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New clues to nerve regeneration

Blocking a growth factor receptor allows damaged axons to re-grow, providing new clues to why nerves typically don't heal

By | October 7, 2005

Turning off a well-known chemical switch may allow severed nerves in adult mammals to regenerate, according to a report in this week'sScience. By jamming the epidermal growth factor (EGF) receptor, the authors blocked harmful signals known to limit repair of damaged axons in the central nervous system. Their finding points to a promising new target for restoring neural function following injury, they say.

Previous research that sought to explain why mammalian axons fail to regenerate in the wounded brain or spinal cord found several inhibitory cues that prevent healing. The culprits include proteins associated with myelin and proteoglycans released by the glial scar that forms after neural injury.

In a search for a signal that might override this chemical blockade, a group led by Zhigang He of Children's Hospital in Boston, Mass. cultured neurons on a myelin substrate. They screened approximately 400 candidate compounds, looking for those that could promote growth in this hostile environment. When exposed to a subset of the molecules, neurons sprouted extensions called neurites, the first step to extending axons. That subset of molecules shared the ability to shut down the EGF receptor. Neurites also grew in the presence of two well-characterized EGF receptor inhibitors, but not a control compound.

"It's surprising finding," said Martin Schwab of the University of Zurich, since activation of the EGF receptor is normally associated with proliferation and growth of cells. Schwab has characterized the signaling pathways of myelin proteins but was not associated with this study. In this case, "the EGF receptor is a bad actor," said Marc Tessier-Lavigne, Senior Vice President for Research at Genentech in South San Francisco, Ca. and a co-author of the paper. "Activation of the receptor is involved in blocking things, not in stimulating growth," he said. "It's an unexpected role for the EGF receptor."

Stephen Strittmatter of Yale University School of Medicine in New Haven, Ct., who first described one of these inhibiting proteins, called Nogo, points out that the connection between Nogo, its receptor and the EGF receptor remains to be worked out. "It is still perhaps a little unclear how the Nogo receptor couples to the EGF receptor and how that coupling is required for inhibition of axon growth," he said.

The authors found that cultured neurons bathed with inhibiting proteoglycans derived from glial scars also grew neurites when the EGF receptor was blocked. That's interesting because proteoglycans and proteins associated with myelin signal through separate biochemical channels, Tessier-Lavigne said. "The EGF receptor seems to be a point of convergence of these two disparate sets of signals," he said.

This common switch could be a potent new target for therapies aimed at repairing damaged nerves. "If with one manipulation – blocking the EGF receptor – you can block the actions of multiple factors, then you can hope to have a bigger effect than if you block any one factor or any one signaling pathway," Tessier-Lavigne told The Scientist.

"The beauty of this observation is that some drugs that will block this pathway have already been approved for the treatment of cancer," said Marie Filbin of Hunter College in New York City, who also works on axon-inhibiting proteins. "If further animal studies prove promising," she said, "the clinical work will move forward very quickly."

Genentech already sells an EGF-receptor-blocking drug called Tarceva, which is approved for the treatment of lung cancer, and plans to begin testing it on a mouse model of spinal cord injury, Tessier-Lavigne said.

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