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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Alternative Splicing / genetics*
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Animals
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Animals, Newborn
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Apoptosis
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Base Sequence
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Cell Survival
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DAX-1 Orphan Nuclear Receptor
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Disorders of Sex Development
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Exons / genetics
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Female
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Genes, Wilms Tumor / genetics*
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Glomerulosclerosis, Focal Segmental / genetics
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Glomerulosclerosis, Focal Segmental / metabolism
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Gonads / abnormalities
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Gonads / embryology
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Gonads / metabolism
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Gonads / pathology
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Male
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Mice
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Mutagenesis / genetics
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Nephrons / abnormalities
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Nephrons / embryology*
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Nephrons / metabolism
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Nephrons / ultrastructure
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Nuclear Proteins*
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA Splice Sites / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Retinoic Acid / genetics
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Repressor Proteins*
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Sex Determination Processes*
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Sex-Determining Region Y Protein
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Syndrome
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Transcription Factors / chemistry
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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WT1 Proteins
Substances
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DAX-1 Orphan Nuclear Receptor
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DNA-Binding Proteins
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Nr0b1 protein, mouse
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Nuclear Proteins
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Protein Isoforms
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RNA Splice Sites
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RNA, Messenger
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Receptors, Retinoic Acid
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Repressor Proteins
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Sex-Determining Region Y Protein
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Sry protein, mouse
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Transcription Factors
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WT1 Proteins