Two Splice Variants of the Wilms' Tumor 1 Gene Have Distinct Functions during Sex Determination and Nephron Formation

• Published in: Cell Vol. 106; no. 3; pp. 319 - 329
• Main Authors: Hammes, Annette, Guo, Jian-Kan, Lutsch, Gudrun, Leheste, Joerg-Robert, Landrock, Danilo, Ziegler, Ulrike, Gubler, Marie-Claire, Schedl, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.08.2001
• Subjects: Active Transport, Cell Nucleus; Alternative Splicing - genetics; Animals; Animals, Newborn; Apoptosis; Base Sequence; Cell Survival; DAX-1 Orphan Nuclear Receptor; Disorders of Sex Development; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Exons - genetics; Female; Genes, Wilms Tumor - genetics; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - metabolism; Gonads - abnormalities; Gonads - embryology; Gonads - metabolism; Gonads - pathology; Male; Mice; Mutagenesis - genetics; Nephrons - abnormalities; Nephrons - embryology; Nephrons - metabolism; Nephrons - ultrastructure; Nuclear Proteins; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Retinoic Acid - genetics; Repressor Proteins; RNA Splice Sites - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex Determination Processes; Sex-Determining Region Y Protein; Syndrome; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Wilms' tumor; Wt1 gene; WT1 Proteins
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(01)00453-6

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.