November 3, 2006

Lecturer untangles nervous system wiring

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Lecturer untangles nervous system wiring

Marc Tessier-Lavigne, Ph.D., delivers last week’s Discovery Lecture.
Photo by Susan Urmy

Marc Tessier-Lavigne, Ph.D., delivers last week’s Discovery Lecture.
Photo by Susan Urmy

The microscopic “arms,” or axons, sent forth by nerve cells during development often follow a long and winding road to reach their final destinations. Fortunately, axons are usually successful in navigating this distance to find their targets.

At the 23rd presentation of the Lamson Lecture, part of the Discovery Lecture series, Marc Tessier-Lavigne, Ph.D., detailed the work of his team and others in deciphering the signals that guide the wiring of the nervous system.

“We've been interested in the mechanisms by which the brain gets wired up during embryonic development,” said Tessier-Lavigne, senior vice president for research drug discovery at Genentech Inc.

Each nerve cell (neuron) sends out a slender cable-like axon that navigates through the embryonic environment to form connections, or synapses, with other neurons, muscle cells or glands. Their growth is highly directed by a structure at the tip of the axon called the growth cone. The growth cone probes the environment for guidance cues, or proteins that instruct it to migrate in a particular direction. Along the way, axons also send out secondary branches to increase the number of connections a single neuron makes.

“A challenge for our field has been to identify the proteins in the environment that guide axons and then to understand how they guide axons,” he said.

Axons are guided through the combined action of attraction and repulsion, Tessier-Lavigne explained.

“About 15 years ago, we knew that there were attractive, repulsive and branch-regulating activities but none of the molecules that mediate these activities were known.”

Tessier-Lavigne and colleagues described the first of these “axonal guidance factors,” called netrin-1, in 1994. Since then, other guidance molecules have been identified, including the slit proteins, and semaphorins and ephrins.

While the netrins appeared to attract axons, slits seemed to repel them. But Tessier-Lavigne and colleagues soon found that their actions were not that clear-cut.

“We thought of these four families of proteins as the classic guidance molecules,” he said. “The surprise was that they were multifunctional; they aren't dedicated to attraction, branching or repulsion. But rather they can be 'interpreted' as attractive, repulsive or branch-regulating cues by different axons depending on the receptor types made by those cells as well as the state of the cell at the time it received the signal.”

“Attraction and repulsion are in the eye of the beholder,” he quipped. “This is true for growth cones just as it is for human beings.”

But how could axons be guided unerringly over distances as great as the distance between the brain and spinal cord, for example? Researchers suspected that there were intermediate targets along the way to break up the journey. But why the axons didn't just “stall out” at these intermediate targets remained an unanswered question.

Tessier-Lavigne described the experiments that he and others used to identify a “switching mechanism” that helps keep axons moving in the right direction.

Studying the developing spinal cord in chick embryos, his lab identified a mechanism that turns off the growth cone's attraction to chemoattractants like the netrins and turns on its repulsion by slits at just the right time — just after the axon crosses the midline of the developing spinal cord.

“So the behavior of growth cones at the midline is therefore reminiscent of some human relations, in which, sadly, an initial attraction or infatuation can be destabilized by a growing repulsion, which not only pushes the parties apart, but if it becomes intense enough, can actually erase all memory of the initial attraction that got them together so that they move on,” he said.

“So we can think of long-range axon guidance …as an example of serial monogamy, although in the case of axons there is usually a happy ending since most axons eventually find a synaptic partner with which to form a lasting relationship.”

Tessier-Lavigne concluded his talk by recounting the increasing evidence indicating that molecules involved in the initial wiring of the nervous system also get reused to wire blood vessels and also to participate in axonal regeneration in the adult nervous system. These revelations hold implications for spinal cord injury and repair as well as the use of angiogenesis inhibitors in cancer therapy.

The Lamson Lecture, co-sponsored by the Department of Pharmacology, was established in 1964 in recognition of the late Paul D. Lamson, M.D., who organized the Department of Pharmacology and served as its first chair from 1925 to 1952.

For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to