Replacement of K‐Ras with H‐Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice

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Abstract
Ras proteins are highly related GTPases that have key roles in regulating growth, differentiation and tumorigenesis. Gene‐targeting experiments have shown that, out of the three mammalian ras genes, only K‐ ras is essential for normal mouse embryogenesis, and that mice deprived of H‐ ras and/or N‐ ras show no major phenotype. We generated mice (HrasKI) in which the K‐ ras gene had been modified to encode H‐Ras protein. HrasKI mice produce undetectable amounts of K‐Ras but—in contrast to mice homozygous for a null K‐ ras allele—they are born at the expected mendelian frequency, indicating that H‐Ras can be substituted for K‐Ras in embryonic development. However, adult HrasKI mice show dilated cardiomyopathy associated with arterial hypertension. Our results show that K‐Ras can be replaced by H‐Ras in its essential function in embryogenesis, and indicate that K‐Ras has a unique role in cardiovascular homeostasis.