FIRST EVIDENCE THAT ONE GENE CONTROLS DEVELOPMENT OF ALL CELLS THAT PRODUCE SEROTONIN IN THE CENTRAL NERVOUS SYSTEM
21 April 2000 - Washington University in St Louis

21 August 2006

One gene controls development of all serotonin cells

Mice missing a gene called Lmx1b do not produce the important brain chemical serotonin, according to research at Washington University School of Medicine in St. Louis. This is the first evidence that one gene controls development of all cells that produce serotonin in the central nervous system, marking significant progress in understanding this critical nervous system pathway.

“While the importance of serotonin in behavior is well known, it is not well understood how the cells that produce this chemical are generated,” says Zhou-Feng Chen, Ph.D., assistant professor of anesthesiology, of molecular biology and pharmacology and of psychiatry. “By understanding this pathway, it may be possible to develop better drug candidates for a number of psychiatric disorders.”

Chen led the study, which appears Advance Online Publication of the journal Nature Neuroscience. The first author is Yu-Qiang Ding, M.D., Ph.D., a research associate in Chen’s laboratory. The study was done in collaboration with researchers at Case Western Reserve University, the Karolinska Institute in Stockholm and the University of Texas, MD Anderson Cancer Center.

Many cells use serotonin to communicate with each other, some of which are located in the brain while others reside in the spinal cord. The chemical is critical for responses such as emotion and pain, and abnormalities in the serotonin pathway can result in a variety of psychiatric disorders, including depression, anxiety and impulsive violence. Antidepressant medications like Prozac treat serotonin imbalances, but according to Chen, it would be better to know how to treat the underlying cause of such diseases.

“It’s like building a house,” he explains. “If you know enough about the foundation of the house and about how each brick fits into the larger structure, you can get a better handle on how to treat any problems.”

A gene called Pet1 also is important for the development of serotonin-producing cells. However, mice lacking Pet1 lose only 70 to 80 percent of this type of cell. In contrast, when Chen and his colleagues examined mice lacking Lmx1b, they found absolutely no serotonin-producing cells. The animals also lost the gene Pet1.

These results suggest that, while the two genes overlap and share a similar function, Lmx1b works at an earlier step than Pet1 and controls development of all serotonin-producing cells. And, since Pet1 only is involved in development of about three-fourths of these cells, Lmx1b must control other genes and pathways.

The team also found that while Lmx1b expression began before that of Pet1, it typically occurred after expression of another gene known to be required for serotonin development, called Nkx2-2. This suggests that Lmx1b represents an intermediate step in the development of serotonin-producing cells.

Cells that produce serotonin in the brain can be divided into two groups: One group makes connections with other cells in the brain, while the second group connects to the spinal cord. It is not clear which gene is responsible for the difference between these two groups. Chen’s team identified one potential candidate, Gata3, which only appears to be involved in the formation of serotonin cells that make connections with the spinal cord, but not with the brain.

Chen’s team currently is in the process of developing mice that lack Lmx1b only in cells that would otherwise produce serotonin. Since the gene also is critical in other organs, mice lacking Lmx1b throughout the body die from kidney failure shortly after birth. With only targeted deletions of the gene, Chen hopes to engineer mice that survive but do not produce serotonin in order to use this as a model for serotonin’s role in behavior and to screen new medications under development.

“We think we will be able to develop the first mouse population that survives without any serotonin,” Chen says. “Such a mouse would allow us to look at how serotonin fundamentally affects pain and depression. We are hoping to collaborate with others at Washington University to study the relationship between this gene and behavior.”

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