Saturday, November 08, 2008

Genes involved in Axon Growth

Coaxing Injured Nerves to Regrow


The adult central nervous system has limited ability to repair itself. That's why spinal cord injuries leave people permanently paralyzed. Now a study with mice finds that removing a particular signaling molecule in adult neurons restores their ability to regenerate damaged axons, the long extensions that convey signals from one neuron to another. The find potentially paves the way for repairing spinal cords and other nervous system injuries. "It's one of the most dramatic results in the history of this field," says Ben Barres, a neurobiologist at Stanford University in Palo Alto, California.

Researchers suspect that adult nerves don't regenerate for two reasons: One, neurons have lost the flexibility they had at about the time of birth, when the brain was still developing; two, compounds near the site of injury inhibit axon growth. A great deal of research has focused on identifying and blocking these compounds, but so far these manipulations have prompted only limited regrowth, says Zhigang He, a neurobiologist at Children's Hospital Boston and Harvard Medical School. In the new study, He and his colleagues searched for a way to help neurons recapture their youthful ability to grow new axons.

They began with a list of candidate genes involved in cell growth and several strains of mice in which each of these genes could be individually deleted once the mice had grown to adulthood. Deleting the gene for a signaling molecule called PTEN had a dramatic effect on nerve regeneration, He's team reports in tomorrow's issue of Science (7 November, p. 963). PTEN inhibits a cell-signaling cascade called the mTOR pathway, which is involved in protein synthesis and cell growth. Normally, axons in the optic nerve of adult mice do not regenerate when crushed--and worse yet, about 80% of the neurons with severed axons die. But in mice lacking PTEN, 50% of neurons survived and about 10% of axons in the optic nerve regrew--as far as 4 millimeters in 28 days.

A few millimeters may not sound like much, but it's a huge distance compared with other studies of axon regeneration, says Barres. "To have any manipulation that can make these axons grow from where they were severed near the retina all the way down the optic nerve is just amazing."

Even so, many questions remain, including whether the regenerating axons are capable of forming working connections with other neurons (He's team did not examine whether the mice lacking PTEN regained their sight) and whether manipulating PTEN or other components of the mTOR pathway can promote axon regeneration in the spinal cord, which many researchers contend is a more hostile environment for regrowth. He says experiments to address these questions are already under way.

Meanwhile, another paper the same issue of Science (7 November, p. 967) provides what may be an important piece of the axon-inhibition puzzle. Previous work had identified several compounds that block axon regeneration and found that they bind to the aptly named Nogo receptor on the surface of neurons. Puzzlingly, however, deleting or blocking the Nogo receptor has not spurred much regeneration. Now, Marc Tessier-Lavigne and colleagues at Genentech in South San Francisco, California, have identified another receptor for these inhibitory compounds. Blocking this receptor, called PirB, enabled cultured neurons to regrow severed axons, and blocking both PirB and the Nogo receptor enabled even more regrowth.

In the long run, the optimal strategy for treating spinal injuries may involve a combination of therapies that restore neurons' ability to grow axons and ones that counteract inhibitory signals near the injury. "You want to do each, and you may need to do both," says Tessier-Lavigne.


Greg Miller, ScienceNOW Daily News, 6 November 2008
http://sciencenow.sciencemag.org/cgi/content/full/2008/1106/1