Abstract
Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation has been widely studied, the control of PSD-95 cellular expression is not understood. We found that Psd-95 was controlled post-transcriptionally during neural development. Psd-95 was transcribed early in mouse embryonic brain, but most of its product transcripts were degraded. The polypyrimidine tract binding proteins PTBP1 and PTBP2 repressed Psd-95 (also known as Dlg4) exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay. The loss of first PTBP1 and then of PTBP2 during embryonic development allowed splicing of exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibited PSD-95 expression and impaired the development of glutamatergic synapses. Thus, expression of PSD-95 during early neural development is controlled at the RNA level by two PTB proteins whose sequential downregulation is necessary for synapse maturation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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Carrier Proteins / genetics
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Cell Differentiation / genetics
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Cells, Cultured
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Cerebral Cortex / cytology
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Dendrites / genetics
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Disks Large Homolog 4 Protein
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Electric Stimulation
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Electrophoretic Mobility Shift Assay
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Embryo, Mammalian
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Excitatory Postsynaptic Potentials / genetics
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Excitatory Postsynaptic Potentials / physiology
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Exons / genetics
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Guanylate Kinases / genetics
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Guanylate Kinases / metabolism*
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Hippocampus / cytology
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Homeodomain Proteins / genetics
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Transgenic
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Neural Stem Cells / physiology
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Neuroblastoma / pathology
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Neurogenesis / genetics
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Neurogenesis / physiology*
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Neurons / cytology
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Neurons / physiology*
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Patch-Clamp Techniques
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Polypyrimidine Tract-Binding Protein / genetics
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Polypyrimidine Tract-Binding Protein / metabolism*
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RNA Isoforms / genetics
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RNA Isoforms / metabolism
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RNA Splicing / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins
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Transcription Factors / genetics
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Transfection
Substances
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Carrier Proteins
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Homeodomain Proteins
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Membrane Proteins
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RNA Isoforms
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RNA, Messenger
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RNA, Small Interfering
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RNA-Binding Proteins
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Transcription Factors
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Upf2 protein, mouse
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empty spiracles homeobox proteins
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Polypyrimidine Tract-Binding Protein
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Green Fluorescent Proteins
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Guanylate Kinases