A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons
Open accessAbstract
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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The data reveal the largest program of neural-regulated alternative splicing events defined to date, associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected.
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
From A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains (2014) · cites this paper as Boutz et al., 2007
Repression of Ptbp2 exon 10 by PTBP1 leads to nonsense-mediated mRNA decay of the Ptbp2 transcript and prevents its expression in PTBP1+ cells.
“The repression of exon 10 leads to nonsense-mediated mRNA decay (NMD) of the Ptbp2 transcript and prevents its expression in PTBP1+ cells15,20,21.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [20]
The mutually exclusive expression pattern of SLM1 and SLM2 is enforced by their cross-regulation via alternative splicing coupled with NMD.
“The mutually exclusive expression pattern of SLM1 and SLM2 is enforced by their cross-regulation via alternative splicing coupled with NMD, as seen with other paralogous pairs of RNA-binding proteins15,20,21,49,53,85,86.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [20]
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- Authors
- Boutz, P. L., Stoilov, P., Li, Q., Lin, C.-H., Chawla, G., Ostrow, K., Shiue, L., Ares, M., & Black, D. L.
- Affiliations
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- University of California, Santa Cruz (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-07-01
- Volume
- 21
- Issue
- 13
- Pages
- 1636-1652
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1899473
- OpenAlex
- W2117293520
- Cited by
- 577
- References
- 91
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 31 · 2023: 28 · 2022: 25 · 2021: 15 · 2020: 20 · 2019: 15 · 2018: 30 · 2017: 27 · 2016: 30 · 2015: 32 · 2014: 44 · 2013: 40 · 2012: 41
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (RO1 GM49662)
- National Institute of General Medical Sciences (R01 GM 49662, R24GM070857, R01GM040478, R01GM049662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- polypyrimidine tract-binding protein, alternative splicing, neuronal development, nonsense-mediated mRNA decay, post-transcriptional regulation, neuronal precursors, postmitotic neurons
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Cells, Cultured, Exons, HeLa Cells, Humans, Mitosis, Nerve Tissue Proteins, Neurons, RNA Processing, Post-Transcriptional, RNA, Messenger, Alternative Splicing, Gene Expression Regulation, Developmental, Oligonucleotide Array Sequence Analysis, Polypyrimidine Tract-Binding Protein, NIH 3T3 Cells, Mice, Rats
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