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Molecular and Cellular Biology, December 2003, p. 9245-9250, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9245-9250.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

While K-ras Is Essential for Mouse Development, Expression of the K-ras 4A Splice Variant Is Dispensable

Sarah J. Plowman,1 D. James Williamson,2,{dagger} Maureen J. O'Sullivan,2 Jennifer Doig,1 Ann-Marie Ritchie,1 David J. Harrison,2 David W. Melton,1 Mark J. Arends,3 Martin L. Hooper,1 and Charles E. Patek1*

Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU,1 Division of Pathology, University of Edinburgh Medical School, Edinburgh EH8 9AG,2 Department of Pathology, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom3

Received 30 June 2003/ Returned for modification 22 August 2003/ Accepted 18 September 2003

In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-rastm{Delta}4A/+ mice produced viable K-rastm{Delta}4A/tm{Delta}4A offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-rastm{Delta}4A/tm{Delta}4A mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.

* Corresponding author. Mailing address: Sir Alastair Currie Cancer Research United Kingdom Laboratories, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom. Phone: 44(0)131-651-1080. Fax: 44(0)131-651-1072. E-mail: charles.patek{at}ed.ac.uk.

{dagger} Present address: Department of General Medicine, Sir Charles Gairdner Hospital, Nedlands, Perth 6009, Western Australia, Australia.

Molecular and Cellular Biology, December 2003, p. 9245-9250, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9245-9250.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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