Subsequently, we attempted to rescue the Adar1p150-/- mice by knocking out both MDA5 and PKR. Long story short, it is a FULL rescue - at the Mendelian ratio! The oldest Adar1p150-/-Ifih1-/-Eif2ak2-/- mice are >42 weeks old now.

Key findings: The activation of PKR is independent of RNA editing, but dependent on RNA binding activities of ADAR1. It is the RNA binding of the cytoplasmic ADAR1p150 isoform that suppresses PKR activation.

We reasoned that PKR may be activated in Adar1-/-Ifih1-/- mice, leading to the early postnatal death. Only upon MDA5 removal, the role of PKR may be revealed. Indeed, we recovered viable Adar1-/-Ifih1-/-Eif2ak2-/- mice with ~40% surviving to adulthood (oldest >95 weeks old!).

Didn’t you do the Dr. Seuss part and beyond with a much more fun format? youtu.be/sweN8d4_MUg