Editing independent dysregulation of Rps3a1 and its pseudogene Rps3a3 in AdarΔ7-9 mice. AdarΔ7-9 mice: dysregulation of Rps3a

Four different Adar knockout alleles have been studied so far. All of them show the same phenotype at E12.5, namely, apoptosis, liver disintegration and elevated immune response triggered via MDA5/MAVS pathway. All the Adar knockout alleles can be rescued by a concomitant deletion of Mavs or Ifih1 (MDA5). However, each of them show a distinct rescued phenotype dependent on the kind of truncation in the Adar allele. AdarΔ2‑13 and AdarΔ7‑9 are used interchangeably as null mice since both of these are devoid of ADAR1 editing. Here, we show that AdarΔ7‑9 can form a truncated, mislocalized and editing deficient protein. We also report an extensive study on the rescued AdarΔ7-9; Mavs -/- mice which interestingly show a phenotype different than any phenotype of other rescued alleles. Histology and cytometry analysis indicated defects in multiple tissues of these mice. However, all the studied tissues showed a dysregulation of Rps3a1 and Rps3a3. Consistent with this, they show a distortion in 40S and 60S ribosomal ratio in polysome profiling of liver tissues. This dysregulation is also seen in AdarΔ2‑13; Mavs -/- but not in AdarE861A/E861A; Ifih1-/-, suggesting editing independent function of ADAR1 in regulating the expression levels of Rps3a1 and Rps3a3.