CELF Family RNA–Binding Protein UNC-75 Regulates Two Sets of Mutually Exclusive Exons of the unc-32 Gene in Neuron-Specific Manners in Caenorhabditis elegans
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{"title"=>"CELF Family RNA-Binding Protein UNC-75 Regulates Two Sets of Mutually Exclusive Exons of the unc-32 Gene in Neuron-Specific Manners in Caenorhabditis elegans", "type"=>"journal", "authors"=>[{"first_name"=>"Hidehito", "last_name"=>"Kuroyanagi", "scopus_author_id"=>"6701813890"}, {"first_name"=>"Yohei", "last_name"=>"Watanabe", "scopus_author_id"=>"55618115100"}, {"first_name"=>"Masatoshi", "last_name"=>"Hagiwara", "scopus_author_id"=>"24388271500"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84874778011", "issn"=>"15537390", "pui"=>"368490548", "sgr"=>"84874778011", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"23468662", "doi"=>"10.1371/journal.pgen.1003337"}, "id"=>"7242ce0a-0b30-3130-8e1f-361bbf9f48e9", "abstract"=>"Tissue-specific and mutually exclusive alternative pre–mRNA splicing is a challenging model for elucidating regulation mechanisms. We previously demonstrated that evolutionarily conserved RBFOX family RNA–binding proteins ASD-1 and FOX-1 and a muscle-specific RNA–binding protein SUP-12 cooperatively direct muscle-specific selection of exon 5B of the C. elegans egl-15 gene. Here we demonstrate that two sets of mutually exclusive exons, 4a–4c and 7a–7b, of the unc-32 gene are regulated in tissue-specific manners and that ASD-1 and FOX-1, expressed in a variety of tissues, can regulate the neuron-specific selection of unc-32 exon 7a in combination with the neuron-specific CELF family RNA–binding protein UNC-75. We determine the cis-elements for the RBFOX family and UNC-75, which separately reside in intron 7b and intron 7a, respectively. By analyzing the partially spliced RNA species, we propose the orders of intron removal and the sites of action for the RBFOX family and UNC-75 in the mutually exclusive selection of exon 7a and exon 7b. We also demonstrate that UNC-75 regulates the neuron-specific selection of exon 4b and propose the models of the mutually exclusive selection of exons 4a, 4b, and 4c. These studies thus provide novel modes of regulation for tissue-specific and mutually exclusive alternative splicing in vivo.", "link"=>"http://www.mendeley.com/research/celf-family-rnabinding-protein-unc75-regulates-two-sets-mutually-exclusive-exons-unc32-gene-neuronsp", "reader_count"=>30, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>10, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>10, "Other"=>2, "Student > Master"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>17, "Medicine and Dentistry"=>2, "Neuroscience"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>2}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/974208"], "description"=>"<p>(<i>A</i>) Schematic structure of the <i>unc-32</i> gene. Numbered boxes indicate exons. The position of the 3′-splice site mutation in the <i>unc-32 (e189)</i> allele is indicated. Black triangles indicate positions and directions of the exonic primers used in the RT-PCR analyses shown in (<i>B</i>). (<i>B</i>) RT-PCR analyses of <i>unc-32</i> exon 4 (left) and exon 7 (right) at the L1 and L4 larval stages. (<i>C</i>, <i>D</i>) Schematic illustration of the symmetric trio of the exon 4 reporter minigenes (<i>C</i>) and the symmetric pair of the exon 7 reporter minigenes (<i>D</i>) and the mRNA isoforms derived from them. The cDNA cassettes and the predicted ORFs for Venus/EGFP, mRFP and ECFP are colored in green, magenta and cyan, respectively. Green circles and red diamonds indicate the artificially-introduced initiation and termination codons, respectively. (<i>E</i>) Fluorescence images of an L4 larva of the exon 4 reporter worm <i>ybIs1891 [eft-3::unc-32E4a-Venus eft-3::unc-32E4b-mRFP eft-3::unc-32E4c-ECFP]</i>. E4a-Venus, E4b-mRFP and E4c-ECFP images in black-white and a merged image with pseudo colors. (<i>F</i>, <i>G</i>) Confocal images of the exon 7 reporter worms <i>ybEx1440 [eft-3::unc-32E7-EGFP eft-3::unc-32E7b-mRFP]</i>. (<i>H</i>) A fluorescence image of the <i>unc-32</i> transcriptional fusion reporter worm <i>ybEx1896 [unc-32::EGFP]</i> containing 1.7-kb of the <i>unc-32</i> promoter. int, intestine; N, neurons in head ganglia; phx, pharynx. Scale bars in (<i>E</i>), (<i>F</i>) and (<i>H</i>), 100 µm; in (<i>G</i>), 20 µm.</p>", "links"=>[], "tags"=>["mutually", "exons", "regulated", "tissue-specific"], "article_id"=>642324, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_mutually_exclusive_exons_of_the_unc_32_gene_are_regulated_in_tissue_specific_manners_/642324", "title"=>"The mutually exclusive exons of the <i>unc-32</i> gene are regulated in tissue-specific manners.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:19:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/974212"], "description"=>"<p>(<i>A</i>) Fluorescence images of the exon 7 reporter worms <i>ybIs1622 [rgef-1::unc-32E7a-EGFP rgef-1::unc-32E7b-mRFP]</i> with dual-bandpass (Dual), green (GFP2) and red (DSR) filters and a bright field image (BF). Note that individual neurons differentially express E7a-EGFP and E7b-mRFP in a cell-type-specific pattern. (<i>B</i>) Nucleotide sequence alignment of intron 7b from <i>C. briggsae</i>, <i>C. elegans</i> and <i>C. remanei</i>. Residues shaded in black and gray are conserved among three and two species, respectively. Conserved stretches are boxed in red and the sequences of the <i>M1</i> and <i>M2</i> mutant pairs of the reporter minigenes are indicated. (<i>C</i>) Schematic illustrations of the mutated pairs of the exon 7 reporter minigenes. Red arrows indicate the positions of the modification. (<i>D</i>) A fluorescence image of the <i>M1</i> mutant reporter worms with a dual-bandpass filter. (<i>E</i>) Fluorescence images of the <i>ybIs1622</i> worms in the <i>asd-1 (yb978)</i> (top), <i>fox-1 (e2643)</i> (middle) and <i>asd-1; fox-1</i> (bottom) backgrounds with a dual-bandpass filter. Scale bars, 200 µm in (<i>A</i>), (<i>D</i>) and (<i>E</i>). (<i>F</i>) Top, radiolabelled wild-type (WT) and mutant (Mut) intron 7b probes. The substituted bases are underlined. Lowercase indicates the sequence derived from the T7 promoter. Bottom left, Neutral PAGE and CBB staining of the recombinant FLAG-tagged ASD-1 and FOX-1 proteins. Bottom right, EMSA using the WT and Mut probes without (−) or with 4-fold dilution series of FLAG-ASD-1 and -FOX-1.</p>", "links"=>[], "tags"=>["ugcaug", "rbfox", "proteins", "neuron-specific", "exon", "7a"], "article_id"=>642328, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_UGCAUG_stretch_and_the_RBFOX_family_proteins_are_involved_in_the_neuron_specific_selection_of_exon_7a_from_the_unc_32_exon_7_reporter_/642328", "title"=>"The UGCAUG stretch and the RBFOX family proteins are involved in the neuron-specific selection of exon 7a from the <i>unc-32</i> exon 7 reporter.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:20:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/974217"], "description"=>"<p>(<i>A</i>) Fluorescence images of the <i>ybIs1622</i> worms with the <i>unc-75</i> mutant alleles <i>yb1700</i>, <i>yb1725</i>, <i>yb1714</i> and <i>yb1701</i> with a dual-bandpass filter. Scale bar, 200 µm. (<i>B</i>) Schematic structure of the <i>unc-75</i> gene and the positions and consequence of the mutations. The ORF is colored in yellow and the regions corresponding to the three RRMs are in orange. The allele names are in the colors representing the color phenotypes. SA, splice acceptor; SD, splice donor. (<i>C</i>) Amino acid sequence alignments of the three RRMs from the CELF3–6 subfamily members <i>C. elegans</i> UNC-75, human CELF3, CELF4, CELF5 and CELF6 and the CELF1–2 subfamily members <i>C. elegans</i> ETR-1, human CELF1 and CELF2. Conserved residues are shaded in black. Residues with similar properties to the consensus are shaded in gray. The secondary structure elements determined for human CELF1 <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#pgen.1003337-Tsuda1\" target=\"_blank\">[51]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#pgen.1003337-Teplova1\" target=\"_blank\">[52]</a> are depicted with the blue rectangles (β-sheets) and the red ellipses (α-helices) below the alignments. The highly conserved RNP1 and RNP2 motifs in each RRM are boxed in magenta. The positions of the missense mutations and the short deletion are indicated with the allele names. Note that <i>yb1725</i> generated a cryptic splice donor site almost exclusively used in the mutant, which resulted in the in-frame deletion of the 4-amino acid stretch indicated. (<i>D</i>) RT-PCR analysis of the UNC-75 mRNAs from the synchronized L1 larvae of N2 (<i>wt</i>), <i>asd-1 (yb978); fox-1 (e2643)</i> and <i>unc-75 (yb1701)</i>.</p>", "links"=>[], "tags"=>["exon", "7a"], "article_id"=>642333, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_UNC_75_is_required_for_the_selection_exon_7a_from_the_unc_32_exon_7_reporter_in_the_nervous_system_/642333", "title"=>"UNC-75 is required for the selection exon 7a from the <i>unc-32</i> exon 7 reporter in the nervous system.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:21:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/974221"], "description"=>"<p>(<i>A</i>) Amino acid sequence alignment of the C-terminal ends of the CELF family proteins and the putative PY-NLSs from the related proteins <i>C. elegans</i> EXC-7, HRPF-1, human hnRNP F, hnRNP H1 and hnRNP H2 (left), human hnRNP A1, hnRNP D and TAP and the C-terminal ends of the RBFOX family proteins human RBFOX1, RBFOX2, mouse RBFOX3, <i>Drosophila</i> A2bp1, <i>C. elegans</i> ASD-1 and FOX-1 (right). The consensus sequences of the PY-NLS are indicated. The amino acid residues that match the consensus are shaded in yellow or orange. φ, hydrophobic residues. The underlines in the UNC-75 sequence indicate residues substituted with alanine in UNC-75(AAA) used in (<i>C</i>). The underlines in the ASD-1 and FOX-1 sequences indicate residues deleted in the truncated constructs used in (<i>E</i>) and (<i>G</i>), respectively. (<i>B</i>, <i>C</i>) Fluorescence images of the HeLa cells transfected with full-length UNC-75 (<i>B</i>) and UNC-75(AAA) (<i>C</i>) stained with anti-UNC-75 (left panels) and Hoechst 33258 (right panels). (<i>D</i>–<i>G</i>) Confocal images of the HeLa cells transfected with HA-tagged full-length ASD-1 (<i>D</i>), ASD-1(1–388) (<i>E</i>), full-length FOX-1 (<i>F</i>) and FOX-1(1–408) (<i>G</i>) stained with anti-ASD-1 (<i>D</i> and <i>E</i>, left panels) or anti-FOX-1 (<i>F</i> and <i>G</i>, left panels) and TO-PRO3 (right panels). Scale bar, 50 µm.</p>", "links"=>[], "tags"=>["c-termini", "fox-1", "evolutionarily", "conserved", "localization"], "article_id"=>642337, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_C_termini_of_UNC_75_ASD_1_and_FOX_1_are_the_evolutionarily_conserved_nuclear_localization_signals_/642337", "title"=>"The C-termini of UNC-75, ASD-1, and FOX-1 are the evolutionarily conserved nuclear localization signals.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:22:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/974231"], "description"=>"<p>(<i>A</i>) Top, schematic illustration of the radiolabelled RNA probes 1 to 4, 2-1 to -4 and 2-1-1 used in the EMSAs. Bottom, sequences of Probe 2-1-1 and its mutants 2-1-1a to -1e. The modified stretches are underlined and the mutant sequences are indicated. Lowercase indicates the sequence derived from the T7 promoter. (<i>B</i>) Left, EMSA using the probes 1 to 4 without (−) or with (+) FLAG-tagged recombinant UNC-75 (FLAG-UNC-75). Right, EMSA using the probes 2-1 to 2-4 without (−) or with 2-fold dilution series of FLAG-UNC-75. (<i>C</i>) EMSAs using Probe 2-1-1 and its mutants shown in (<i>A</i>) without (−) or with 4-fold dilution series of FLAG-UNC-75.</p>", "links"=>[], "tags"=>["binds", "intron", "7a"], "article_id"=>642345, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_UNC_75_directly_and_specifically_binds_to_a_short_fragment_in_unc_32_intron_7a_in_vitro_/642345", "title"=>"UNC-75 directly and specifically binds to a short fragment in <i>unc-32</i> intron 7a <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:23:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/974236"], "description"=>"<p>(<i>A</i>) Left, neutral PAGE and CBB staining of the recombinant FLAG-tagged wild-type (WT) UNC-75 protein and the mutant proteins UNC-75(G53S), UNC-75(G165E) and UNC-75(L431F). Right, EMSA using Probe 2-1-1 without or with 2-fold dilution series of the wild-type and mutant UNC-75 proteins. (<i>B</i>) Left, CBB staining of the recombinant FLAG-tagged full-length UNC-75 protein (WT; lane 1) and UNC-75(1–114) (RRM1; lane 2), UNC-75(121–213) (RRM2; lane 3) and UNC-75(417–514) (RRM3; lane 4) proteins. Right, EMSA using Probe 2-1-1 and 2-fold dilution series of the three UNC-75 RRM proteins and the full-length protein. (<i>C</i>) EMSA using Probe 2-2-1 (lanes 1–3) and five mutant probes (lanes 4–18) without (−) or with 2-fold dilution series of UNC-75 (417–514) protein. (<i>D</i>) Fluorescence images of the wild-type (<i>ybIs1622</i>; top) and <i>M6</i> mutant (bottom) of the exon 7 reporter worms with a dual-bandpass filter. Scale bar, 200 µm.</p>", "links"=>[], "tags"=>["unc-75", "mediates", "binding", "uuguuguguugu", "intron"], "article_id"=>642350, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RRM3_of_UNC_75_mediates_specific_binding_to_the_UUGUUGUGUUGU_stretch_in_unc_32_intron_7a_/642350", "title"=>"RRM3 of UNC-75 mediates specific binding to the UUGUUGUGUUGU stretch in <i>unc-32</i> intron 7a.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:24:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/974242"], "description"=>"<p>(<i>A</i>) RT-PCR analysis of the mature mRNAs from the endogenous <i>unc-32</i> gene (left) and the exon 7 reporter transgene <i>ybIs1622</i> (right) in the wild-type (lane 1), <i>asd-1 (yb978); fox-1 (e2643)</i> double (lane 2) and <i>unc-75 (yb1725)</i> (lane 3) backgrounds. Note that the isoform with double inclusion or double skipping of exons 7a and 7b was not detected. (<i>B</i>) RT-PCR analyses of the partially spliced RNAs from <i>ybIs1622</i> in the wild-type, <i>asd-1; fox-1</i> and <i>unc-75</i> backgrounds. The schematic structures of the RT-PCR products are indicated on the right. Black and blue arrowheads indicate the positions and directions of the exonic and the intronic primers, respectively. RTase, reverse transcriptase. (<i>C</i>) Averages of the relative amounts of the partially spliced RNAs to the pre-mRNA. Error bars indicate S.E.M. (n = 3). *p<0.005 and **p<0.001, Student's t-test. (<i>D</i>) Schematic models of the mutually exclusive selection of <i>unc-32</i> exons 7a and 7b. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#s3\" target=\"_blank\">Discussion</a> for detail.</p>", "links"=>[], "tags"=>["rbfox", "unc-75", "differentially", "intron", "excision"], "article_id"=>642354, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_RBFOX_family_and_UNC_75_differentially_regulate_the_intron_excision_from_the_unc_32_pre_mRNA_/642354", "title"=>"The RBFOX family and UNC-75 differentially regulate the intron excision from the <i>unc-32</i> pre-mRNA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:24:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/974249"], "description"=>"<p>(<i>A</i>) RT-PCR analysis of endogenous <i>unc-32</i> exon 4 in the synchronized L1 worms of N2 (<i>wt</i>; lane 1), <i>asd-1 (yb978); fox-1 (e2643)</i> (lane 2) and <i>unc-75 (yb1701)</i> (lane 3). (<i>B</i>) Fluorescence images of an L4 worm of the <i>ybIs1891</i> reporter allele in the <i>unc-75 (yb1701)</i> background as in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#pgen-1003337-g001\" target=\"_blank\">Figure 1F</a>. Scale bar, 100 µm. (<i>C</i>) RT-PCR analyses of the partially spliced RNAs from the endogenous <i>unc-32</i> gene in N2 and <i>unc-75 (yb1701)</i> as in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#pgen-1003337-g007\" target=\"_blank\">Figure 7B</a>. (<i>D</i>) Relative amounts of the six partially spliced RNAs normalized to the pre-mRNA analyzed in (<i>C</i>). (<i>E</i>) Schematic illustration of the neuron-specific selection of exon 4b by UNC-75. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003337#s3\" target=\"_blank\">Discussion</a> for detail. (<i>F</i>) Microphotoimages of the <i>unc-32 (e189)</i> (left) and the <i>unc-75 (yb1725); unc-32 (e189)</i> (right) worm. Scale bar, 200 µm. Note that the <i>unc-32</i> worm exhibits the coiler Unc phenotype.</p>", "links"=>[], "tags"=>["regulates", "neuron-specific", "exon"], "article_id"=>642358, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_UNC_75_regulates_the_neuron_specific_selection_of_unc_32_exon_4b_/642358", "title"=>"UNC-75 regulates the neuron-specific selection of <i>unc-32</i> exon 4b.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-01 13:25:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/974253", "https://ndownloader.figshare.com/files/974257", "https://ndownloader.figshare.com/files/974261", "https://ndownloader.figshare.com/files/974267", "https://ndownloader.figshare.com/files/974272", "https://ndownloader.figshare.com/files/974278", "https://ndownloader.figshare.com/files/974281", "https://ndownloader.figshare.com/files/974291", "https://ndownloader.figshare.com/files/974293", "https://ndownloader.figshare.com/files/974294", "https://ndownloader.figshare.com/files/974298", "https://ndownloader.figshare.com/files/974301"], "description"=>"<div><p>An enormous number of alternative pre–mRNA splicing patterns in multicellular organisms are coordinately defined by a limited number of regulatory proteins and <i>cis</i> elements. Mutually exclusive alternative splicing should be strictly regulated and is a challenging model for elucidating regulation mechanisms. Here we provide models of the regulation of two sets of mutually exclusive exons, 4a–4c and 7a–7b, of the <i>Caenorhabditis elegans uncoordinated (unc)-32</i> gene, encoding the <i>a</i> subunit of V<sub>0</sub> complex of vacuolar-type H<sup>+</sup>-ATPases. We visualize selection patterns of exon 4 and exon 7 <i>in vivo</i> by utilizing a trio and a pair of symmetric fluorescence splicing reporter minigenes, respectively, to demonstrate that they are regulated in tissue-specific manners. Genetic analyses reveal that RBFOX family RNA–binding proteins ASD-1 and FOX-1 and a UGCAUG stretch in intron 7b are involved in the neuron-specific selection of exon 7a. Through further forward genetic screening, we identify UNC-75, a neuron-specific CELF family RNA–binding protein of unknown function, as an essential regulator for the exon 7a selection. Electrophoretic mobility shift assays specify a short fragment in intron 7a as the recognition site for UNC-75 and demonstrate that UNC-75 specifically binds via its three RNA recognition motifs to the element including a UUGUUGUGUUGU stretch. The UUGUUGUGUUGU stretch in the reporter minigenes is actually required for the selection of exon 7a in the nervous system. We compare the amounts of partially spliced RNAs in the wild-type and <i>unc-75</i> mutant backgrounds and raise a model for the mutually exclusive selection of <i>unc-32</i> exon 7 by the RBFOX family and UNC-75. The neuron-specific selection of <i>unc-32</i> exon 4b is also regulated by UNC-75 and the <i>unc-75</i> mutation suppresses the Unc phenotype of the exon-4b-specific allele of <i>unc-32</i> mutants. Taken together, UNC-75 is the neuron-specific splicing factor and regulates both sets of the mutually exclusive exons of the <i>unc-32</i> gene.</p> </div>", "links"=>[], "tags"=>["celf", "unc-75", "regulates", "sets", "mutually", "exons", "neuron-specific", "manners"], "article_id"=>642362, "categories"=>["Molecular Biology", "Neuroscience", "Genetics"], "users"=>["Hidehito Kuroyanagi", "Yohei Watanabe", "Masatoshi Hagiwara"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003337.s001", "https://dx.doi.org/10.1371/journal.pgen.1003337.s002", "https://dx.doi.org/10.1371/journal.pgen.1003337.s003", "https://dx.doi.org/10.1371/journal.pgen.1003337.s004", "https://dx.doi.org/10.1371/journal.pgen.1003337.s005", "https://dx.doi.org/10.1371/journal.pgen.1003337.s006", "https://dx.doi.org/10.1371/journal.pgen.1003337.s007", "https://dx.doi.org/10.1371/journal.pgen.1003337.s008", "https://dx.doi.org/10.1371/journal.pgen.1003337.s009", "https://dx.doi.org/10.1371/journal.pgen.1003337.s010", "https://dx.doi.org/10.1371/journal.pgen.1003337.s011", "https://dx.doi.org/10.1371/journal.pgen.1003337.s012"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CELF_Family_RNA_Binding_Protein_UNC_75_Regulates_Two_Sets_of_Mutually_Exclusive_Exons_of_the_unc_32_Gene_in_Neuron_Specific_Manners_in_Caenorhabditis_elegans__/642362", "title"=>"CELF Family RNA–Binding Protein UNC-75 Regulates Two Sets of Mutually Exclusive Exons of the <em>unc-32</em> Gene in Neuron-Specific Manners in <em>Caenorhabditis elegans</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-03-01 13:26:22"}

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Relative Metric

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