Glaucoma is a family of neurodegenerative diseases that can lead to death of retinal ganglion cells (RGCs), which results in progressive vision loss and ultimately blindness. RGCs are neurons in the optic nerve that relay visual impulses from the retina to the brain where final visual processing occurs. Although the causes of RGC degeneration are not completely understood, axon loss is an early component in the disease. Axons are the fiber-like extensions of a neuron which transmit electrical signals to other neuronal cells. Developing neurons can regenerate new axons; however, adult neurons cannot. Investigators are examining the genetic mechanisms involved in axonal loss and regeneration. These studies provide insight necessary to develop therapies for glaucoma and other common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease.
NIH investigators examined changes in neuronal gene expression during the developmental time period when the ability to regenerate axons declines. This allowed investigators to identify genes that are highly expressed and thus likely to play a role in inhibiting axon regeneration. One highly expressed gene, KLF4 (Kruppel-like factor 4), suppresses axon growth by 50 percent in cell cultures, suggesting an important role in controlling axon formation. Conversely, adult mice lacking KLF4 expression in RGCs experienced significant axon growth after nerve injury. KLF4 is one of 17 members of the family of KLF transcription factors that regulate gene expression cooperatively and competitively. In total, these investigators found that eight KLFs, including KLF4 and KLF9, suppressed axon growth, and two of them, KLF6 and KLF7, significantly increased axon growth. These results suggest that multiple KLF transcription factors act in concert to regulate the formation and growth of axons.
Public Impact Statement/Significance:
This is the first study to demonstrate that mature neurons can regenerate axons by manipulating KLF genes. Furthermore, the balance of the expression of several members of this gene family may offer clues about how to increase the intrinsic regenerative capacity of mature CNS neurons damaged by injury or disease.
R03EY016790; P30EY014801; NS061348.
Moore DL et al., KLF Family Members Regulate Intrinsic Axon Regeneration Ability. Science. 2009; 326(5950): 298-301. PubMed
Last Reviewed: January 2010