PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2
Open accessAbstract
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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The highest enrichment was observed in developing brain, germinal matrix, cortex-derived neurospheres, and ESC-derived neurons, consistent with ASD as a neurodevelopmental disorder with largely prenatal origins.
“The highest enrichment was observed in the developing brain, germinal matrix, cortex-derived neurospheres, and embryonic stem cell (ESC)-derived neurons, consistent with ASD as a neurodevelopmental disorder with largely prenatal origins, as supported by data from analysis of rare de novo variants 76 .”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [76]
The Results section (‘Psd-95 mRNA is actively transcribed but lost to AS-NMD’; page unavailable) examines PSD-95 regulation in developing brain and cortical neurons, not enrichment across the listed tissues and cell types. Searches for germinal matrix, neurospheres, ESC-derived neurons, ASD, and rare de novo variants found no passage addressing the attributed enrichment or prenatal-origin claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredBoth common and rare variation in ASD preferentially affects genes expressed during corticogenesis, highlighting a potential spatiotemporal convergence of genetic risk on this developmental epoch.
“Interestingly, both common and rare variation in ASD preferentially affects genes expressed during corticogenesis 76 , highlighting a potential spatiotemporal convergence of genetic risk on this specific developmental epoch, despite the disorder's profound genetic heterogeneity.”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [76]
The Results passage on primary cortical cultures describes developmental regulation of PSD-95 by PTBP1 and PTBP2, not the distribution of ASD genetic risk. Searches for common and rare ASD variation and for genetic risk during corticogenesis found no passage addressing the attributed claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredOverexpression of either PTBP1 or PTBP2 in mature neurons inhibits exon 18 inclusion, PSD95 protein expression and excitatory synapse formation.
“Overexpression of either PTBP1 or PTBP2 in mature neurons inhibits exon 18 inclusion, PSD95 protein expression and excitatory synapse formation67.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [67]
High expression of PTBP2 during early development extends the expression of the embryonic splicing programme until late in neuronal maturation.
“Thus the high expression of PTBP2 during early development extends the expression of the embryonic splicing programme until late in neuronal maturation.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [67]
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- Authors
- Zheng, S., Gray, E. E., Chawla, G., Porse, B. T., O'Dell, T. J., & Black, D. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- University of Copenhagen (DK)
- Corresponding author
- Black, Douglas L
- Venue
- Nature Neuroscience
- Published
- 2012-01-15
- Volume
- 15
- Issue
- 3
- Pages
- 381-388
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3288398
- OpenAlex
- W2026441189
- Cited by
- 254
- References
- 50
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 29 · 2023: 18 · 2022: 14 · 2021: 21 · 2020: 15 · 2019: 14 · 2018: 21 · 2017: 14 · 2016: 18 · 2015: 18 · 2014: 19 · 2013: 20 · 2012: 5
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Lundbeckfonden (R5-2006-99)
- National Institute of Mental Health (F32 MH84562, R01MH060919, F31MH085462)
- National Institute of General Medical Sciences (R01GM049662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- PSD-95, PTBP1, PTBP2, polypyrimidine tract-binding protein, alternative splicing, nonsense-mediated mRNA decay, post-transcriptional regulation, synapse maturation, glutamatergic synapses, neuronal maturation, embryonic brain development
- MeSH terms
- Disks Large Homolog 4 Protein, Empty Spiracles Homeobox Proteins, Age Factors, Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, Cerebral Cortex, Dendrites, Electric Stimulation, Embryo, Mammalian, Exons, Hippocampus, Membrane Proteins, Mice, Transgenic, Neuroblastoma, Neurons, RNA Splicing, RNA, Messenger, Transcription Factors, Transfection, RNA-Binding Proteins, Homeodomain Proteins, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Excitatory Postsynaptic Potentials, Electrophoretic Mobility Shift Assay, RNA, Small Interfering, Polypyrimidine Tract-Binding Protein, Green Fluorescent Proteins, Mice, Guanylate Kinases, Neurogenesis, Neural Stem Cells, RNA Isoforms
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