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Cited by 41RNA Research and SplicingGenetics and Neurodevelopmental DisordersRNA regulation and disease

Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching

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Dawicki-McKenna, Jennine M., Felix, Alex J., Waxman, Elisa A., Cheng, Congsheng, Amado, Defne A., Ranum, Paul T., Bogush, Alexey, Dungan, Lea V. +6 more·2023·Nature Communications
DOI 10.1038/s41467-023-38273-3PMC PMC10164156

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Abstract

Alternative splicing of neuronal genes is controlled partly by the coordinated action of polypyrimidine tract binding proteins (PTBPs). While PTBP1 is ubiquitously expressed, PTBP2 is predominantly neuronal. Here, we define the PTBP2 footprint in the human transcriptome using brain tissue and human induced pluripotent stem cell-derived neurons (iPSC-neurons). We map PTBP2 binding sites, characterize PTBP2-dependent alternative splicing events, and identify novel PTBP2 targets including SYNGAP1 , a synaptic gene whose loss-of-function leads to a complex neurodevelopmental disorder. We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and nonsense-mediated decay, and that antisense oligonucleotides (ASOs) that disrupt PTBP binding redirect splicing and increase SYNGAP1 mRNA and protein expression. In SYNGAP1 haploinsufficient iPSC-neurons generated from two patients, we show that PTBP2-targeting ASOs partially restore SYNGAP1 expression. Our data comprehensively map PTBP2-dependent alternative splicing in human neurons and cerebral cortex, guiding development of novel therapeutic tools to benefit neurodevelopmental disorders.

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  • Prior mechanistic studies have shown that PTBP1 normally suppresses productive expression of PTBP2 through alternative splicing coupled to nonsense-mediated decay.

    “Prior mechanistic studies have shown that PTBP1 normally suppresses productive expression of PTBP2 through alternative splicing coupled to nonsense-mediated decay.”

    From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [22]

    The Results section on PTBP2-dependent synaptic genes reports that PTBP1 levels fall while PTBP2 levels rise during neuronal differentiation, but it does not say that PTBP1 suppresses PTBP2 expression. Searches for PTBP1, PTBP2, alternative splicing, and nonsense-mediated decay found NMD mechanisms involving SYNGAP1, not PTBP2. No page numbers are available in our copy. (LLM, conf=0.75)

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Research works printed but not linked: 48

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Cited by

Sorted by citations

Authors
Dawicki-McKenna, J. M., Felix, A. J., Waxman, E. A., Cheng, C., Amado, D. A., Ranum, P. T., Bogush, A., Dungan, L. V., Maguire, J. A., Gagne, A. L., Heller, E. A., French, D. L., Davidson, B. L., & Prosser, B. L.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
  • Davidson, Beverly L.
  • Prosser, Benjamin L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-05-06
Volume
14
Issue
1
Pages
2628-2628
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-38273-3
PMC
PMC10164156
OpenAlex
W4372352541
Cited by
41
References
6
Citations by year
2026: 15 · 2025: 11 · 2024: 9 · 2023: 6
FWCI
3.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS118280)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
PTBP2, alternative splicing, SYNGAP1, polypyrimidine tract-binding protein, nonsense-mediated mRNA decay, antisense oligonucleotides, splice switching, iPSC-derived neurons, haploinsufficiency, neurodevelopmental disorders, human transcriptome, cerebral cortex, synaptic genes
MeSH terms
Brain, Humans, Nerve Tissue Proteins, RNA Splicing, RNA, Messenger, Alternative Splicing, ras GTPase-Activating Proteins, Heterogeneous-Nuclear Ribonucleoproteins, Polypyrimidine Tract-Binding Protein, Induced Pluripotent Stem Cells

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