Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-α4 (encoded by Kpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops.
The authors declare no competing or financial interests.
M.B., H.W. and M.Ö. designed the experiments. M.B., H.W. and A.W. performed the experiments. M.E. set up the primary cortical culture system and performed initial experiments. M.B. and M.Ö. wrote the manuscript.
This work was supported by the Swedish Research Council (Vetenskapsrådet) (grant K2013-66X-20702-06-4 to M.Ö.).
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.200055.supplemental
- Received November 23, 2016.
- Accepted December 30, 2016.
- © 2017. Published by The Company of Biologists Ltd