Researchers at the Burke Medical Research Institute have identified a key pathway in the regeneration of damaged neurons. In a study published May 8 in the Journal of Experimental Medicine, they report that activation of a protein called B-RAF promotes the growth of neurons after injury in both the peripheral and central nervous systems of mice, a finding that may eventually lead to new treatments for conditions as diverse as spinal cord injuries and glaucoma.
When you place your hand on the tabletop or over a fire, signals are transmitted from your fingertips to your spinal cord along sensory neurons—whose long branching arms, known as axons, can stretch to several feet—like messages traveling across a telegraph line. Injury or disease can damage axons and break down these lines of communication. Axons in the central nervous system (the CNS, consisting of brain, eyes and spinal cord) cannot regenerate after an injury in higher animal such as mice and humans.
Earlier work had shown that axon growth can be blocked by disabling the proteins B-RAF and C-RAF, part of the RAF-MEK growth-signaling pathway involved in neuronal development. This growth-signaling pathway is inactive in adult animals. “But that didn’t necessarily mean that activation of B-RAF would actively promote axon growth or even regeneration,” says Jian Zhong, Ph.D. (left), the director of Molecular Regeneration and Neuroimaging Laboratory at BMRI. Dr. Zhong worked with Kevin J. O’Donovan, Ph.D. (right), Kaijie Ma, B.M., and Hengchang Guo, Ph.D., of BMRI, and collaborators from Harvard Medical School, Temple University School of Medicine, Icahn School of Medicine at Mount Sinai, and Centre Hospitalier Universitaire de Québec, to investigate if indeed B-RAF can promote axon growth and regeneration.
To isolate the effects of B-RAF in the nervous system, Dr. Zhong and colleagues genetically engineered mice so that B-RAF in neurons could be turned on at will. Activation of B-RAF enabled normal growth of sensory axons in mouse embryos that lacked a crucial nerve growth-signaling pathway and would normally not develop proper sensory innervation.
The researchers then tested whether boosting B-RAF in adult mice could help repair injured sensory axons, which are not part of the CNS. In mice with identical neuronal injuries, those with activated B-RAF showed significant axon regrowth. The regenerating axons even reconnected with the spinal cord, seemingly unchecked by the inhibitory cues that normally inhibit regeneration in the adult spinal cord.
Next, the researchers set their sights on the more elusive goal—regeneration inside the adult CNS. “To enable axon regrowth after central nervous system injury, that’s the dream,” says Dr. Zhong. In an encouraging step towards fulfilling that dream, the researchers found that B-RAF activation strongly enhances axon regeneration in injured optic nerve.
Moreover, when they combined B-RAF activation with another manipulation, the inactivation of the PTEN gene, the combined axon regeneration was even greater than they had expected from a simple additive effect.
The difficulty of axon regeneration accounts for the permanence of many spinal cord and traumatic brain injuries. “Before, we didn’t know if neurons in the mammalian central nervous system could ever regrow axons to any useful lengths,” says Dr. Zhong. The new study shows that regeneration in the central nervous system can be dramatically boosted by genetic activation of a growth-signaling pathway that is normally active only in the embryo. B-RAF as a potent activator of axon regrowth may be key to future therapies to reverse loss of vision, sensation, or locomotion after CNS injury. As yet, Dr. Zhong and colleagues have not reported any recovery of visual function in their mice. But he is optimistic: "We are working on it, definitely."