title: Alternative splicing of Wilms tumor suppressor 1 (Wt1) exon 4 results in protein isoforms with different functions.
abstract: The Wilms tumor suppressor gene Wt1 encodes a zinc finger transcription factor that is essential for development of multiple organs including kidneys, gonads, spleen and heart. In mammals Wt1 comprises 10 exons with two characteristic splicing events: inclusion or skipping of exon 5 and alternative usage of two splice donor sites between exons 9 and 10. Most fish including zebrafish and medaka possess two wt1 paralogs, wt1a and wt1b, both lacking exon 5. Here we have characterized wt1 in guppy, platyfish and the short-lived African killifish Nothobranchius furzeri. All fish except zebrafish show alternative splicing of exon 4 of wt1a but not of wt1b with the wt1a(-exon 4) isoform being the predominant splice variant. With regard to function, Wt1a(+exon 4) showed less dimerization but stimulated transcription more effectively than the Wt1a(-exon 4) isoform. A specific knockdown of wt1a exon 4 in zebrafish was associated with anomalies in kidney development demonstrating a physiological function for Wt1a exon 4. Interestingly, alternative splicing of exon 4 seems to be an early evolutionary event as it is observed in the single wt1 gene of the sturgeon, a species that has not gone through teleost-specific genome duplication.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Schnerwitzki
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Perner
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Hoppe
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pietsch
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mehringer
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Beutenbergstrasse 11a, 07745 Jena, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Hänel
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany; Friedrich Schiller University, Fürstengraben 1, 07743 Jena, Germany. Electronic address: cenglert@fli-leibniz.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D003532:Cyprinodontiformes / Q000196:embryology / Q000235:genetics; D005399:Fishes / Q000002:abnormalities* / Q000235:genetics; D023781:Fundulidae / Q000196:embryology / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D007668:Kidney / Q000002:abnormalities*; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000235:genetics; D009990:Oryzias / Q000196:embryology / Q000235:genetics; D011036:Poecilia / Q000196:embryology / Q000235:genetics; D060910:Pronephros / Q000002:abnormalities*; D020033:Protein Isoforms / Q000235:genetics; D055503:Protein Multimerization; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D020798:Two-Hybrid System Techniques; D025721:WT1 Proteins / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D060172:Morpholinos; D020033:Protein Isoforms; D025721:WT1 Proteins
keywords: Glomerulus; Kidney development; Morpholino; Pronephros; Transcription factor; Zebrafish