The discovery of this gene family, as published in the October 9 issue of Science, is a big step forward for both visual science and neuroscience. The finding may one day lead to treatment advances for diseases such as glaucoma and optic nerve stroke (also called anterior ischemic optic neuropathy, or AION), as well as spinal cord injury and other neurodegenerative diseases of the brain and spinal cord.
The axons of retinal ganglion cells (RGCs) form the optic nerve which transmits electrical impulses from the retina to the brain allowing a person to see. RGCs that are damaged or injured result in diminished or lost vision. Once thought incapable of regenerating, RGCs showed improved regeneration in the optic nerve after manipulating one of these recently identified genes.
Jeffrey Goldberg, M.D., Ph.D., assistant professor of ophthalmology at the Bascom Palmer Eye Institute, is the senior author of the study. “Neurons in the central nervous system grow normally during development and then they turn off their growth ability, such that they can’t reconnect properly in adults following injury or disease,” says Goldberg. “Scientists have mostly studied the environment where the growth failure occurs, for example, the optic nerve. We were looking to see if there was a problem within the RGCs themselves, rather than in the environment.”
Co-author Darcie L. Moore, a graduate student in the neuroscience program working at Bascom Palmer, screened more than 100 genes looking to discover which would have a role in retinal ganglion cell regeneration. The team identified Krűppel-like factor-4 (KLF4) as a transcriptional repressor of axon growth in RGCs and other central nervous system (CNS) neurons. When collaborator, co-author Murray Blackmore, a postdoctoral fellow at the University of Miami’s Miami Project to Cure Paralysis, found a related gene (KLF6) in a similar screen on neurons from the cerebral cortex, the team expanded its studies to look at the whole KLF family. They found that the entire KLF family may play a role in regulating regenerative ability not just in the optic nerve, but also in neurons in the brain.
Vance Lemmon, Ph.D., professor of neurological surgery and co-author, says of the findings, “We are excited because the study gives insight to how genes that control regeneration are turned on and off. In particular, KLF4 seems to be more powerful at inhibiting regeneration than two other KLFs that enhance growth, so future studies need to attack the regeneration inhibitory KLFs.” Another co-author, John Bixby, Ph.D., professor of pharmacology, adds, “It now appears that KLF family members are an important group of regulatory genes for several different classes of CNS neurons.” The researchers hope to expand their studies to further improve on optic nerve and spinal cord regeneration, and to develop methods to translate their findings into human use.