Sci. Aging Knowl. Environ., 30 April 2003
Go or No-Go?
Mixed results complicate hopes for nerve regeneration
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/17/nw63
Key Words: neurite outgrowth corticospinal tract reticulon
When Christopher Reeve lobbies Congress on behalf of spinal cord injury research, it sounds as though treatments are just around the corner. But new work underscores the complexities that plague the enterprise. Three studies of mice that lack a nerve growth inhibitor show conflicting results. The observations suggest that the molecule by itself might not be an effective target for potential therapies.
As embryos develop, their neurons wind through the body to form a functional nervous system. But adults lose this flexibility: Severed or damaged neurons in the spinal cord can't reform lost connections. Scientists have tracked down several growth-hindering molecules. For instance, a protein called Nogo prevents neurons from extending across a culture dish, and injection of an antibody that incapacitates Nogo encourages some neurons to regrow in rodents with sliced spinal cords. But not all neurons respond to the antibody, and other nerve growth inhibitors exist, so the magnitude of Nogo's effect remains foggy.
Now, three groups have created mice that lack Nogo. Each team first assessed whether the alteration hindered the growth of nerve cells transferred from animals to culture dishes. Neurons didn't extend when treated with neural proteins extracted from normal animals, but they did when exposed to proteins purified from the mutant rodents--as expected if Nogo is missing. Next, the groups assessed neuron regeneration in the animals. Using similar surgical techniques, each team partially cut the spinal cords of mice, waited 2 weeks, and examined the tissue at the site of the incision. Neurologist Stephen Strittmatter of Yale University and colleagues found that, in about half of the animals, 10% of nerves sprouted and grew across the cut; neuroscientist Martin Schwab of the University of Z�rich in Switzerland and colleagues observed regrowth in about half as many neurons. Neuroscientist Marc Tessier-Lavigne of Stanford University in California and colleagues found no evidence of regeneration
The reason for the discrepancy isn't clear, but some hints deserve further investigation. The gene that encodes Nogo makes three different versions of the protein, denoted Nogo-A, Nogo-B, and Nogo-C. Strittmatter's team obliterated Nogo-A and Nogo-B; Schwab and co-workers took out Nogo-A, but Nogo-B production increased. The extra Nogo-B might compensate for loss of Nogo-A, says Schwab. Tessier-Lavigne's group removed Nogo-A and Nogo-B, but it remains unclear why those mice behaved differently from those of Strittmatter and colleagues. Differences in genetic background could underlie the discrepancies, says Tessier-Lavigne. In addition, age might contribute, says Strittmatter: Older mice were less proficient at regeneration than were younger animals in his team's experiments.
Researchers who study spinal cord injuries eagerly anticipated the results of the studies, says neuroscientist Karim Fouad of the University of Alberta in Canada, hoping to see a clean demonstration that blocking Nogo spurs nerve growth. Although the results cool some researchers' enthusiasm about Nogo's potential as a drug target, the observations "highlight the fact that there are multiple signals that block regeneration," says neuroscientist Lisa McKerracher of the University of Montreal in Canada, and suggest that targeting molecules that act after those signals have converged might prompt more robust regeneration. Perhaps further experiments will eventually lead to the Hollywood ending that Superman desires.
April 30, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150