Control of development and disease from an unlikely source
August 18, 2009 - 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 an 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.
For more information contact Peggy Jones, Children’s Memorial Research Center
at 773.755.6341 or pmjones@childrensmemorial.org.