Partial functional overlap of the three ras genes in mouse embryonic development

In mammals, three ras genes, H-ras, N-ras and K-ras, encode homologous but distinct 21-kDa Ras proteins. We examined the in vivo functional relationship of the three ras genes in mouse embryonic development by investigating the phenotypes of mice deficient in one or multiple ras genes. H-ras−/− mice and N-ras−/− mice as well as a substantial proportion of H-ras−/−/N-ras−/− mice expressing only the K-ras gene were viable, while K-ras−/− mice were embryonically lethal, as have been reported previously. N-ras−/−/K-ras+/− mice died neonatally, while H-ras−/−/K-ras−/− embryos died much earlier than K-ras homozygous mutant fetuses. To further investigate the functional relationship of the ras genes in embryonic development, we introduced a human H-ras transgene into single or multiple ras mutant mice and found that the transgene rescued mice, including triple ras mutants, from embryonic lethality in association with correction of thin ventricular walls of the heart in null K-ras mutant mice. In situ hybridization revealed that the expression of the H-ras transgene on embryonic day E13.5 and E15.5 was more intense in major organs, including the heart, than those of endogenous ras genes. We therefore conclude that the functions of the ras genes are partially overlapping in mouse embryonic development.