A molecule that helps the body’s motor nerve cells grow along proper paths during embryonic development also plays a major role in inhibiting spinal-cord neurons from regenerating after injury, researchers at UT Southwestern Medical Center have found. In cultured cells, the researchers found that a component of myelin – a substance that normally insulates and stabilizes long nerve fibers in adult vertebrates – chemically blocks the ability of nerve cells to grow through myelin that is released when the spinal cord is damaged. While other myelin components also block nerve growth, a component called ephrin-B3 inhibits such activity as well or better than that of other known blocking agents combined, UT Southwestern researchers report in an upcoming issue of the Proceedings of the National Academy of Sciences.
“I believe that to the extent that overcoming myelin-based inhibition is going to provide some sort of functional recovery for spinal cord injury patients, understanding ephrins is a major step forward,” said Dr. Luis Parada, senior author on the paper and director of the Center for Developmental Biology and the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration at UT Southwestern. A mixture of molecules and proteins, myelin insulates nerve fibers and impedes them from having contact with other nerve cells. After a spinal-cord injury, myelin is released into the tissues. Not only does myelin encourage the growth of scars – called glial scars – which physically block nerve cells from regrowing in the damaged area, but components of myelin also chemically prevent nerve cells from regrowing there as well.
Considerable research has been done in the past 10 years to identify elements in myelin that chemically inhibit the regeneration of nerve cells, Dr. Parada said. Three individual components – the molecules Nogo, MAG and OMgp – have been shown to do so in isolation. Developmental biologists at UT Southwestern have been studying how ephrin-B3 helps control how and where nerve fibers grow during early development. They previously showed that the molecule throws up “fences” that repel developing nerves and guide them along the pathways to their appropriate connections to muscles.
In 2002 Dr. Mark Henkemeyer, associate professor in the Center for Developmental Biology and of cell biology and one of the authors of the PNAS study, found that such a “fence” is erected specifically down the middle of the cortical spinal tract, which is damaged during spinal-cord injury.
In the current study, Dr. Parada and his colleagues asked: What is this molecule, whose normal function is to be repellent during embryonic development, doing in the mature system?
“To our surprise, we found that ephrin-B3, which normally is present as a ‘wall’ down the middle of adult spinal cords, also is found in very high levels in adult myelin,” said Dr. Parada.
The researchers knew from previous work that ephrin-B3 interacts with receptors on neurons in the cortical spinal cord. So, in the lab, led by the study’s lead author Dr. M. Douglas Benson, a postdoctoral research fellow, they cultured neurons together with isolated ephrin-B3 and confirmed that the molecule activated the neuron’s receptors. They then cultured normal myelin together with the neurons and got the same results.
However, when they cultured neurons with myelin from which the ephrin-B3 had been removed, the receptors were not activated. The findings suggest that there is much more to be learned about myelin-based inhibition, Dr. Parada said. “We firmly believe that ephrin-B3 is an important, functional, relevant component of myelin, although there may be other elements that are left to be discovered,” he said.
Dr. Parada added that several factors must be overcome before spinal-cord regeneration and recovery from injury can occur in a meaningful way for patients.
“We have to figure out how to dissolve the glial scars or impede their formation,” he said. “We also need to get mature neurons to be better at growing, similar to the way they do during embryonic development. And finally, we have to remove myelin-based inhibition. If and when we achieve those three things, then we’ll have robust regeneration of injured nerves.”
Other Center for Developmental Biology researchers involved with the study were Dr. Mark Lush, postdoctoral research fellow, and Dr. Q. Richard Lu, assistant professor. Dr. Mario Romero, assistant professor of neurology, also contributed.
The research was supported by the National Institute of Neurological Disorders and Stroke and the Christopher Reeve Paralysis Foundation Consortium on Spinal Cord Injury.