A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart
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From a large-scale screen using splicing microarrays and RT-PCR, we identified 63 alternative splicing (AS) events that are coordinated in 3 distinct temporal patterns during mouse heart development. More than half of these splicing transitions are evolutionarily conserved between mouse and chicken. Computational analysis of the introns flanking these splicing events identified enriched and conserved motifs including binding sites for CUGBP and ETR-3-like factors (CELF), muscleblind-like (MBNL) and Fox proteins. We show that CELF proteins are down-regulated >10-fold during heart development, and MBNL1 protein is concomitantly up-regulated nearly 4-fold. Using transgenic and knockout mice, we show that reproducing the embryonic expression patterns for CUGBP1 and MBNL1 in adult heart induces the embryonic splicing patterns for more than half of the developmentally regulated AS transitions. These findings indicate that CELF and MBNL proteins are determinative for a large subset of splicing transitions that occur during postnatal heart development.
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Similar dynamic changes in Rbfox1 and Rbfox2 expression were previously observed in the heart during postnatal development.
“Similar dynamic changes in Rbfox1 and Rbfox2 expression were previously observed in the heart during postnatal development (Kalsotra et al., 2008).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Kalsotra et al., 2008
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- Authors
- Kalsotra, A., Xiao, X., Ward, A. J., Castle, J. C., Johnson, J. M., Burge, C. B., & Cooper, T. A.
- Affiliations
- Baylor College of Medicine (US)
- Massachusetts Institute of Technology (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-23
- Volume
- 105
- Issue
- 51
- Pages
- 20333-20338
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2629332
- OpenAlex
- W1992481904
- Cited by
- 508
- References
- 42
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 23 · 2023: 22 · 2022: 32 · 2021: 26 · 2020: 23 · 2019: 28 · 2018: 34 · 2017: 27 · 2016: 29 · 2015: 31 · 2014: 36 · 2013: 41 · 2012: 36
- FWCI
- 10.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Weizmann Institute of Science
- National Institutes of Health
- University of California, Los Angeles
- National Heart, Lung, and Blood Institute (R01 HL45565, R01HL045565)
- National Human Genome Research Institute (R01HG002439, HG002439)
- National Institute of General Medical Sciences (R01GM076493)
- 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 › RNA and protein synthesis mechanisms
- Keywords
- alternative splicing, heart development, CUGBP1, MBNL1, muscleblind-like proteins
- MeSH terms
- CELF Proteins, CELF1 Protein, Animals, Binding Sites, Chickens, DNA-Binding Proteins, Heart, RNA-Binding Proteins, Alternative Splicing, Gene Expression Regulation, Developmental, Mice
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