Using mouse models to unlock the secrets of non-synonymous RNA editing

The deamination of adenosine to inosine by RNA editing is a widespread post-transcriptional process that expands genetic diversity. Selective substitution of inosine for adenosine in pre-mRNA transcripts can alter splicing, mRNA stability, and the amino acid sequence of the encoded protein. The functional consequences of RNA editing-dependent amino acid substitution are known for only a handful of RNA editing substrates. Many of these studies began in heterologous mammalian expression systems; however, the gold-standard for determining the functional significance of transcript-specific re-coding A-to-I editing events is the generation of a mouse model that expresses only one RNA editing-dependent isoform. The frequency of site-specific RNA editing varies spatially, temporally, and in some diseases, therefore, determining the profile of RNA editing frequency is also an important element of research. Here we review the strengths and weaknesses of existing mouse models for the study of RNA editing, as well as methods for quantifying RNA editing frequencies in vivo. Importantly, we highlight opportunities for future RNA editing studies in mice, projecting that improvements in genome editing and high-throughput sequencing technologies will allow the field to excel in coming years.