PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Sika Zheng; Erin E Gray; Geetanjali Chawla; Bo Torben Porse; Thomas J O'Dell; Douglas L Black

doi:10.1038/nn.3026

PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Sika Zheng, Erin E Gray, Geetanjali Chawla, Bo Torben Porse, Thomas J O'Dell, Douglas L Black

Institut for Klinisk Medicin

127 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Neuroscience
Vol/bind	15
Udgave nummer	3
Sider (fra-til)	381-8, S1
ISSN	1097-6256
DOI	https://doi.org/10.1038/nn.3026
Status	Udgivet - mar. 2012

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10.1038/nn.3026

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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.",

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author = "Sika Zheng and Gray, {Erin E} and Geetanjali Chawla and Porse, {Bo Torben} and O'Dell, {Thomas J} and Black, {Douglas L}",

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AU - Zheng, Sika

AU - Gray, Erin E

AU - Chawla, Geetanjali

AU - Porse, Bo Torben

AU - O'Dell, Thomas J

AU - Black, Douglas L

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N2 - 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.

AB - 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.

KW - Age Factors

KW - Animals

KW - Carrier Proteins

KW - Cell Differentiation

KW - Cells, Cultured

KW - Cerebral Cortex

KW - Dendrites

KW - Electric Stimulation

KW - Electrophoretic Mobility Shift Assay

KW - Embryo, Mammalian

KW - Excitatory Postsynaptic Potentials

KW - Exons

KW - Gene Expression Regulation, Developmental

KW - Green Fluorescent Proteins

KW - Guanylate Kinase

KW - Hippocampus

KW - Homeodomain Proteins

KW - Membrane Proteins

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KW - Mice, Transgenic

KW - Neural Stem Cells

KW - Neuroblastoma

KW - Neurogenesis

KW - Neurons

KW - Patch-Clamp Techniques

KW - Polypyrimidine Tract-Binding Protein

KW - RNA Isoforms

KW - RNA Splicing

KW - RNA, Messenger

KW - RNA, Small Interfering

KW - Transcription Factors

KW - Transfection

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DO - 10.1038/nn.3026

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SN - 1097-6256

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SP - 381-8, S1

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 3

ER -

PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Abstract

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