p53 and Fas system deficiencies in mice result in altered reproduction, development and tumorigenesis

Mice with a targeted disruption of the p53 tumor suppressor gene were crossed with gld mice (deficient in Fas ligand) to study interactions between these two apoptotic systems in an in vivo system. Specifically, the research asked whether the phenotypes already reported for the individual gene deficiencies were altered or enhanced by the absence of a second apoptotic gene. To address this question, female reproductive function, neural tube development, and tumorigenesis were examined in addition to male reproductive function.;FasL+/+p53-/- female mice had reduced pregnancy rates, litter sizes and weaning rates, and the absence of both p53 and FasL further affected female fertility by reducing ability of female mice to successfully deliver litters. Thus, it is likely that the two apoptotic systems have complementary roles in parturition. The absence of FasL had no effect on the development of previously reported neural tube defects in p53 deficient female mice. In tumorigenesis, the absence of FasL in p53+/- mice led to a shift in tumor spectrum from sarcomas to primarily lymphomas and reduced life span, suggesting that FasL plays a role in lymphoma development. Finally, in testis, the double deficiency did not alter spermatogenesis in terms of spermatid head counts, testis weights, fertility, or seminiferous tubule diameters. Although each of the individual gene deficiencies conferred protection against apoptosis in male germ cells in injuries such as ionizing radiation and phthalate exposure, the combination of FasL and p53 deficiencies did not confer any more protection than either of the gene deficiencies alone, suggesting that in these injuries, the Fas and p53 pathways converge. Interestingly, although FasL mutant mice were not resistant to radiation-induced germ cell apoptosis, Fas receptor mutant mice were resistent, and a p53-dependent increase in Fas expression was noted in testis following exposure to 5 Gy radiation. This suggests that Fas is involved in the radiation response in testis, but that FasL is not necessary. Together, this data indicates that p53 and the Fas system can work in complementary roles, as they do in parturition, or can converge as part of one pathway, as in the male germ cell apoptotic response to ionizing radiation. These differences are tissue- and injury-specific.