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

doi:10.1128/MCB.21.5.1444-1452.2001

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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), butit remains unclear whether they play specific or overlapping cellularroles. To gain insight into such functional roles, here we generatedand analyzed H-ras null mutant mice, which were then also bredwith N-ras knockout animals to ascertain the viability and propertiesof potential double null mutations in both loci. Mating amongheterozygous H-ras^+/ mice produced H-ras^/ offspring with a normal Mendelian pattern of inheritance, indicatingthat the loss of H-ras did not interfere with embryonic and fetalviability 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 lymphocytesubsets in the spleen and thymus showed no significant differencesbetween wild-type and H-ras^/ mice. Analysis of neuronal markers in the brains of knockoutand wild-type H-ras mice showed that disruption of this locusdid not impair or alter neuronal development. Breeding betweenour H-ras mutant animals and previously available N-ras null mutantsgave rise to viable double knockout (H-ras^//N-ras^/) offspring expressing only K-ras genes which grew normally, werefertile, and did not show any obvious phenotype. Interestingly,however, lower-than-expected numbers of adult, double knockoutanimals were consistently obtained in Mendelian crosses betweenheterozygous N-ras/H-ras mice. Our results indicate that, as forN-ras, H-ras gene function is dispensable for normal mouse development,growth, fertility, and neuronal development. Additionally, ofthe three ras genes, K-ras appears to be not only essential butalso sufficient for normal mousedevelopment.

^* 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.

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