While K-ras Is Essential for MouseDevelopment, Expression of the K-ras 4A Splice VariantIsDispensable

Abstract

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-ras ^tmΔ4A/+ mice produced viable K-ras ^{tmΔ4A/tmΔ4A} offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras ^{tmΔ4A/tmΔ4A} mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola × 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.

ACKNOWLEDGMENTS

This study was supported by a Medical Research Council studentship and grants from the Cancer Research Campaign (CRC, now Cancer Research UK), the Melville Trust for the Care and Cure of Cancer, Action Research for the Crippled Child (new Action Medical Research), and the Row Fogo Charitable Trust.