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Molecular and Cellular Biology, March 2001, p. 1444-1452, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1444-1452.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development

Luis M. Esteban,1,2 Carlos Vicario-Abejón,3 Pedro Fernández-Salguero,4 Alberto Fernández-Medarde,1,2 Nalini Swaminathan,1 Kate Yienger,2 Eva Lopez,2 Marcos Malumbres,5 Ron McKay,3 Jerrold M. Ward,6 Angel Pellicer,5 and Eugenio Santos1,2,*

Centro de Investigación del Cáncer, IBMCC, CSIC-USAL, University of Salamanca, Salamanca,1 and Departamento Bioquímica y Biología Molecular, Universidad de Extremadura, Badajoz,4 Spain; Laboratory of Cellular and Molecular Biology, National Cancer Institute,2 and Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke,3 Bethesda, and Veterinary and Tumor Pathology Section, National Cancer Institute, Frederick,6 Maryland; and Department of Pathology and Kaplan Cancer Center, New York University Medical Center, New York, New York5

Received 20 June 2000/Returned for modification 5 September 2000/Accepted 16 October 2000

Mammalian cells harbor three highly homologous and widely expressed members of the ras family (H-ras, N-ras, and K-ras), but it remains unclear whether they play specific or overlapping cellular roles. To gain insight into such functional roles, here we generated and analyzed H-ras null mutant mice, which were then also bred with N-ras knockout animals to ascertain the viability and properties of potential double null mutations in both loci. Mating among heterozygous H-ras+/- mice produced H-ras-/- offspring with a normal Mendelian pattern of inheritance, indicating that the loss of H-ras did not interfere with embryonic and fetal viability in the uterus. Homozygous mutant H-ras-/- mice reached sexual maturity at the same age as their littermates, and both males and females were fertile. Characterization of lymphocyte subsets in the spleen and thymus showed no significant differences between wild-type and H-ras-/- mice. Analysis of neuronal markers in the brains of knockout and wild-type H-ras mice showed that disruption of this locus did not impair or alter neuronal development. Breeding between our H-ras mutant animals and previously available N-ras null mutants gave rise to viable double knockout (H-ras-/-/N-ras-/-) offspring expressing only K-ras genes which grew normally, were fertile, and did not show any obvious phenotype. Interestingly, however, lower-than-expected numbers of adult, double knockout animals were consistently obtained in Mendelian crosses between heterozygous N-ras/H-ras mice. Our results indicate that, as for N-ras, H-ras gene function is dispensable for normal mouse development, growth, fertility, and neuronal development. Additionally, of the three ras genes, K-ras appears to be not only essential but also sufficient for normal mouse development.

* Corresponding author. Mailing address: Centro de Investigación del Cáncer, CSIC-USAL, Campus Unamuno, Univ. of Salamanca, 37007 Salamanca, Spain. Phone: 34 923 294720. Fax: 34 923 294743. E-mail: cicancer{at}usal.es.

Molecular and Cellular Biology, March 2001, p. 1444-1452, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1444-1452.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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