Cell
Volume 106, Issue 3, 10 August 2001, Pages 319-329
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Article
Two Splice Variants of the Wilms' Tumor 1 Gene Have Distinct Functions during Sex Determination and Nephron Formation

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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.

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Present address and author for correspondence: School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom, NE1 7RU, e-mail: [email protected]