Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention
Open accessAbstract
Differentiated cells acquire unique structural and functional traits through coordinated expression of lineage-specific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and nonneuronal cells. However, in nonneuronal cells, the splicing of 3′-terminal introns within these genes is repressed by the polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these intron-containing transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery, including the nuclear pore-associated protein Tpr and the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out, thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context.
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Intron retention is increasingly regarded as a regulatory event that can control gene expression.
“Intron retention is a specific form of alternative splicing that is increasingly regarded as a regulatory event that can control gene expression (Kalyna et al., 2012, Wong et al., 2013, Yap et al., 2012).”
From Impact of Alternative Splicing on the Human Proteome (2017) · cites this paper as Yap et al., 2012
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- Authors
- Yap, K., Lim, Z. Q., Khandelia, P., Friedman, B., & Makeyev, E. V.
- Affiliations
- Nanyang Technological University (SG)
- Harvard University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-01
- Volume
- 26
- Issue
- 11
- Pages
- 1209-1223
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3371409
- OpenAlex
- W2160598189
- Cited by
- 286
- References
- 65
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 22 · 2023: 20 · 2022: 21 · 2021: 21 · 2020: 23 · 2019: 16 · 2018: 16 · 2017: 35 · 2016: 25 · 2015: 24 · 2014: 15 · 2013: 12 · 2012: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- intron retention, neuronal differentiation, PTBP1, presynaptic proteins, mRNA export, exosomes, TPR, nonsense-mediated mRNA decay, neurogenesis, lineage-specific gene expression, mRNA degradation
- MeSH terms
- Animals, Brain, Cell Differentiation, Cells, Cultured, Introns, Nerve Tissue Proteins, Neurons, Proto-Oncogene Proteins, RNA Precursors, RNA Splicing, RNA, Messenger, Shiga Toxin 1, Nuclear Pore Complex Proteins, Heterogeneous-Nuclear Ribonucleoproteins, Polypyrimidine Tract-Binding Protein, Cell Line, Tumor, Syntaxin 1, Mice, Exosomes, Gene Knockdown Techniques
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