Scientists Identify Gene Essential for Nerve Regeneration

Scientists Identify Gene Essential for Nerve Regeneration. By Daniel Gorelick
Findings point to new mechanism for repairing damaged nerves
america.gov, January 27, 2009

Washington — Scientists have identified a gene required to repair severed nerve cells — a finding that could one day be used in the development of treatments for spinal cord injuries, according to a report published January 22 in the journal Science.

“We discovered a molecular target for a future drug that could vastly improve the ability of a neuron to regenerate after injury,” said Michael Bastiani, the University of Utah scientist who led the research team.

Each year, between 10 and 83 people out of every million people worldwide suffer a spinal cord injury, according to a 2006 study in the journal Spinal Cord. One-third of those injured become paralyzed in all four limbs. Complications from spinal cord injuries include urinary tract infections, depression, pneumonia and renal failure. The estimated lifetime costs are between $1 million and $3 million per injury, depending on the extent of the injury and the age at which it occurs, according to the Christopher Reeve Foundation, a nonprofit organization dedicated to curing spinal cord injuries.

The gene identified in the study, dlk-1, is unique because it is not required for normal growth in embryos, yet it is “absolutely required for regeneration” after injury, Bastiani said. “Most of us believed that virtually everything we found in regeneration also would be involved in development, so it is surprising.”

When the dlk-1 gene was mutated, neurons failed to regrow after injury. When scientists artificially activated dlk-1, regrowth was accelerated.

The study was performed using the nematode worm C. elegans, many of whose neurons are able to regenerate after injury. Many of the genes important for the function of the nervous system in worms, including dlk-1, are also present in humans.


SCREENING FOR REGENERATION

Although worms and humans seem worlds apart, the worm is an ideal tool to identify genes important for neuron regeneration, according to lead author Marc Hammarlund, assistant professor at Yale University School of Medicine.

The C. elegans worm is tiny and transparent, enabling scientists to watch its development unfold cell by cell from embryo to adult, a discovery that led to the Nobel Prize in medicine in 2002. The worm’s tiny size and completely sequenced genome make it amenable to genetic screens, a technique where researchers mutate thousands of genes to identify those few involved in a particular physiological function.

Hammarlund and colleagues used worms genetically engineered to contain a population of glowing green neurons, making them easy to distinguish under the microscope. (See “Four Americans Share in Nobel Science Prizes.”)

Researchers then mutated the beta-spectrin gene. Neurons in these mutants are damaged by the mechanical strain of normal movement. Unlike in mammals, worm neurons can regenerate, so as the worms move their neurons are cycling between damage and regrowth. Using a technique called RNA interference, Hammarlund interfered with the function of more than 5,000 genes individually and examined whether regeneration was impaired.

The dlk-1 gene stood out because when it was mutated, the neuron regeneration decreased dramatically, Hammarlund said. He then took normal worms and used a laser to severe nerve cells; when dlk-1 was over-activated, the severed neurons regrew faster than normal.

Hammarlund told America.gov that more than 60 genes were identified in the screen and could play a role in regeneration. The dlk-1 gene is, thus far, the best understood, but Lebanese postdoctoral fellow Rachid El Bejjani is now studying the other genes identified in the screen.


FUTURE GROWTH

The link between dlk-1 and nerve regeneration in worms prompts many questions as scientists look to translate their findings to humans.

The function of dlk-1 in normal, adult neurons is not known, Hammarlund said. He was surprised to discover that although dlk-1 is required for the regrowth of damaged neurons, it is not required for the initial growth of neurons in embryos.

In humans, damaged cells in the peripheral nervous system regrow far better than those in the central nervous system. It is not clear why, but it is possible that dlk-1 is preferentially active in the periphery, a question that scientists now will examine, according to Hammarlund. Also not known is whether dlk-1 can spur regrowth of neurons regardless of the damage — it may turn out that dlk-1 is more effective at repairing neurons damaged by trauma than those damaged by a stroke.

One caution is that dlk-1 needs to be activated at the time of injury — activation even two hours after neurons were cut with a laser failed to bring forth robust regrowth. Hammarlund acknowledges that this narrow window is a barrier to treating traumatic nerve damage in humans, but is confident that eventually “we’ll get there.”

“In the future, we would like to develop drugs that could activate this chain of molecular events in nerve cells and stimulate regeneration of diseased and injured nerve cells,” said Erik Jorgenson, a coauthor of the study and scientific director of the Brain Institute at the University of Utah. “At this point, we can’t do that. But this study gives us hope that in the future, we will have a rational approach for stimulating regeneration.”