Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry

Abstract

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.

Critical roles of long noncoding RNAs in Drosophila spermatogenesis

“…Those studies were generally conducted in cell-based in vitro systems; however, phenotypes at the cellular and organismal levels are frequently discrepant. For example, loss-of-function studies of Malat1 or Dlx6os1 in mouse revealed subtle or undetectable phenotypes (Bond et al 2009;Eißmann et al 2012), despite the fact that these lncRNAs appear to be important at the cellular level. Therefore, the gold standard in the field is the targeted in vivo silencing or deletion of specific lncRNAs (Mattick 2013).…”

Long Noncoding RNAs: Past, Present, and Future

“…The noncoding Evf2 locus, which is associated with an enhancer located between two homeodomain TFs, Dlx5 and Dlx6, was shown by in vivo knockout experiments to regulate the development of GABAnergic interneurons in the postnatal mouse forebrain. It acts through both cis (transcription-based) repression of Dlx6 and trans (transcript-based) activation of Dlx5 (Bond et al 2009). In addition, a number of lncRNAs might be necessary in the specification of neuronal vs. glial fate, perhaps through the recruitment of epigenetic complexes such as PRC2 (Ng et al 2011).…”

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

“…A role for lncRNA genes in brain development and function is supported by the fact that ablation of two lncRNA loci, Evf2 and Pantr2 (linc-Brn1b), perturbs neuronal development (11,12). Loss of Evf2, a developmentally regulated lncRNA that controls transcriptional activity through cooperation with the homeodomain protein DLX-2 (11), leads to abnormal development and synaptic function of hippocampal GABAergic interneurons (11).…”

“…Loss of Evf2, a developmentally regulated lncRNA that controls transcriptional activity through cooperation with the homeodomain protein DLX-2 (11), leads to abnormal development and synaptic function of hippocampal GABAergic interneurons (11). Similarly, ablation of the Pantr2 locus results in a decreased number of intermediate progenitors in the developing telencephalon, reduced neurons in L2/3 of the cerebral cortex, and disorganization of the barrel cortex (12).…”