Checkpoints keep a growing nerve cell alive.

To reach the distant finish line, marathon runners depend on periodic checkpoints where they can pick up food and water. Imagine a macabre race in which those checkpoints are even more vital: Unless the runners reach each one at the correct time, they die a quick death.

The developing brain and spinal cord may employ just such an unforgiving strategy to ensure that nerve cells form appropriate connections. A new study suggests that as a nerve fiber grows to its destination, the cell depends for survival on substances secreted by targets along the fiber's way.

This conclusion, reported in the Oct. 21 NATURE, stems from a chance observation made by Hao Wang, now at Merck Research Labs in West Point, Pa., and Marc Tessier-Lavigne of the Howard Hughes Medical Institute at the University of California, San Francisco. For some time, the two scientists have studied the many signals that guide the fibers, or axons, that extend from one nerve cell to others.

They've examined how axons in the developing spinal cord of rats first grow around the cord's perimeter toward a wedge-shaped structure, the floor plate, at the cord's midline. The axons then turn and extend along the length of the cord.

In laboratory dishes, the nerve-cell axons flourished, but only for a day, the researchers unexpectedly found.

"Like clockwork, they would all die unless [tissue from the] floor plate was present," says Tessier-Lavigne.

Neuroscientists have known for decades that the final nerve-cell targets of axons secrete substances that keep most, but not all, of the fibers that reach them alive. By limiting the availability of the survival factors, the targets seem to prune away unneeded axons.

While these scientists knew that intermediate targets such as the floor plate gave directional cues to growing axons, they had had no clear-cut evidence that these targets also provide factors that kept the nerve cells from committing suicide. This mechanism may guarantee that nerve fibers don't get mistargeted in the maturing brain, says Tessier-Lavigne.

"These studies suggest that if the axons follow the correct route, they'll survive. If they stray, they'll die," agrees John G. Flanagan of Harvard Medical School in Boston.

The rat axons don't become dependent on the floor plate until a day after they start to grow, which is about the time it would take them to reach that region of the spinal cord, notes Tessier-Lavigne. He and his colleagues have not yet identified the floorplate factor or factors that keep the nerve cells thriving, although they tested more than two dozen proteins known to influence nerve-cell growth and movement.

"You name it, we tried it," says Tessier-Lavigne.

After several days of growth along the floor plate in spinal-cord tissue samples, the extending axons developed a dependence on chemicals called neurotrophins. It's unclear whether they lost their need for the floor-plate factor, however.

Finding the survival factor made by the floor plate is crucial to future experiments, says Flanagan. Its discovery could also spark new ideas about stopping nerve-cell death in diseases, he speculates.

While searching for the elusive factor, the investigators will examine whether the intermediate targets of other types of axons perform a similar function. Perhaps only axons that travel long distances, such as the fibers in the spinal cord, face such stringent conditions, says Tessier-Lavigne.

[ILLUSTRATION OMITTED]