Functional redundancy of the three ras genes which uses ras genes knock-out mice.

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In mammals, three ras genes, H-ras, N-ras and K-ras encode homologous but distinct 21-kDa Ras proteins. No clear evidence for the individual in vivo functions of each ras gene and functional redundancy of the three ras genes has yet been reported. We herein show the functional redundancy of the three ras genes, H-ras, N-ras and K-ras, by investigating the phenotypes of mice deficient in each of these genes, mice deficient in multiple ras genes and H-ras transgenic mice. H-ras-/- mice and N-ras-/- mice as well as a substantial proportion of H-ras-/- N-ras-/- mice that express only the K-ras gene are viable, while K-ras-/- mice have been previously shown to be embryonically lethal. An investigation of neonatal death of N-ras-/- K-ras+/- and H-ras-/- N-ras-/- mice has shown that a part of these mice died because of chylous ascites and intestinal lymphedema. Most ras mutant mice lacking 2 or more ras alleles exhibited a similar phenotype. The incidence of intestinal lymphedema increases as the number of null alleles of any three ras genes increase, which thus suggests that the function of three ras genes is redundant. To prove this hypothesis, we introduce the human H-ras transgenes into single and multiple ras mutant mice and found the H-ras transgenes to rescue all abnormalities exhibited in the development of these ras mutant mice. We therefore conclude that the function of the ras genes is redundant in vivo.