WESTPORT, CT (Reuters Health) Dec 27 - Scientists have found that when two axonal growth cone proteins are administered, nerves in the spinal cord of adult mice can be prodded into regenerating at about 40% of the rate of peripheral nerves.
Dr. J. H. Pate Skene, from Duke University Medical Center, Durham, North Carolina, and colleagues studied dorsal root ganglion (DRG) neurons, which are unique in having axons projecting into both the peripheral and central nervous systems. Regeneration of DRG spinal axons occurs only if the peripheral nerve has also been injured, Dr. Skene noted in an interview with Reuters Health.
Expression of growth-associated protein (GAP) 43 in axonal growth cones is correlated with regeneration of peripheral nerves, but does not trigger regeneration on its own, he explained. To look for other genes involved in axon regeneration, he and his associates took injured DRG neurons from mice transgenic for GAP-43, CAP-23 (another protein induced by peripheral nerve injury), or both and measured axon growth.
While more DRG neurons expressing either gene individually sprouted only short axons, neurons expressing both genes sprouted long axons similar, but not identical, to the axon growth that occurs after peripheral nerve injury, the researchers found.
To see if expression of GAP-43 and CAP-23 can promote spinal regeneration in mice in the absence of peripheral injury, Dr. Skene and colleagues induced lesions in the DRG spinal axons in mice transgenic for both genes, either gene alone, or neither gene. To optimize the environment and maximize the chances of observing regeneration, they also grafted a segment of peripheral nerve into the spinal cord lesion.
In the January 2001 issue of Nature Neuroscience, they report that mice expressing both genes in the same neuron had about 7% of their neurons regenerate into and through the peripheral nerve graft at least 5 mm. In comparison, normal mice with an injury of the DRG peripheral nerve had about 17% regeneration.
"We probably don't have everything, but if you turn that around, that's 60 times more effective than doing nothing at all," Dr. Skene pointed out.
What GAP-43 and CAP-23 do is not clear, he noted, although they are abundant in growth cones and are known to be involved in cellular signaling. "For most of the last decade, the focus [in the regeneration field] has revolved around environmental issues," he said. "I hope that we're emphasizing that the neuron's capability is also important."
A question for future study, Dr. Skene said, is how competent the spinal nerves are in regenerating, for example whether they grow in the native environment in the absence of a peripheral nerve segment. His group would also like to find out what other genes are turned on during peripheral nerve injury that would increase spinal axon regeneration, and investigate whether gene therapy or some other method could be used to turn on the expression of these genes in neurons after injury.
In an accompanying editorial, Dr. Clifford J. Woolf, from Massachusetts General Hospital and Harvard Medical School, in Charlestown, comments that the work "represents a major advance in the understanding of which molecules are required to induce injured axons to grow over long distances."
Nat Neurosci 2001;4:7-9,38-43.
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