Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains

Development of pulmonary adenomas (PAs) in mice is under the genetic control of multiple host genes. We have established a new set of SMXA recombinant inbred strains from PA-susceptible A/J and PA-resistant SM/J mice. The number of urethan-induced PAs was variable among substrains of the SMXA recombinant inbred strains, indicating the involvement of multiple genes, SMXA24 mice were highly resistant to PA, although they had susceptible alleles at all four known susceptibility genes, including kras2 and MHC. To identify the resistance gene in SMXA24, progeny of reciprocal F₁ crosses and progeny of backcrosses to A/J were given urethan at 4 weeks of age and examined for induced PA at the age of 5 months. In reciprocal F₁ cross progeny, the incidence of PA was very low, indicating that the resistance was a semidominant trait. Quantitative trait analysis of the backcross generation revealed significant linkages to loci on chromosome 12 (logarithm of odds score, 6.47) and chromosome 11 (logarithm of odds score, 4.35). To date, two PA resistance (PAR) genes, Par1 (located on chromosome 11) and Par2 (located on chromosome 18), have been reported. From the map position, one of the resistance genes on chromosome 11 was indistinguishable from Par1. However, another resistance gene on chromosome 12 was new, and we named this gene Par3. A likely candidate gene for Par3 is nPKCη, which is expressed exclusively in skin and lung and is down-regulated in PA. Par1 and Par3 seemed to act synergistically.