Children's National Neuroscience Team Uncovers a Key Gene for Stress Systems Development
Washington, DC – Children’s National Health System investigators have uncovered landmark findings about a gene that plays an essential role in the developing nervous system, particularly in specifying neurons required for the brain’s stress system. The Center for Neuroscience Research team led by Principal Investigator Joshua Corbin, PhD, found that the gene, known as Dbx1, which is only active during embryonic stages, has a footprint long after its initial activity becomes dormant.This discovery takes a big step towards understanding gene processes and impacts on behavior. Dbx1 is a gene found in many different life forms, from flies to humans. The report, published in Neuron shows that while Dbx1 is only expressed during a tight window of time in brain development, it sets forth a cascade of events that impacts the expression of other genes critical for proper brain development.
The Children’s National study focused on the removal of Dbx1 from the mouse hypothalamus, which regulates innate behaviors such as feeding, mating, aggression and predator avoidance. In their study, the researchers found that removal of Dbx1 in mice before birth virtually eliminates the specific aspects of the animals’ stress response later in life.
In mice models, the research reveals that this embryonic gene is critical for establishment of the brain’s stress axis. When investigators genetically removed Dbx1 from the mice, it failed to trigger appropriate responses to innate stressors, such as the odor of a natural predator.
“Now we have a piece of information that sheds light on the genetic programs that drive innate behavior circuit formation. We now understand much better how this system is established from early stages of brain development. How that development unfolds has been, up to now, poorly understood, a kind of black box,” says Dr. Corbin.
The findings are significant in opening the door to learning how similar evolutionarily conserved brain structures are formed in humans. The long-term impacts of specific genetic mutations may affect these developmental processes, areas of investigation which would demand further study, Dr. Corbin adds.
“The Dbx1 gene has a very specific function to developing and building circuits and behavior,” Dr. Corbin says. With the removal of the Dbx1, “basically the mice don’t have the normal stress response because they lack this gene. The circuitry of the stress was not really there.” The study findings were surprising in that researchers found the lack of Dbx1 had an impact that was “very selective and very specific” on both developmental programs and behavior, Dr. Corbin says.
In a video interview, first author Katie Sokolowski, PhD, said the findings were important for revealing the patterning mechanisms of gene circuits and behavioral impacts. “The results were really incredible, revealing that the removal of the Dbx1, a transcription factor, has a huge impact on adult behaviors like stress, long after expression of the gene ceases,” said Dr. Sokolowski.
In their study, the authors wrote: “Our data reveal that Dbx1-dependent transcriptional control is a common developmental mechanism for specification of functionally related neurons in two distinct hypothalamic nuclei and links embryonic patterning of the manifestation of innate behaviors.”
The study included a multidisciplinary team from academic groups around the world that joined to focus various approaches to answer complicated questions, Dr. Corbin says. Other researchers included Kevin S. Jones, PhD, Assistant Professor in the Department of Biology at Howard University and a former Children’s National researcher, as well as researchers from the University of University of California, San Francisco, and the Universite Paris Diderot, France and Kumamoto University in Japan.
Contact: Emily Hartman at 202-476-4500.