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Molecular and Cellular Biology, April 2003, p. 2608-2613, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2608-2613.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mice Lacking the 68-Amino-Acid, Mammal-Specific N-Terminal Extension of WT1 Develop Normally and Are Fertile

Colin G. Miles,¹ Joan Slight,¹ Lee Spraggon,¹ Maureen O'Sullivan,² Charles Patek,³ and Nicholas D. Hastie^1*

Medical Research Council Human Genetics Unit, Western General Hospital,¹ Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU,³ University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom²

Received 4 October 2002/ Returned for modification 18 November 2002/ Accepted 14 January 2003

Mutations in the Wilms' tumor 1 gene, WT1, cause pediatric nephroblastoma and the severe genitourinary disorders of Frasier and Denys-Drash syndromes. High levels of WT1 expression are found in the developing kidney, uterus, and testis—consistent with this finding, the WT1 knockout mouse demonstrates that WT1 is essential for normal genitourinary development. The WT1 gene encodes multiple isoforms of a zinc finger-containing protein by a combination of alternative splicing and alternative translation initiation. The use of an upstream, alternative CUG translation initiation codon specific to mammals results in the production of WT1 protein isoforms with a 68-amino-acid N-terminal extension. To determine the function in vivo of mammal-specific WT1 isoforms containing this extension, gene targeting was employed to introduce a subtle mutation into the WT1 gene. Homozygous mutant mice show a specific absence of the CUG-initiated WT1 isoforms yet develop normally to adulthood and are fertile. Detailed histological analysis revealed normal development of the genitourinary system.

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* Corresponding author. Mailing address: MRC Human Genetics Unit, Western General Hospital, Crewe Rd., Edinburgh EH4 2XU, United Kingdom. Phone: 44(0)131-332-2471. Fax: 44(0)131-467-8456. E-mail: Nick.Hastie{at}hgu.mrc.ac.uk.

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Molecular and Cellular Biology, April 2003, p. 2608-2613, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2608-2613.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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