"We believe we have found a new signaling pathway in the brain," says study leader David M. Ornitz, M.D., Ph.D., professor of molecular biology and pharmacology at Washington University School of Medicine in St. Louis. "Once we learn what FGF14 does at the molecular level, I believe we may uncover a new mechanism for regulating nerve cell function."
The work is published in the July 3 issue of the journal Neuron. It is the first study to examine the role of FGF14 in living animals and could provide new targets for testing future drugs designed to treat movement disorders and seizures, says Ornitz, who also leads the cancer and developmental biology program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
Ornitz and the team of investigators developed a strain of mice lacking the gene for FGF14. They expected these mice to have brain abnormalities and to perhaps die before birth. To their surprise, however, the mice seemed physically healthy and lived relatively normal lives, though most were about 15 percent under-weight after two weeks of age.
But the young mice did develop coordination problems and abnormal posture. Compared with normal mice, the genetically altered animals walked sluggishly and shuffled, and they had reduced muscle strength. They also were less sensitive to stimulants such as cocaine and amphetamines and were more prone to drug-induced seizures. The investigators also examined the animals' brains. When they disabled the gene for FGF14, the team had ensured that a fraction of the protein remained intact and replaced the rest with a protein that appears blue when exposed to certain chemicals.
This marker molecule revealed that FGF14 was primarily found in three regions of the mouse nervous system: the cerebellum and basal ganglia in the brain and the motor tracts of the spinal cord. All three areas are involved in regulating movement. The basal ganglia, in particular, are affected by Parkinson's disease and other movement disorders.
Also surprisingly, FGF14 fragments also showed up in the long projections--the axons--of the nerve cells.
"This tells us that FGF14 recognizes the machinery that transports material down the axon to the area of the synapse, where nerve impulses jump from one neuron to the next," says Ornitz.
What it does at the synapse is a question Ornitz plans to investigate next. He speculates that FGF14 could signal the formation or release of neurotransmitters, modulate electrical signals or mechanisms that transport electrical signals or regulate the transport of molecules down the axon.
"Any number of things are possible," he says.
One thing is certain, though. "It's pretty clear now that FGF14 is not a growth factor," he says.
Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD, Chen C, Nardi A, Reid DC, Yamada K, Ornitz DM. Ataxia and Paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron, 35, 1-20, July 3, 2002.
Funding from the National Institutes of Health and the Virginia Friedhofer Charitable Trust supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.