p53 is not necessary for DUX4 pathology

Darko Bosnakovski; Erik A. Toso; Olivia O. Recht; Anja Cucak; Abhinav K Jain; Michelle C. Barton; Michael Kyba

We have previously generated a mouse model with a doxycycline-inducible 2.7 kb DUX4 transgene (Dandapat et al. 2014; Dandapat et al. 2016) , referred to as iDUX4[2.7]. One of the interesting features of this mouse is that the very low basal level of expression from the Tet-on promoter in the absence of doxycycline leads to various non-muscle phenotypes, especially in males, where 80% die as embryos, with the remaining 20% being severely runted and all dying before 6 weeks of age. Females are less severely affected and can thus propagate the strainbecause the transgene is X-linked, X-inactivation diminishes the phenotype in females. We reasoned that if p53 were necessary for the pathological effects of DUX4 on embryonic cell types, then on a p53 knockout background, males ought to be born at normal ratios, and ought to be relatively healthy compared to siblings with a functional copy of p53. We therefore crossed the iDUX4[2.7] transgene onto the p53 knockout background. Female carriers were obtained that were homozygous for the p53 knockout and these were bred to male p53 heterozygotes. We genotyped 65 progeny from this backcross and obtained no DUX4+ males, neither on the p53 knockout nor on the heterozygous background (Fig. 2) . Thus, absence of p53 has no effect on the pathological effects of DUX4 on development in the iDUX4[2.7] strain.