2B has been shown to be involved in splicing processes of Nasp (nuclear autoantigenic sperm protein), MAPT (microtubule associated protein tau) and SMN (survival motor neuron), and is therefore implicated in spermatogenesis and neurological diseases like AlzheimerM-^Rs disease, dementia, ParkinsonM-^Rs disease and spinal muscular atrophy. Here we generated a neuronal-specific Tra2b knock-out mouse that lacks Tra2b expression in neuronal and glial precursor cells by using the Nestin-Cre. Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system. Using whole brain RNA on exon arrays we identified differentially expressed alternative exons of Tubulin?1 and Shugoshin like2 as in vivo targets of Tra2b. Most interestingly, we found increased expression of the cyclin dependent kinase inhibitor 1a (p21) which we could functionally link to neuronal precursor cells in the affected brain regions. We provide further evidence that the absence of Tra2b causes p21 upregulation and ultimately cell death in NSC34 neuronal-like cells. These findings demonstrate that Tra2b regulates splicing events essential for maintaining neuronal viability during development. Apoptotic events triggered via p21 might not be restricted to the developing brain but could possibly be generalized to the whole organism and explain early embryonic lethality in Tra2b-depleted mice.

2013-12-16 | E-MTAB-2157 | biostudies-arrayexpress

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

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.

2022-12-08 | GSE220062 | GEO

RNA Sequencing analyses of control and HuD KO (Elavl4 null) mouse cortical transcriptomes

Project description:Purpose: The goal of this study was to analyse RNA-seq data to determine the effect of deletion of the RNA-binding protein HuD in transcriptiome-wide alternative splicing and polyadenylation in the neocortex of adult HuD KO vs. wild type littermates (controls) Methods: Cortical mRNA profiles of adult HuD KO (Elavl4 -/-) mice and Control mice were generated by RNA sequencing, in triplicate, using Illumina NovaSeq 6000 platform. The quality of raw RNA-sequencing reads was evaluated using FastQC software (version 0.11.5) and adapters were removed using the Cutadapt (version 1.15) and Trimmomatic (version 0.38) software. Alternative splicing was evaluated using rMATS software (version 4.0.2) and BAM files were converted to BedGraph before examining alternative polyadenylation using DaPars software (version 0.9.1) Methods (cont.): RNA-seq data was aligned to the M musculus genome (UCSC browser, mm10) using STAR (version 2.7.3a), and MultiQC (version 1.8) was used to perform a final quality check on STAR alignment files. If alignments were found to be the same read length and have >80% reads mapped to a unique location, the data was considered good quality and alternative splicing and polyadenylation analyses were performed. Sequence reads per sample were aligned to the mouse genome (build mm10). Results: HuD KO affected alternative splicing of 310 genes, including 17 validated HuD targets such as Cbx3, Cspp1, Snap25 and Gria2. In addition, deletion of HuD affected polyadenylation of 53 genes, with the majority of significantly altered mRNAs shifting towards usage of the proximal polyadenylation signal (PAS), resulting in shorter 3’ untranslated regions (3’ UTRs). Conclusions: HuD KO had a greater effect on alternative splicing than polyadenylation, with many of the affected genes implicated in several neuronal functions and neuropsychiatric disorders.

2021-03-17 | GSE169023 | GEO

The PTBP1-associated long noncoding RNA Pnky regulates embryonic and postnatal neural stem cells

Project description:While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a novel, neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates a critical stage of neurogenesis from embryonic and postnatal NSC populations.

2015-03-15 | GSE65542 | GEO

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data