The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation
Open accessAbstract
We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2−/− neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron.
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PTBP1 depletion has also been linked to broader neurogenic regulatory circuits, including the miR-124/REST pathway involved in neuronal induction and the PTBP2/miR-9/BRN2 axis implicated in neuronal maturation.
“PTBP1 depletion has also been linked to broader neurogenic regulatory circuits, including the miR-124/REST pathway involved in neuronal induction and the PTBP2/miR-9/BRN2 axis implicated in neuronal maturation.”
From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [25]
The Introduction says miR-124 represses PTBP1, PTBP1 depletion induces PTBP2, and depletion can induce neuronal differentiation. The Results and Discussion link PTBP2 to neuronal maturation, but our copy does not describe a miR-124/REST pathway or a PTBP2/miR-9/BRN2 axis. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPtbp2 mutant mice are paralysed and unresponsive to touch at birth and show perinatal lethality with respiratory failure.
“These mice are paralysed and unresponsive to touch at birth and show perinatal lethality with respiratory failure, possibly owing to a loss of innervation to the diaphragm.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [64]
Emx1-Ptbp2−/− brains begin to show cortical atrophy as early as P5, and by P15 the cortex shows massive cell death and is almost completely degenerated.
“Emx1–Ptbp2−/− brains begin to show cortical atrophy as early as P5, and by P15 the cortex shows massive cell death and is almost completely degenerated.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [64]
Cultured Ptbp2−/− embryonic cortical neurons initially appear normal in plating efficiency and neurite outgrowth, but exhibit progressive cell death beginning in the second week.
“cultured Ptbp2−/− embryonic cortical neurons initially appear normal in plating efficiency and neurite outgrowth, but exhibit progressive cell death beginning in the second week.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [64]
All Ptbp2 mutant mouse models show precocious expression of many adult mRNA isoforms.
“All of the Ptbp2 mutant mouse models show a precocious expression of many adult mRNA isoforms encoding proteins that affect a variety of cellular functions, including the regulation of transcription, synaptic transmission, synapse organization and endocytosis63,64.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [64]
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 [64]
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References 68 · Cited by 174
- Authors
- Li, Q., Zheng, S., Han, A., Lin, C.-H., Stoilov, P., Fu, X.-D., & Black, D. L.
- Affiliations
- University of California, Los Angeles (US)
- West Virginia University (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Black, Douglas L
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2014-01-21
- Volume
- 3
- Pages
- e01201-e01201
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC3896118
- OpenAlex
- W2001547716
- Cited by
- 174
- References
- 68
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 15 · 2023: 17 · 2022: 12 · 2021: 12 · 2020: 12 · 2019: 15 · 2018: 18 · 2017: 11 · 2016: 23 · 2015: 11 · 2014: 8 · 2013: 1
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-10-09)
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Research Repository @ WVU (West Virginia University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- Brain & Behaviour Research Foundation (formerly NARSAD)
- National Institutes of Health (K99 MH096807, R01 GM084317, R01 GM49662)
- Brain and Behavior Research Foundation
- 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 › Developmental Biology and Gene Regulation
- Keywords
- PTBP2, alternative splicing, neuronal maturation, cortical development, neurodegeneration, transcriptome-wide analysis, neurite outgrowth, synaptic transmission, postnatal brain development
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Gene Expression Regulation, Molecular Sequence Data, Nerve Tissue Proteins, Nervous System, Neurons, Sequence Analysis, DNA, Gene Expression Profiling, Polypyrimidine Tract-Binding Protein, Mice, Gene Knockout Techniques
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