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Researchers Pinpoint Genes with Key Role in Neuronal Growth and Regeneration

For release: Friday, November 20, 2009

The adult brain has a relatively poor capacity to grow and recover from damage.  Within the developing brain, however, nerve cells must grow long fibers, navigate toward their targets and form complex connections.  Many neuroscientists theorize that reactivating this capacity for growth could be the key to effective therapies for stroke and other neurological injuries.

In a new study funded by the National Institute of Neurological Disorders and Stroke (NINDS), investigators identified a set of genes that are regulated during development, and that in turn regulate the capacity of nerve cells to grow.  In the future, drugs or small molecules that target these genes could be used to stimulate nerve regeneration following an injury.

The study was published in Science,* and was led by scientists at the University of Miami Miller School of Medicine in Florida.  The senior authors were Jeffrey Goldberg, M.D., Ph.D., assistant professor of ophthalmology and neuroscience, along with Vance Lemmon, Ph.D., professor of neurosurgery, and John Bixby, Ph.D., professor of pharmacology and neuroscience.

Most of the experiments focused on retinal ganglion cells, which originate at the back of the eye, in the retina, and send their axons to the brain via the optic nerve.  Dr. Goldberg’s group previously surveyed the expression (activity) of thousands of genes in these neurons at different ages in rats, from embryonic life to adulthood.  They also charted the neurons’ decline in growth capacity over time, and found that it coincided with changes in gene expression.

In the new study, Dr. Goldberg and his colleagues examined 111 of these developmentally regulated genes, giving isolated neurons an overload of each gene to test their individual effects on growth.  A gene called KLF4 dramatically suppressed the number and length of neurites (nerve fibers) on each cell.  The researchers found similar results whether they looked at retinal ganglion cells or other brain cells, including cortical neurons, which include the neurons affected in spinal cord injuries.

The researchers also used state-of-the-art genetic techniques to eliminate the KLF4 gene from the retinal ganglion cells of mice.  Compared to genetically normal mice, adult mice lacking KLF4 showed enhanced neuronal regeneration after an injury to their optic nerves.

Further study revealed that several members of the KLF gene family regulate neurite growth, some with negative effects similar to KLF4 and others with positive effects.  With increasing age, some of the growth-suppressing KLF genes become more highly expressed while the growth-enhancing KLF become less expressed.  All of the KLF genes are transcription factors, which means that they regulate the activity of other genes.

“Manipulating multiple KLF genes may be a useful strategy…to increase the intrinsic regenerative capacity of mature central nervous system neurons damaged by injury or disease,” the authors wrote.

-By Daniel Stimson, Ph.D.

*Moore DL et al.  “KLF Family Members Regulate Intrinsic Axon Regeneration Ability.” Science, October 9, 2009, Vol. 326, pp. 298-301.

Last Modified November 20, 2009