ADAR1 catalyses adenosine-to-inosine (A-to-I) editing in double-stranded RNA, influencing RNA sequence, stability, and structure. It has two isoforms: cytoplasmic ADAR1p150, linked to viral infection and interferon mediation, and nuclear/nucleolar ADAR1p110. While the roles of ADAR1p150 are well-documented, the function of ADAR1p110 has remained unclear.
We recently generated viable adult mice lacking ADAR1 protein (Adar1-/-), editing function (Adar1E861A/E861A), and ADAR1p150 (Adar1p150-/-) by simultaneously deleting viral MDA5 and PKR, two essential viral dsRNA sensors that would otherwise trigger unwanted immune activation. The editing and ADAR1p150 deficient mice survived to adulthood and have normal weights and post-natal growth. In contrast, 60% of the Adar1-/-mice, lacking both p150 and p110, died postnatally, while the 40% surviving adults were smaller than Adar1+/+ littermates. This suggests the potential function of ADAR1p110 in postnatal development and weight regulation independent of RNA editing but dependent on its protein expression.
Analysis of the newborn Adar1-/- pups, revealed abnormal p110-dependent gene expression changes in a key organs and disruptions in energy homeostasis. Further analysis of adult mice provided additional possible explanations for the reduced postnatal survival. We also generated ADAR1-specific knockout mouse models in the organ of interest and monitored their survival. Overall, my results will provide in vivo evidence for the essential role of ADAR1p110 in ensuring mouse survival