Abstract
Neuregulin-1 (Nrg-1) contains an intracellular domain (Nrg-ICD) that translocates into the nucleus, where it may regulate gene expression upon neuronal depolarization. However, the identity of its target promoters and the mechanisms by which it regulates transcription have been elusive. Here we report that, in the mouse cochlea, synaptic activity increases the level of nuclear Nrg-ICD and upregulates postsynaptic density protein-95 (PSD-95), a scaffolding protein that is enriched in post-synaptic structures. Nrg-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. The Nrg-ICD-Eos complex induces endogenous PSD-95 expression in vivo through a signaling pathway that is mostly independent of gamma-secretase regulation. This upregulation of PSD-95 expression by the Nrg-ICD-Eos complex provides a molecular basis for activity-dependent synaptic plasticity.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acoustic Stimulation / methods
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Animals
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Carrier Proteins / physiology*
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Cell Line
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Cochlea / cytology
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Cochlea / physiology
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Cochlea / radiation effects
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DNA-Binding Proteins / physiology
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Disks Large Homolog 4 Protein
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Electrophoretic Mobility Shift Assay / methods
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Extracellular Space / metabolism
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Extracellular Space / radiation effects
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Gene Expression Regulation / radiation effects
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Genes, Reporter / physiology
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Guanylate Kinases
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Humans
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Ikaros Transcription Factor
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Mice
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Mutagenesis
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / physiology*
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Neuregulin-1 / physiology*
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Neuronal Plasticity / physiology
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Neuronal Plasticity / radiation effects
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Neurons / cytology
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Neurons / physiology*
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Neurons / radiation effects
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Oligonucleotide Array Sequence Analysis / methods
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Potassium Chloride / pharmacology
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Promoter Regions, Genetic / physiology
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RNA, Messenger / biosynthesis
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Signal Transduction / physiology
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Subcellular Fractions / metabolism
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Time Factors
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Transcription Factors / physiology
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Transcription, Genetic / physiology*
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Transfection / methods
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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IKZF1 protein, human
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Neuregulin-1
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RNA, Messenger
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Transcription Factors
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Zfpn1a4 protein, mouse
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postsynaptic density proteins
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Ikaros Transcription Factor
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Potassium Chloride
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Guanylate Kinases