Nerve-ending molecules that can do it all.

For at least a century, neurobiologists have suspected that developing nerve cells are somehow told what connections to make. The extensions, called axons, that sprout from motor neurons and activate toe muscles thread their way from the spinal cord down to the foot, ignoring all other muscles along the way.

"The challenge is to understand how the guidance can be so very accurate," says Marc Tessier-Lavigne of the Howard Hughes Medical Institute at the University of California, San Francisco. Over the past year or so, his research group and several others have been doing just that, identifying molecules that help steer axons in the right direction (SN: 8/27/94, p.135).

Now, they are finding out just how numerous and how versatile these chemical signposts can be. Sometimes, the markers stay stationary; other times, they leave the target and help direct an axon to the correct place. Moreover, molecules that researchers find in worms and grasshoppers have chemical equivalents in mice and chickens, Tessier-Lavigne points out.

His group discovered two such mobile signposts, called netrins, that diffuse from target cells. Some axons sense netrins and grow toward increasing concentrations of these chemicals. But other axons grow away from netrin, he reports this week at the Society for Neuroscience meeting held in Miami. Nor are netrins the only signals with dual effects, he adds.

Last year, Jonathan A. Raper of the University of Pennsylvania in Philadelphia found a substance, collapsin, that paralyzes the advancing axon tip. New evidence shows that while collapsin repulses some tips, called growth cones, it attracts others, says Tessier-Lavigne.

In addition, Raper has announced at the meeting the discovery of a second, and most likely a third, kind of collapsin, made by different cells or at different times during the development of the nervous system. Thus, like netrins, collapsin molecules may represent a family of molecules whose unknown number of members have similar structures and functions, Raper notes.

Work by Corey S. Goodman of the University of California, Berkeley, also reported at the meeting, suggests that the guidance molecules his group has found also belong to a larger chemical family. These chemicals may attract or repel an axon, depending on the makeup of the axon's molecular docking sites, Goodman says. His group finds that some axons have docking sites for both connectin and semaphorin II, two such guidance molecules. The former sits on the cell surface, and the latter diffuses through the environment around these cells.

"[The axon] is probably responding to many cues at one time," Raper notes.

Those cues can be very subtle. Raper finds that it takes very little collapsin, for example, to alter an axon's path. "And [the growth cone] is integrating all the information at once," he adds.

The body may have a reason for bombarding the axon with so much information. "To be sure [the axon] won't get misrouted, [the body] has to overspecify the route," suggests Tessier-Lavigne.

Although Goodman found his first semaphorin in insects, other chemical signposts in the semaphorin family now include collapsin, which Raper found first in chicks, and semaphorin III, which exists in humans.