Arc/Arg3.1 functionally defines migrating 1 dendritic cells and regulates actin dynamics
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71937 | GEO | 2015/08/12
SECONDARY ACCESSION(S): PRJNA292505
REPOSITORIES: GEO
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Project description:The immediate early gene product activity-regulated cytoskeleton-associate protein (Arc or Arg3.1) is a major regulator long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is not defined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. In vitro biochemical and biophysical analysis of purified recombinant Arc show formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in mammalian brain. Using in situ protein crosslinking to trap weak Arc-Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While heavier Arc species or putative trimers and tetramers were detected, they were of lower abundance. In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced expression of dimer during four hours of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with lowest levels in the DG. Taken together the results implicate Arc dimers as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and pronounced enhanced expression during DG LTP.
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Project description:Synapse dysfunction and synaptic loss are a central feature of neurodegenerative disorders, including prion disease. The cellular prion protein (PrPC) binds prion, amyloid-β, tau, and α-synuclein oligomers, resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the initial signaling events are unclear. Here we used a transcriptomic approach focused on the early-stage, prion-infected hippocampus of male wild type mice, and identify immediate early genes, including the synaptic activity response gene, Arc/Arg3.1, as significantly upregulated. In a longitudinal study of the prion-infected hippocampus, Arc/Arg-3.1 protein increased, from early to terminal disease. Notably, metabotropic glutamate receptor levels (mGluR5 dimers) were markedly reduced over time, while phosphorylated AMPA receptors (pGluA1-S845) levels increased. Sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger a chronic Arc response, an increase in phosphorylated GluA1, and a reduction in mGluR5 receptors beginning in early disease.
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Project description:Transcription of immediate early genes (IEGs) in neurons is exquisitely sensitive to neuronal activity, but the mechanism underlying the earliest of these transcription events is largely unknown. Here we demonstrate that very fast IEGs (VF-IEGs) such as arc/arg3.1 are poised for rapid transcription by the stalling of RNA Polymerase II (Pol II) just downstream of the transcription start site. RNAi-depletion of two subunits of Negative Elongation Factor, a mediator of Pol II stalling, reduces the Pol II occupancy of the arc promoter and compromises the rapid induction of arc and other VF-IEGs. In contrast, reduction of Pol II stalling did not prevent expression of fast IEGs (F-IEGs). These F-IEGs are expressed with comparatively slower kinetics and largely lack promoter proximal Pol II stalling. Taken together, our data strongly indicate that very fast kinetics of neuronal IEG expression require poised Pol II and suggest a role for this mechanism in transcription-dependent learning and memory. Examination of Pol II bindnig genome-wide in rat neurons
2011-05-24 | E-GEOD-22878 | biostudies-arrayexpress
Project description:Transcription of immediate early genes (IEGs) in neurons is exquisitely sensitive to neuronal activity, but the mechanism underlying the earliest of these transcription events is largely unknown. Here we demonstrate that very fast IEGs (VF-IEGs) such as arc/arg3.1 are poised for rapid transcription by the stalling of RNA Polymerase II (Pol II) just downstream of the transcription start site. RNAi-depletion of two subunits of a mediator of Pol II stalling, Negative Elongation Factor, reduces Pol II occupancy of the arc promoter and compromises rapid induction of arc and other VF-IEGs. In contrast, reduction of Pol II stalling did not prevent expression of other fast IEGs (F-IEGs). These F-IEGs are expressed with comparatively slower kinetics and largely lack promoter proximal Pol II stalling. Taken together, our data strongly indicate that very fast kinetics of neuronal IEG expression require poised Pol II and suggest a role for this mechanism in transcription-dependent learning and memory.
2011-04-15 | GSE22622 | GEO
Project description:Transcription of immediate early genes (IEGs) in neurons is exquisitely sensitive to neuronal activity, but the mechanism underlying the earliest of these transcription events is largely unknown. Here we demonstrate that very fast IEGs (VF-IEGs) such as arc/arg3.1 are poised for rapid transcription by the stalling of RNA Polymerase II (Pol II) just downstream of the transcription start site. RNAi-depletion of two subunits of a mediator of Pol II stalling, Negative Elongation Factor, reduces Pol II occupancy of the arc promoter and compromises rapid induction of arc and other VF-IEGs. In contrast, reduction of Pol II stalling did not prevent expression of other fast IEGs (F-IEGs). These F-IEGs are expressed with comparatively slower kinetics and largely lack promoter proximal Pol II stalling. Taken together, our data strongly indicate that very fast kinetics of neuronal IEG expression require poised Pol II and suggest a role for this mechanism in transcription-dependent learning and memory. TTX withdrawal induced neuronal activity. To study activity-induced gene expression, neurons were treated with TTX for 48 hours and then TTX was washed out either for 15 minutes (W15) or for 45 minutes (W45). Gene expression was measured in these two groups in comparison to TTX treated neurons.
2011-04-14 | E-GEOD-22622 | biostudies-arrayexpress
Project description:Transcription of immediate early genes (IEGs) in neurons is exquisitely sensitive to neuronal activity, but the mechanism underlying the earliest of these transcription events is largely unknown. Here we demonstrate that very fast IEGs (VF-IEGs) such as arc/arg3.1 are poised for rapid transcription by the stalling of RNA Polymerase II (Pol II) just downstream of the transcription start site. RNAi-depletion of two subunits of Negative Elongation Factor, a mediator of Pol II stalling, reduces the Pol II occupancy of the arc promoter and compromises the rapid induction of arc and other VF-IEGs. In contrast, reduction of Pol II stalling did not prevent expression of fast IEGs (F-IEGs). These F-IEGs are expressed with comparatively slower kinetics and largely lack promoter proximal Pol II stalling. Taken together, our data strongly indicate that very fast kinetics of neuronal IEG expression require poised Pol II and suggest a role for this mechanism in transcription-dependent learning and memory.
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