Large-scale mRNA sequencing determines global regulation of RNA editing during brain development

RNA editing by adenosine deamination have been shown to generate multiple isoforms of several neural receptors, often with profound effects on receptor function. However, little is known about the regulation of editing activity during development. We have developed a large scale RNA sequencing protocol to determine adenosine-to-inosine (A-to-I) editing frequencies in the coding region of genes in the mammalian brain. Using the 454 sequencing technology we are able to determine even low levels of editing with high accuracy. The efficiency of editing for 28 different sites where analyzed during the development of the mouse brain from embryogenesis to adulthood. We show that with few exceptions the editing efficiency is low during embryogenesis, increasing gradually at different rates up to the adult mouse. The variation in editing give receptors like the Htr2c and the GABAA a different set of protein isoforms during the development than in the adult animal. Further we show that this regulation on editing activity cannot be explained by an altered expression of the ADAR proteins rather the presence of a regulatory network that controls the editing activity during the development.