International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 46 - INVESTIGATION OF THE ROLES OF WILMS’ TUMOUR SUPRESSOR 1 (WT1) ISOFORMS, WT1+KTS AND WT1-KTS, IN MURINE UROGENITAL DEVELOPMENT

D Lahiri
University of Bath

Dutton JR, Ward A
University of Bath

The Wilms’ Tumour suppressor gene, WT1, encodes a zinc finger transcription factor that is essential for correct development of the urogenital system.  alternative splicing of the zinc finger region causes an insertion of deletion of three amino acids creating two classes of isoform, WT1+KTS and WT1-KTS.  Mutation of these isoforms, and disruption of the isoform ratios are linked to Denys Drash and Frasier syndromes in which abnormalities of the urogenital system occur.  These isoforms are thought to have distinct roles within the nucleus with WT1+KTS implicated in splicing, whilst WT1-KTS acts as a transcription factor.  We have generated mice overexpressing WT1-KTS by creating transgenic lines expressing a WT1-KTS transgene, and bred them with WT1 knockout animals to study the effects of the WT1-KTS isoform on genito-urinary development in isolation from the other isoforms.  Preliminary data shows that males expressing the WT1-KTS transgene and heterozygous for WT1 are sterile.  Using green fluorescent protein fusion constructs in cell culture, we demonstrate that the dynamic subnuclear localisation of the two isoforms result, in part, from the presence of a nucleolar localisation signal within the zinc finger regions.  Combining transgenic in vitro techniques with in vivo cell culture work, our findings help elucidate the mechanisms by which the WT1 isoforms are distributed in the nucleus, and suggest a model demonstrating how their separate functions are maintained.


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