Summer
2011

Discovery

Pet-1 Gene Helps Maintain the Brain Serotonin System

Pet-1 Gene Helps Maintain the Brain Serotonin System

Using new gene targeting approaches developed at Case Western Reserve University School of Medicine, researchers discovered that the transcription factor gene Pet-1 works through the entire lifespan to help develop and maintain the serotonin system. The level of serotonin in the brain has been implicated in many psychiatric disorders, including anxiety disorders, so research into Pet-1 could be key for understanding the causes of these conditions.

In the 1990s, a research team led by Evan Deneris, PhD, professor of neurosciences, discovered a transcription factor they called Pet-1, which tells the genome in a serotonin neuron which genes should be turned on to make the serotonin neuron function properly. "I knew from the very first day that it was going to completely redirect my lab into studies of the development of the serotonin system," says Deneris.

To discover the gene's function, Deneris's lab created a biologic model that never developed a functional Pet-1 gene during the fetal stage. This led to the development of adult-stage emotional alterations in the model.

Next, to determine whether the Pet-1 gene functioned not only in the fetal stages, but even in adulthood to help maintain the serotonin system, the researchers reduced the expression of the Pet-1 gene in a biologic model in adulthood, leaving intact its function during fetal life.

"The first thing that we found was the development of increased anxiety-like behavior," says Deneris. "This said, for the first time, that disruption of serotonergic transcriptional mechanisms at any stage in life, not just during development, can contribute to behavior pathogenesis." This means that Pet-1 is still expressed in adult brains because it's still needed to keep the serotonin system going—and when Pet-1 is not expressed, the serotonin system is thrown out of whack and anxiety-related disorders can crop up.

The researchers' hope is that figuring out the full extent of what Pet-1 does will lead to a better understanding of anxiety-related disorders. The next step: Deneris and his team know some of the genes that are regulated by Pet-1, but they surmise there are many more; they now plan to identify all of the genes that are regulated by Pet-1 during fetal life and adulthood.