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Cited by 187RNA Research and SplicingRNA regulation and diseaseRNA and protein synthesis mechanisms

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Fox-1 family of RNA-binding proteins

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Kuroyanagi, Hidehito·2009·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-009-0120-5PMC PMC2777236
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Abstract

The Fox-1 family of RNA-binding proteins are evolutionarily conserved regulators of tissue-specific alternative splicing in metazoans. The Fox-1 family specifically recognizes the (U)GCAUG stretch in regulated exons or in flanking introns, and either promotes or represses target exons. Recent unbiased bioinformatics analyses of alternatively spliced exons and comparison of various vertebrate genomes identified the (U)GCAUG stretch as a highly conserved and widely distributed element enriched in intronic regions surrounding exons with altered inclusion in muscle, heart, and brain, consistent with specific expression of Fox-1 and Fox-2 in these tissues. Global identification of Fox-2 target RNAs in living cells revealed that many of the Fox-2 target genes themselves encode splicing regulators. Further systematic elucidation of target genes of the Fox-1 family and other splicing regulators in various tissues will lead to a comprehensive understanding of splicing regulatory networks.

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Fig. 1 The Fox-1 family RNA-binding proteins are phylogenetically conserved. a Amino acid sequence alignment of the RRM domain of the Fox-1 family proteins in human and mouse (Fox-1, Fox-2, and Fox-3), zebrafish (a2bp1, LOC797814, zFox-1/2bp1l, and zgc85694), fruitfly (Drosophila CG32062), and nematode (C. elegans FOX-1, ASD-1, and SPN-4). Identical amino acid residues are shaded in orange and residues with similar properties are in yellow. The secondary structure of the human Fox-1 RRM domain is indicated above the alignment [23]. b Schematic illustration of the domain structure of mouse Fox-1 and Fox-2, zebrafish Fox-1/A2bp1l, and C. elegans FOX-1. RRM domain is in orange. Identities of amino acid sequences of each domain compared to that of mouse Fox-1 are indicated. Amino acid positions are indicated. c Amino acid sequence alignment of putative hPY-NLS of the Fox-1 family proteins. The C-terminal-most regions of mouse Fox-1, Fox-2, zebrafish a2bp1, zFox-1/2bp1l, Drosophila CG32062, and C. elegans FOX-1 and ASD-1 are aligned with confirmed hPY-NLS of human hnRNP A1, hnRNP D, hnRNP F, and TAP [18]. Residues that match the consensus of hPY-NLS [18] are shaded in orange and yellow. ϕ, hydrophobic side chain. Positions of the N-terminal-most residues are indicated. d Solution structure of the RRM domain of Fox-1/Fox-2 in complex with 5′-UGCAUGU-3′ in ribbon (protein backbone) and stick (RNA) representation. Right panel Image of left panel rotated by 90° as indicated. Important protein side chains and peptide bonds involved in hydrophobic or static interactions with the RNA are represented as sticks. Oxygen, nitrogen, hydrogen, and phosphorus atoms are in red, blue, light yellow, and magenta, respectively. Carbon atoms in the protein, the RNA backbone, and bases are in green, yellow, and gray, respectively. Hydrogen bonds are indicated as cyan dotted sticks. Hydrogen atoms in the RNA backbone are omitted except for one involved in a hydrogen bond. Illustrations were generated from a dataset deposited as ‘2err’ in PDBj database with MOLMOL [78]
Fig. 1 The Fox-1 family RNA-binding proteins are phylogenetically conserved. a Amino acid sequence alignment of the RRM domain of the Fox-1 family proteins in human and mouse (Fox-1, Fox-2, and Fox-3), zebrafish (a2bp1, LOC797814, zFox-1/2bp1l, and zgc85694), fruitfly (Drosophila CG32062), and nematode (C. elegans FOX-1, ASD-1, and SPN-4). Identical amino acid residues are shaded in orange and residues with similar properties are in yellow. The secondary structure of the human Fox-1 RRM domain is indicated above the alignment [23]. b Schematic illustration of the domain structure of mouse Fox-1 and Fox-2, zebrafish Fox-1/A2bp1l, and C. elegans FOX-1. RRM domain is in orange. Identities of amino acid sequences of each domain compared to that of mouse Fox-1 are indicated. Amino acid positions are indicated. c Amino acid sequence alignment of putative hPY-NLS of the Fox-1 family proteins. The C-terminal-most regions of mouse Fox-1, Fox-2, zebrafish a2bp1, zFox-1/2bp1l, Drosophila CG32062, and C. elegans FOX-1 and ASD-1 are aligned with confirmed hPY-NLS of human hnRNP A1, hnRNP D, hnRNP F, and TAP [18]. Residues that match the consensus of hPY-NLS [18] are shaded in orange and yellow. ϕ, hydrophobic side chain. Positions of the N-terminal-most residues are indicated. d Solution structure of the RRM domain of Fox-1/Fox-2 in complex with 5′-UGCAUGU-3′ in ribbon (protein backbone) and stick (RNA) representation. Right panel Image of left panel rotated by 90° as indicated. Important protein side chains and peptide bonds involved in hydrophobic or static interactions with the RNA are represented as sticks. Oxygen, nitrogen, hydrogen, and phosphorus atoms are in red, blue, light yellow, and magenta, respectively. Carbon atoms in the protein, the RNA backbone, and bases are in green, yellow, and gray, respectively. Hydrogen bonds are indicated as cyan dotted sticks. Hydrogen atoms in the RNA backbone are omitted except for one involved in a hydrogen bond. Illustrations were generated from a dataset deposited as ‘2err’ in PDBj database with MOLMOL [78]CC BY-NC · PubMed Central
Fig. 2 Schematic illustration of alternative splicing regulation by the Fox-1 family. a The Fox-1 family represses exon inclusion by binding to (U)GCAUG element(s) in the upstream intronic flanking (UIF) region. b The Fox-1 family enhances exon inclusion by binding to the (U)GCAUG element(s) in the downstream intronic flanking (DIF) region. Boxes indicate exons and horizontal lines indicate introns. Blue horizontal lines indicate the UIF and DIF regions. Orange boxes indicate (U)GCAUG elements. (U)GCAUG elements are frequently found in multiple copies, and increasing the number of UGCAUG elements exerted a stronger effect on the splicing regulation
Fig. 2 Schematic illustration of alternative splicing regulation by the Fox-1 family. a The Fox-1 family represses exon inclusion by binding to (U)GCAUG element(s) in the upstream intronic flanking (UIF) region. b The Fox-1 family enhances exon inclusion by binding to the (U)GCAUG element(s) in the downstream intronic flanking (DIF) region. Boxes indicate exons and horizontal lines indicate introns. Blue horizontal lines indicate the UIF and DIF regions. Orange boxes indicate (U)GCAUG elements. (U)GCAUG elements are frequently found in multiple copies, and increasing the number of UGCAUG elements exerted a stronger effect on the splicing regulationCC BY-NC · PubMed Central
Fig. 3 Schematic structure and major splicing patterns of the mouse Fox-1/A2bp1 and Fox-2/Rbm9 genes. Boxes indicate exons and horizontal lines indicate introns. Use of these exons is supported by cDNA and/or EST sequences in GenBank/EMBL/DDBJ databases, and the exons are designated after [19] for Fox-2/Rbm9 and human orthologs in [14]. Coding regions are coloured; RRM domains in orange, brain-specific region in green, muscle-specific region in magenta, other isoform-specific regions in blue, and common regions in yellow. The size of the exons is not proportional to that of the introns
Fig. 3 Schematic structure and major splicing patterns of the mouse Fox-1/A2bp1 and Fox-2/Rbm9 genes. Boxes indicate exons and horizontal lines indicate introns. Use of these exons is supported by cDNA and/or EST sequences in GenBank/EMBL/DDBJ databases, and the exons are designated after [19] for Fox-2/Rbm9 and human orthologs in [14]. Coding regions are coloured; RRM domains in orange, brain-specific region in green, muscle-specific region in magenta, other isoform-specific regions in blue, and common regions in yellow. The size of the exons is not proportional to that of the intronsCC BY-NC · PubMed Central
Fig. 4 A model for repression of prespliceosome complex formation by the Fox-1 family. The repression of calcitonin-specific exon 4 of calcitonin/CGRP pre-mRNA in neuronal cells by the Fox-1 family involves two distinct regulatory events. First, the −34 element in the UIF region prevents E′ complex formation through repressing SF1 binding to the branch point (B). Second, the +45 exonic element blocks transition to E complex via inhibiting U2AF65 binding to polypyrimidine tract (PY). This figure is modified from [49]
Fig. 4 A model for repression of prespliceosome complex formation by the Fox-1 family. The repression of calcitonin-specific exon 4 of calcitonin/CGRP pre-mRNA in neuronal cells by the Fox-1 family involves two distinct regulatory events. First, the −34 element in the UIF region prevents E′ complex formation through repressing SF1 binding to the branch point (B). Second, the +45 exonic element blocks transition to E complex via inhibiting U2AF65 binding to polypyrimidine tract (PY). This figure is modified from [49]CC BY-NC · PubMed Central
Fig. 5 Fox-1 family proteins ASD-1 and FOX-1 regulate tissue-specific mutually exclusive alternative splicing of the FGFR gene, egl-15, in C. elegans. a Tissue-specific mutually exclusive selection exons of the egl-15 gene of C. elegans. Note that muscle-specific exon 5A resides downstream of exon 5B. b Schematic illustration of muscle-specific repression of exon 5B. Nucleotide sequence of the UIF region is presented. The cis-elements for tissue-specific regulation are in orange. Fox, ASD-1 or FOX-1; SUP, SUP-12. (c,d) Left lateral view of adult hermaphrodite worms expressing egl-15 alternative splicing reporter in body wall muscles and vulval muscles in the wild-type (wt) background (c) and the asd-1; fox-1 double mutant background (d). Merged images of DIC and confocal images of GFP (green) and RFP (magenta). The egl-15 alternative splicing reporter worms express either RFP, representing exon 5A selection, or GFP, representing exon 5B selection, in body wall muscles and vulval muscles (see [16] for detail). Note that in the asd-1; fox-1 double mutant, vulval muscles (arrowheads) express GFP and are mislocalized off the vulva (Vul, arrows), and late embryos with reporter expression in body wall muscles retained in the uterus. Anterior is to the left. Scale bar in (c) 50 μm. (c,d) are modified from [16]
Fig. 5 Fox-1 family proteins ASD-1 and FOX-1 regulate tissue-specific mutually exclusive alternative splicing of the FGFR gene, egl-15, in C. elegans. a Tissue-specific mutually exclusive selection exons of the egl-15 gene of C. elegans. Note that muscle-specific exon 5A resides downstream of exon 5B. b Schematic illustration of muscle-specific repression of exon 5B. Nucleotide sequence of the UIF region is presented. The cis-elements for tissue-specific regulation are in orange. Fox, ASD-1 or FOX-1; SUP, SUP-12. (c,d) Left lateral view of adult hermaphrodite worms expressing egl-15 alternative splicing reporter in body wall muscles and vulval muscles in the wild-type (wt) background (c) and the asd-1; fox-1 double mutant background (d). Merged images of DIC and confocal images of GFP (green) and RFP (magenta). The egl-15 alternative splicing reporter worms express either RFP, representing exon 5A selection, or GFP, representing exon 5B selection, in body wall muscles and vulval muscles (see [16] for detail). Note that in the asd-1; fox-1 double mutant, vulval muscles (arrowheads) express GFP and are mislocalized off the vulva (Vul, arrows), and late embryos with reporter expression in body wall muscles retained in the uterus. Anterior is to the left. Scale bar in (c) 50 μm. (c,d) are modified from [16]CC BY-NC · PubMed Central

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Metadata

Authors
Kuroyanagi, H.
Affiliations
Tokyo Medical and Dental University (JP)
Corresponding author
Kuroyanagi, Hidehito
ORCID
Kuroyanagi, Hidehito
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2009-08-18
Volume
66
Issue
24
Pages
3895-3907
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-009-0120-5
PMC
PMC2777236
OpenAlex
W2057774013
Cited by
187
References
78
Citations by year
2026: 5 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 13 · 2021: 7 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 23 · 2015: 10 · 2014: 10 · 2013: 17 · 2012: 11
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Tokyo Medical and Dental University
  • 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, intronic splicing enhancer, muscle, heart, brain, splicing regulators, splicing regulatory network, vertebrate genomes
MeSH terms
RNA Splicing Factors, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Humans, Molecular Sequence Data, RNA-Binding Proteins, Spliceosomes, Sequence Homology, Amino Acid, Alternative Splicing

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