A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG
Open accessAbstract
Alternative splicing is one of the central mechanisms that regulate eukaryotic gene expression. Here we report a tissue-specific RNA-binding protein, Fox-1, which regulates alternative splicing in vertebrates. Fox-1 bound specifically to a pentanucleotide GCAUG in vitro. In zebrafish and mouse, fox-1 is expressed in heart and skeletal muscles. As candidates for muscle-specific targets of Fox-1, we considered two genes, the human mitochondrial ATP synthase gamma-subunit gene (F1gamma) and the rat alpha-actinin gene, because their primary transcripts contain several copies of GCAUG. In transfection experiments, Fox-1 induced muscle-specific exon skipping of the F1gamma gene via binding to GCAUG sequences upstream of the regulated exon. Fox-1 also regulated mutually exclusive splicing of the alpha-actinin gene, antagonizing the repressive effect of polypyrimidine tract-binding protein (PTB). It has been reported that GCAUG is essential for the alternative splicing regulation of several genes including fibronectin. We found that Fox-1 promoted inclusion of the fibronectin EIIIB exon. Thus, we conclude that Fox-1 plays key roles in both positive and negative regulation of tissue-specific splicing via GCAUG.
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Rbfox proteins bind the (U)GCAUG element, which is frequently conserved across vertebrates.
“Rbfox proteins are known as tissue-specific splicing factors which bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Jin et al., 2003
Rbfox binding downstream of an exon activates inclusion, while binding in the alternative exon or upstream intron represses inclusion.
“According to this map, Rbfox binding in the downstream intron activates exon inclusion and binding in the alternative exon or upstream intron represses exon inclusion, consistent with observations from several tissue-specific exons (Jin et al., 2003; Underwood et al., 2005).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Jin et al., 2003
Rbfox1, Rbfox2, and Rbfox3 regulate alternative splicing in the nervous system.
“The RNA-binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Jin et al., 2003
Functional divergence among Rbfox members could arise from increased variation in their N-terminal and C-terminal regions, which have been shown to be important in splicing regulation.
“However, the functional divergence of the different members could arise from the increased variation in the N terminal and Cterminal regions, which were shown to also be important in splicing regulation (Jin et al., 2003; Nakahata and Kawamoto, 2005; Sun et al., 2011).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Jin et al., 2003
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- Authors
- Jin, Y., Suzuki, H., Maegawa, S., Endo, H., Sugano, S., Hashimoto, K., Yasuda, K., & Inoue, K.
- Affiliations
- Nara Institute of Science and Technology (JP)
- University of Miami (US)
- University of Pennsylvania (US)
- Jichi Medical University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- National Institute of Infectious Diseases (JP)
- Corresponding author
- Inoue, Kunio
- Venue
- The EMBO Journal
- Published
- 2003-02-17
- Volume
- 22
- Issue
- 4
- Pages
- 905-912
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC145449
- OpenAlex
- W2093506762
- Cited by
- 311
- References
- 47
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 15 · 2023: 11 · 2022: 9 · 2021: 6 · 2020: 16 · 2019: 12 · 2018: 14 · 2017: 12 · 2016: 16 · 2015: 11 · 2014: 16 · 2013: 18 · 2012: 15
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- 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
- RNA-binding proteins, alternative splicing, tissue-specific splicing, exon skipping, polypyrimidine tract-binding protein, alpha-actinin, zebrafish, mice
- MeSH terms
- RNA Splicing Factors, Actinin, Animals, Fibronectins, Molecular Sequence Data, Oligonucleotides, Organ Specificity, RNA Splicing, Zebrafish, RNA-Binding Proteins, Caenorhabditis elegans Proteins, Zebrafish Proteins, Mice, In Vitro Techniques
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