Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant activation of melanoma differentiation-associated protein 5 (MDA5)-mediated sensing of unedited endogenous transcripts, whereas Adar1 p110 -specific deficient mice die postnatally through RNA editing-independent mechanisms. ADAR1 mutations cause Aicardi-Goutières syndrome (AGS), a congenital autoinflammatory disease accompanied by encephalopathy with a type I interferon (IFN) signature. However, the roles of ADAR1 in neurons remain elusive. Here, we show that neuron-specific deletion of Adar1 (both p110 and p150 ) in mice caused early postnatal lethality with elevated expression of type I IFN-stimulated genes (ISGs). Ventricular obstruction due to hypoplasia of the choroid plexus and ependymal cells, which was accompanied by gliosis, was observed. Of note, both selective restoration of ADAR1 p150 function and deletion of MDA5 largely normalized type I ISG expression and ameliorated ventricular obstruction but failed to rescue early postnatal lethality. Furthermore, selective restoration of RNA editing-independent function of ADAR1 p110 was also insufficient to rescue the early postnatal lethality, suggesting that both ADAR1 p110 and p150 in neurons are essential for postnatal survival.
Todo et al. (Fri,) studied this question.