Behind the Wheel of an Axon

DENVER--Researchers have uncovered the steering mechanism that helps neurons in the embryonic brain navigate to the correct destination. The results shed new light on brain development and could lead to ways to regrow severed nerves.

As the embryonic brain wires itself up, nascent axons--extensions that interconnect neurons and allow them to communicate--are guided by structures called growth cones. Researchers now know a lot about the chemical signals that lure growth cones, but they know much less about how the growth cones follow those signals and steer the axonal wires. Paul Forscher of Yale University and his colleagues focused on the cellular machinery that helps growth cones steer.

Growth cones send out dozens of thin threadlike feelers to help sense the world around them. When the growth cones encounter a potential partner neuron, they strengthen the backbone of one of the feelers to form an axon. Forscher's team and others recently showed that each feeler was supported by two types of fibers, microtubules and actin filaments. When there's no potential partner nearby, microtubules in the feeler run on a treadmill of actin filaments that reel them back toward the cell body as fast as they can grow. As a result, growth cones go nowhere in particular. But when a feeler encounters another neuron, it senses gluelike chemicals on its surface. Then the treadmill slows, microtubules grow, and the feeler solidifies into an axon.

To see how the feelers steer in response to the gluelike chemicals, Forscher's team blocked the young neurons from building microtubules, which caused them to sit still on the treadmill and be carried back to the center of the cell. That stopped an enzyme called Src that relays signals inside the cell, and that, in turn, stopped the axon from steering where it needed to go, the team reported here 15 February at the meeting of the American Association for the Advancement of Science, which publishes ScienceNOW. The researchers also found that the microtubules tugged on a rubber-band-like arc of protein at the base of the feeler as they grew outward. This suggests that the physical tension on this arc is what triggers the signals that steer the growth cone. The new insights could help researchers design treatments to regrow wasted and severed nerves, Forscher says.

The team's work "is the first time we're getting a handle on how signals outside the growth cone control the cytoskeleton," says neurobiologist Shelley Halpain of the Scripps Research Institute in San Diego.

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