Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription.

ABSTRACT: N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.

SUBMITTER: Chen LF

PROVIDER: S-EPMC7307204 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The NMDA receptor subunit GluN3A regulates a program of synaptic activity-induced and MEF2C-dependent transcription

Project description:N-methyl-D-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the GluN2 subunit composition of NMDARs determines whether NMDARs activate the transcription factor CREB. However, whether the developmentally-regulated GluN3A subunit also modulates NMDAR-induced transcription was unknown. Here we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. This enhancement is mediated by the accumulation of phosphorylated p38 MAP kinase in the nucleus, which drives the activation of the transcription factor MEF2C and promotes the transcription of a subset of synaptic activity-induced genes including Bdnf and Arc. Our evidence that GluN3A negatively regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity on the program of synaptic activity-regulated gene transcription in developing neurons.

2019-07-08 | GSE133917 | GEO

The NMDA receptor subunit GluN3A regulates a program of synaptic activity-induced and MEF2C-dependent transcription

Project description:The NMDA receptor subunit GluN3A regulates a program of synaptic activity-induced and MEF2C-dependent transcription

| PRJNA553067 | ENA

Nucleotide sequence and variations of the bovine myocyte enhancer factor 2C (MEF2C) gene promoter in Bos taurus cattle.

Project description:Myocyte Enhancer Factor 2 (MEF2) proteins are a small family of transcription factors that play pivotal role in morphogenesis and myogenesis of skeletal, cardiac, and smooth muscle cells. In vertebrates, there are four MEF2 genes, referred to as MEF2A, -B, -C, and -D, that are located on different chromosomes. After birth MEF2A, MEF2B, MEF2D transcriptions are expressed ubiquitously, whereas MEF2C transcripts are restricted to skeletal muscle, brain, and spleen. In this study, on the basis of the sequences of the bovine chromosome 7 genomic contig, available in the GenBank database, sets of PCR primers were designed and to amplify the bovine MEF2C gene promoter region, exon 1 (5'UTR) and part sequence of the intron 1. Seven overlapping fragments of the bovine MEF2C gene were amplified and then sequenced. Altogether, these fragments were composed in the 3,120-bp sequence which was deposited in the GenBank database under accession no. GU211007. The sequence fragment included the putative site of the promoter region and transcription start of the exon 1. The sequence analysis of these fragments in individual animals representing different Bos taurus breeds revealed four variations in promoter region: g.-1606C>T, g.-1336_-1335DelG, g.-818C>T, g.-613_-612DelA and four SNPs within intron 1: g.2711A>G, g. 2913A>G, g.2962G>T and g.3014A>G. No polymorphism was found within sequence of the exon 1 (5'UTR). These polymorphisms were identified for first time using these sequences and were confirmed by RFLP or MSSCP methods.

| S-EPMC3024517 | biostudies-literature

Myocyte Enhancer Factor 2c Regulates Dendritic Complexity and Connectivity of Cerebellar Purkinje Cells.

Project description:Mef2c haploinsufficiency is implicated in behavioral deficits related to autism, schizophrenia, and intellectual disability. Although perturbations in the cerebellum, notably Purkinje cells, have been linked to these neurological disorders, the underlying mechanisms remain poorly understood. In this study, we investigated the roles of Mef2c in cerebellar Purkinje cells during the first three weeks of postnatal development. Our analysis revealed that in comparison to other members of the Mef2 family, Mef2c expression is limited to postnatal Purkinje cells. Because the role of Mef2c has not been assessed in GABAergic neurons, we set out to determine the functional significance of Mef2c by knocking down the expression of Mef2c selectively in Purkinje cells. We found that the loss of Mef2c expression during the first and second postnatal week results in an increase in dendritic arborization without impact on the general growth and migration of Purkinje cells. The influence of Mef2c on dendritic arborization persists throughout the first three weeks, but is most prominent during the first postnatal week suggesting a critical period of Mef2c activity. Additionally, the loss of Mef2c expression results in an increase in the number of spines accompanied by an increase in Gad67 and vGluT1 puncta and decrease in vGluT2 puncta. Thus, our results reveal the specific expression and functional relevance of Mef2c in developing Purkinje cells and offer insight to how disruption of the expression of Mef2c in a GABAergic neuronal subtype may lead to pathogenesis of cerebellar-associated disorders.

| S-EPMC6505522 | biostudies-literature

Myocyte enhancer factor 2c, an osteoblast transcription factor identified by dimethyl sulfoxide (DMSO)-enhanced mineralization.

Project description:Rapid mineralization of cultured osteoblasts could be a useful characteristic in stem cell-mediated therapies for fracture and other orthopedic problems. Dimethyl sulfoxide (DMSO) is a small amphipathic solvent molecule capable of stimulating cell differentiation. We report that, in primary human osteoblasts, DMSO dose-dependently enhanced the expression of osteoblast differentiation markers alkaline phosphatase activity and extracellular matrix mineralization. Furthermore, similar DMSO-mediated mineralization enhancement was observed in primary osteoblast-like cells differentiated from mouse mesenchymal cells derived from fat, a promising source of starter cells for cell-based therapy. Using a convenient mouse pre-osteoblast model cell line MC3T3-E1, we further investigated this phenomenon showing that numerous osteoblast-expressed genes were elevated in response to DMSO treatment and correlated with enhanced mineralization. Myocyte enhancer factor 2c (Mef2c) was identified as the transcription factor most induced by DMSO, among the numerous DMSO-induced genes, suggesting a role for Mef2c in osteoblast gene regulation. Immunohistochemistry confirmed expression of Mef2c in osteoblast-like cells in mouse mandible, cortical, and trabecular bone. shRNAi-mediated Mef2c gene silencing resulted in defective osteoblast differentiation, decreased alkaline phosphatase activity, and matrix mineralization and knockdown of osteoblast specific gene expression, including osteocalcin and bone sialoprotein. A flow on knockdown of bone-specific transcription factors, Runx2 and osterix by shRNAi knockdown of Mef2c, suggests that Mef2c lies upstream of these two important factors in the cascade of gene expression in osteoblasts.

| S-EPMC3191047 | biostudies-literature

Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A.

Project description:The Ca2+ hypothesis for Alzheimer's disease (AD) conceives Ca2+ dyshomeostasis as a common mechanism of AD; the cause of Ca2+ dysregulation, however, is obscure. Meanwhile, hyperactivities of N-Methyl-D-aspartate receptors (NMDARs), the primary mediator of Ca2+ influx, are reported in AD. GluN3A (NR3A) is an NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for sustained Ca2+ homeostasis and its deficiency is pathogenic for AD. Cellular, molecular, and functional changes were examined in adult/aging GluN3A knockout (KO) mice. The GluN3A KO mouse brain displayed age-dependent moderate but persistent neuronal hyperactivity, elevated intracellular Ca2+ , neuroinflammation, impaired synaptic integrity/plasticity, and neuronal loss. GluN3A KO mice developed olfactory dysfunction followed by psychological/cognitive deficits prior to amyloid-β/tau pathology. Memantine at preclinical stage prevented/attenuated AD syndromes. AD patients' brains show reduced GluN3A expression. We propose that chronic "degenerative excitotoxicity" leads to sporadic AD, while GluN3A represents a primary pathogenic factor, an early biomarker, and an amyloid-independent therapeutic target.

| S-EPMC8685302 | biostudies-literature

Zebrafish Vestigial Like Family Member 4b Is Required for Valvulogenesis Through Sequestration of Transcription Factor Myocyte Enhancer Factor 2c.

Project description:A variety of cardiac transcription factors/cofactors, signaling pathways, and downstream structural genes integrate to form the regulatory hierarchies to ensure proper cardiogenesis in vertebrate. Major interaction proteins of the transcription cofactor vestigial like family member 4 (VGLL4) include myocyte enhancer factor 2 (MEF2) and TEA domain transcription factors (TEAD), both of which play important roles in embryonic cardiac development and in adulthood. In this study, we identified that the deficiency of zebrafish vgll4b paralog, a unique family member expressed in developing heart, led to an impaired valve development. Mechanistically, in vgll4b mutant embryos the disruption of Vgll4b-Mef2c complex, rather than that of Vgll4b-Tead complex, resulted in an aberrant expression of krüppel-like factor 2a (klf2a) in endocardium. Such misexpression of klf2a eventually evoked the valvulogenesis defects. Our findings suggest that zebrafish Vgll4b plays an important role in modulating the transcription activity of Mef2c on klf2a during valve development in a blood-flow-independent manner.

| S-EPMC6874126 | biostudies-literature

Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors.

Project description:N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a central role in development, synaptic plasticity, and neurological disease. NMDAR subunit composition defines their biophysical properties and downstream signaling. Casein kinase 2 (CK2) phosphorylates the NR2B subunit within its PDZ-binding domain; however, the consequences for NMDAR localization and function are unclear. Here we show that CK2 phosphorylation of NR2B regulates synaptic NR2B and NR2A in response to activity. We find that CK2 phosphorylates NR2B, but not NR2A, to drive NR2B-endocytosis and remove NR2B from synapses resulting in an increase in synaptic NR2A expression. During development there is an activity-dependent switch from NR2B to NR2A at cortical synapses. We observe an increase in CK2 expression and NR2B phosphorylation over this same critical period and show that the acute activity-dependent switch in NR2 subunit composition at developing hippocampal synapses requires CK2 activity. Thus, CK2 plays a central role in determining the NR2 subunit content of synaptic NMDARs.

| S-EPMC2947143 | biostudies-literature

Open-channel blockade is less effective on GluN3B than GluN3A subunit-containing NMDA receptors.

Project description:The GluN3 subunits of the N-methyl-d-aspartate (NMDA) receptor are known to reduce its Ca(2+) permeability and Mg(2+) sensitivity, however, little is known about their effects on other channel blockers. cRNAs for rat NMDA receptor subunits were injected into Xenopus oocytes and responses to NMDA and glycine were recorded using two electrode voltage clamp. Channel block of receptors containing GluN1-1a/2A, GluN1-1a/2A/3A or GluN1-1a/2A/3B subunits was characterised using Mg(2+), memantine, MK-801, philanthotoxin-343 and methoctramine. IC(50) values for Mg(2+) and memantine increased when receptors contained GluN3A subunits and were further increased when they contained GluN3B, e.g. IC(50)s at -75mV for block of GluN1-1a/2A, GluN1-1a/2A/3A and GluN1-1a/2A/3B receptors respectively were 4.2, 22.4 and 40.1μM for Mg(2+), and 2.5, 7.5 and 17.5μM for memantine. Blocking activity was found to be fully or partially restored when G or R (at the N and N+1 sites respectively) were mutated to N in GluN3A. Thus, the changes cannot be attributed to the loss of the N or N+1 sites alone, but rather involve both sites or residues elsewhere. Block by MK-801 and philanthotoxin-343 was also reduced by GluN3A, most strongly at -100mV but not at -50mV, and by GluN3B at all V(h). Methoctramine was the least sensitive to introduction of GluN3 subunits suggesting a minimal interaction with the N and N+1 sites. We conclude that GluN3B-containing receptors provide increased resistance to channel block compared to GluN3A-containing receptors and this must be due to differences outside the deep pore region (N site and deeper).

| S-EPMC3657159 | biostudies-literature

GluN3A-NMDA receptors constrain protein synthesis and memory by limiting synaptic GIT1/mTORC1 assembly

Project description:Protein synthesis has been implicated in learning and memory, but regulatory mechanisms operating at the synaptic level have not been identified yet. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that couple synaptic stimuli to mTORC1-dependent protein synthesis; and identify non-conventional NMDA receptors containing GluN3A subunits as key negative regulators of GIT1’s binding to mTOR. GluN3A removal enables GIT1/mTOR complex formation, switches on mTORC1-dependent synthesis of plasticity proteins and enhances memory. The memory enhancement becomes evident with light training and can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood. Notably, unlike the memory enhancement seen after global manipulations of translation, GluN3A deletion does not compromise memory flexibility or extinction. These findings identify a novel regulatory mechanism whereby GIT1/GluN3A interactions set local modes of protein synthesis and gate memory formation, offering a potentially selective target for cognitive enhancement.

2021-11-09 | GSE175920 | 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