The Kohtz laboratory is studying RNA regulatory mechanisms during brain development. In 2006, we reported the first ultraconserved long non-coding RNA, Evf2, and demonstrated the potential of long non-coding RNAs to regulate transcription (Feng et al 2006, Genes and Development 20, 1470-84). Since then, we have focused our work on the mechanism and biological significance of long non-coding RNA gene regulation in terms of their relevance to GABAergic interneuron development. Defective GABAergic transmission either directly contributes to, or has been implicated in a number of developmental disorders, including epilepsy, autism, and schizophrenia. In 2009, we reported that loss of the Evf2 long non-coding RNA in mice results in GABAergic defects in the hippocampus, resulting in circuitry defects (Bond et al 2009, Nature Neuroscience 12, 1020-1027. Using novel genetic mouse models established in the lab, we are continuing to study long non-coding RNA gene regulatory mechanisms in the developing mouse brain.
Current Research Projects
Long non-coding RNA gene regulation
A major focus of the lab is studying how long non-coding RNAs regulate gene expression. In order to define long non-coding RNA/protein complexes (ribonucleic acid-protein complexes, RNPs), we have established a long-standing collaboration with the Yates lab at Scripps. Characterization of the Evf2/RNP suggests a novel mechanism of long non-coding RNA gene repression (manuscript submitted). Different categories of proteins have been identified in the Evf2 RNP, providing the basis for future investigation.
Long non-coding RNA control of neuronal development
We are investigating how the Evf2 long non-coding RNA controls development of different interneuron subpopulations. In order to do this, we use genetic fate-mapping of interneurons in mice lacking Evf2. Our results indicate that Evf2 control of interneuron subpopulations in regionally controlled. Future experiments will determine the relationship between long non-coding RNA gene regulatory networks and interneuron subpopulation control.
Behavioral phenotypes of Evf2 mutants
The importance of GABAergic interneurons in orchestrating multiple developmental events and maintaining homeostasis in adult brain circuitry is leading us to test how Evf2 controls behavior. Our results show that a single long non-coding RNA controls complex behaviors in mice. The gene regulatory network responsible for these changes in behavior will be investigated in the future.