Can mental disorders result from altered non-coding RNA-dependent gene regulation during embryonic development? This is a question posed by Jhumku Kohtz, PhD, of Children's Memorial Research Center. Kohtz, along with her laboratory and colleagues at Northwestern University's Feinberg School of Medicine, has published research in the August issue of Nature Neuroscience that finds for the first time that a non-coding RNA (ncRNA) called Evf2 is important for gene regulation and the development of interneurons that produce GABA, the major inhibitory neurotransmitter in the brain. The absence or reduction of GABA is implicated in different psychiatric disorders such as schizophrenia, Tourette's syndrome, epilepsy, and Rett syndrome, an autism spectrum disorder.
Until this paper, it had not been known how long ncRNAs function during neural development, or whether subtle effects on gene regulation in the embryo could last through adulthood. Kohtz and colleagues show that the Evf2 RNA controls gene expression in a region of the developing brain that is the source of GABAergic interneurons, which are known to migrate to adult brain regions involved in higher functions like learning and memory. While it remains to be determined whether mice lacking Evf2 actually exhibit cognitive or social interaction defects, the researchers show that circuitry in the hippocampus, a region involved in learning and memory, is altered in mice lacking Evf2. They also provide a mechanistic explanation of how the Evf2 RNA controls gene expression by showing that Evf2 recruits key transcription factors, including MECP2, a gene mutated in Rett syndrome, to specific sites in DNA. Says Kohtz, "The majority of cellular RNAs are non-coding, and have been thought to be non-functional. It has become clear that ncRNAs play important roles in a variety of cellular processes. By showing that loss of a single ncRNA can affect neuronal development with long-lasting effects through adulthood, our data raise the possibility that mental disorders may be determined by subtly altering gene expression in the developing brain. This raises important questions on how mental disorders should be studied in the future. Genome-wide studies that are performed to identify mutations that correlate with specific disorders will need to consider that altered ncRNAs may be causing disease. It will be especially important to identify maternal/environmental and/or genetic factors that influence RNA function, and that may contribute to the development of specific mental disorders. If subtle effects on gene expression during development can result in mental disorders in the adult, these data reinforce the importance of prenatal care during pregnancy."
Jhumku Kohtz, PhD, is Associate professor of Pediatrics at the Feinberg School; and a scientist in the Developmental Biology Program and Director of Research Technologies at the research center.
This work was funded by National Institute of Child Health and Human Development, the Illinois Regenerative Medicine Institute and an Illinois Excellence in Academic Medicine grant to Kohtz.
Children's Memorial Research Center is the research arm of Children's Memorial Hospital, the pediatric teaching hospital for Northwestern University's Feinberg School of Medicine. The research center is also one of 29 interdisciplinary research centers and institutes of the Feinberg School, where principal investigators who are part of the research center are full-time faculty members. Built upon a team approach, the research center generates knowledge that will lead to cures for the diseases of children with additional focus on the pediatric precursors of adult diseases. The research center actively encourages a synergy of ideas among physician scientists, basic scientists, technicians, nurses and trainees in various disciplines. Its thematic research programs bridge gaps between the biomedical, clinical and social sciences and provide an environment to accomplish common goals.