Balanced gene regulation by an embryonic brain non-coding RNA is critical for GABA circuitry in adult hippocampus

Summary

Genomic studies demonstrate that while the majority of the mammalian genome is transcribed, only about 2% of these transcripts are protein coding. We have been investigating how the long, polyadenylated Evf2 non-coding RNA regulates transcription of homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. Here we show that in developing ventral forebrain, Evf2 recruits DLX and MECP2 transcription factors to key DNA regulatory elements in the Dlx 5/6 intergenic region and controls Dlx5, Dlx6, and GAD67 expression through trans and cis-acting mechanisms. Evf2 mouse mutants have reduced numbers of GABAergic interneurons in early post-natal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and GAD67 RNA levels return to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurs. These results suggest that non-coding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.