title: Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation.
abstract: Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.
authors.affiliation: MDC for Molecular Medicine, Developmental Genetics, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hammes
authors.forename: J K
authors.initials: JK
authors.lastname: Guo
authors.forename: G
authors.initials: G
authors.lastname: Lutsch
authors.forename: J R
authors.initials: JR
authors.lastname: Leheste
authors.forename: D
authors.initials: D
authors.lastname: Landrock
authors.forename: U
authors.initials: U
authors.lastname: Ziegler
authors.forename: M C
authors.initials: MC
authors.lastname: Gubler
authors.forename: A
authors.initials: A
authors.lastname: Schedl
mesh_terms: D021581:Active Transport, Cell Nucleus; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001483:Base Sequence; D002470:Cell Survival; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012734:Disorders of Sex Development; D005091:Exons / Q000235:genetics; D005260:Female; D016162:Genes, Wilms Tumor / Q000235:genetics*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism; D006066:Gonads / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000235:genetics; D009399:Nephrons / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012097:Repressor Proteins; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein; D013577:Syndrome; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D025721:WT1 Proteins
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539966:Nr0b1 protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D014157:Transcription Factors; D025721:WT1 Proteins