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

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Abstract

Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation is widely studied, the control of PSD-95 cellular expression is not understood. We find that Psd-95 is controlled post-transcriptionally during neural development. Psd-95 is transcribed early in mouse embryonic brain, but most of its product transcripts are degraded. The polypyrimidine tract binding proteins, PTBP1 and PTBP2, repress Psd-95 exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay (NMD). The loss first of PTBP1 and then of PTBP2 during embryonic development allows splicing of Exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibits PSD-95 expression and impairs 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 down-regulation is necessary for synapse maturation.

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The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

Eugene V. Makeyev, Jiangwen Zhang, Monica A. Carrasco … (2007)

Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.

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Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping.

Yuanchao Xue, Yu Zhou, Tongbin Wu … (2009)

Recent transcriptome analysis indicates that > 90% of human genes undergo alternative splicing, underscoring the contribution of differential RNA processing to diverse proteomes in higher eukaryotic cells. The polypyrimidine tract-binding protein PTB is a well-characterized splicing repressor, but PTB knockdown causes both exon inclusion and skipping. Genome-wide mapping of PTB-RNA interactions and construction of a functional RNA map now reveal that dominant PTB binding near a competing constitutive splice site generally induces exon inclusion, whereas prevalent binding close to an alternative site often causes exon skipping. This positional effect was further demonstrated by disrupting or creating a PTB-binding site on minigene constructs and testing their responses to PTB knockdown or overexpression. These findings suggest a mechanism for PTB to modulate splice site competition to produce opposite functional consequences, which may be generally applicable to RNA-binding splicing factors to positively or negatively regulate alternative splicing in mammalian cells. 2009 Elsevier Inc.

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A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.

Paul L Boutz, Peter Stoilov, Qin Li … (2007)

Many metazoan gene transcripts exhibit neuron-specific splicing patterns, but the developmental control of these splicing events is poorly understood. We show that the splicing of a large group of exons is reprogrammed during neuronal development by a switch in expression between two highly similar polypyrimidine tract-binding proteins, PTB and nPTB (neural PTB). PTB is a well-studied regulator of alternative splicing, but nPTB is a closely related paralog whose functional relationship to PTB is unknown. In the brain, nPTB protein is specifically expressed in post-mitotic neurons, whereas PTB is restricted to neuronal precursor cells (NPC), glia, and other nonneuronal cells. Interestingly, nPTB mRNA transcripts are found in NPCs and other nonneuronal cells, but in these cells nPTB protein expression is repressed. This repression is due in part to PTB-induced alternative splicing of nPTB mRNA, leading to nonsense-mediated decay (NMD). However, we find that even properly spliced mRNA fails to express nPTB protein when PTB is present, indicating contributions from additional post-transcriptional mechanisms. The PTB-controlled repression of nPTB results in a mutually exclusive pattern of expression in the brain, where the loss of PTB in maturing neurons allows the synthesis of nPTB in these cells. To examine the consequences of this switch, we used splicing-sensitive microarrays to identify different sets of exons regulated by PTB, nPTB, or both proteins. During neuronal differentiation, the splicing of these exon sets is altered as predicted from the observed changes in PTB and nPTB expression. These data show that the post-transcriptional switch from PTB to nPTB controls a widespread alternative splicing program during neuronal development.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature Neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 19 December 2011

Publication date (Electronic): 15 January 2012

Publication date PMC-release: 01 September 2012

Volume: 15

Issue: 3

Pages: 381-S1

Affiliations

[1 ]Howard Hughes Medical Institute, University of California at Los Angeles

[2 ]Interdepartmental Ph.D. Program for Neuroscience, University of California at Los Angeles, California 90095, USA

[3 ]Finsen Laboratory, Rigshospitale, University of Copenhagen, Copenhagen, Denmark

[4 ]Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

[5 ]Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

[6 ]Department of Physiology, University of California at Los Angeles, California 90095, USA

[7 ]Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, California 90095, USA

Author notes

[8 ]To whom correspondence should be addressed. dougb@ 123456microbio.ucla.edu

Article

Manuscript ID: nihpa344267

DOI: 10.1038/nn.3026

PMC ID: 3288398

PubMed ID: 22246437

SO-VID: 0ba65682-1105-4fea-af7f-eef623266cbd

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Funding

Funded by: National Institute of Mental Health : NIMH

Award ID: R01 MH060919-07 || MH

Funded by: National Institute of General Medical Sciences : NIGMS

Award ID: R01 GM049662-19 || GM

Funded by: National Institute of General Medical Sciences : NIGMS

Award ID: R01 GM049662-18 || GM

Funded by: National Institute of General Medical Sciences : NIGMS

Award ID: R01 GM049662-17 || GM

Funded by: National Institute of Mental Health : NIMH

Award ID: F31 MH085462-02 || MH

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

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Most cited references 43

The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping.

A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.

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Cited by 88

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