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Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation

Official URL:https://doi.org/10.1016/S0092-8674(01)00453-6
PubMed:View item in PubMed
Creators Name:Hammes, A. and Guo, J.K. and Lutsch, G. and Leheste, J.R. and Landrock, D. and Ziegler, U. and Gubler, M.C. and Schedl, A.
Journal Title:Cell
Journal Abbreviation:Cell
Page Range:319-329
Date:10 August 2001
Keywords:Cell Nucleus Active Transport, Alternative Splicing, Apoptosis, Cell Survival, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Exons, Wilms Tumor Genes, Focal Segmental Glomerulosclerosis, Gonads, Mutagenesis, Nephrons, Nuclear Proteins, Protein Isoforms, RNA Splice Sites, Messenger RNA, Retinoic Acid Receptors, Repressor Proteins, Sex Determination (Genetics), Gonadal Sex Reversal, Sex-Determining Region Y Protein, Syndrome, Transcription Factors, WT1 Proteins, Animals, Mice
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.
Publisher:Cell Press (U.S.A.)
Item Type:Article

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