Stanford Medical School researchers have discovered a key gene that controls the development of connections between the brain and the spinal cord. Scientists hope to combine the discovery with further stem-cell research, with the goal of one day giving doctors the power to re-grow spinal cord tissue in injured patients.

Biology Prof. Susan McConnell co-authored the report with research associate Bin Chen and graduate student Laura Schaevitz. Their findings were first published in the November 2005 issue of Proceedings of the National Academy of Sciences (PNAS), and their work was presented at the annual conference of the American College of Neuropsychopharmacology in December. The study was funded by the National Institutes of Health.

The gene, called Fezl, is a DNA-binding protein that controls the development and placement of nerve cells in the body. Researchers isolated it after studying the fetal development of mice, whose nervous systems are similar to human nervous systems. Their hypotheses about Fezl’s role in brain and spinal cord development were confirmed when genetically altered mice, whose Fezl gene had been “knocked out,” failed to develop proper brain-spinal cord connections.

“Normally, Fezl is required for certain brain cells to grow along the pathway that leads into the spinal cord,” said McConnell in an interview with the Stanford News Service. “In the mice lacking the gene for Fezl, this pattern of corticospinal tract development was not observed.”

The implications of the study have excited many in the field.

“The discovery of Fezl is a critical finding in unlocking the intricacies of human brain development and could have important implications in the future treatment of spinal cord injuries,” McConnell said. “Fezl is another critical step in piecing together a complete picture of brain and spinal cord development.”

While applications to medical treatment have yet to be developed, there is hope that isolating the genes that connect the brain and spinal cord will lead to treatment for related injuries, which are particularly severe due to the difficulty the body has in regenerating severed nerve connections called axons. Axon trauma often results in paralysis.

Now that Fezl has been isolated, Chen explained, two major questions remain.

“If we find a way to force Fezl’s expression in the cerebral cortex, we may be able to make these neurons send axons to the spinal cord,” she said. “Second, we want to know what genes are being regulated by Fezl. The goal is to dissect out the whole Fezl genetic pathway.”

The Stanford team’s discovery has fueled enthusiasm and speculation over possible future applications to stem cell therapies. Doctors and researchers may one day be able to use their knowledge of Fezl’s role in fetal spine-brain development to stimulate the re-growth of connections that have been damaged in adult patients. Stem-cell therapies, in particular, rely on knowledge of nature’s cues to undifferentiated cells, which cause them to develop in specialized ways.

As both McConnell and Chen noted, however, much remains to be investigated.

“People have been talking about using stem cell therapy to replace diseased neurons in neurodegenerative disease or spinal injury,” Chen explained. “By studying the Fezl genetic pathway and other similar pathways, we may find a way to manipulate the stem cells to make them become the type of neurons needed for therapeutic purposes.”