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Gradient guides nerve growth down spinal cord

August 15, 2005

The same family of chemical signals that attracts developing sensory nerves up the spinal cord toward the brain serves to repel motor nerves, sending them in the opposite direction, down the cord and away from the brain, report researchers at the University of Chicago in the September 2005 issue of Nature Neuroscience (available online August 14). The finding may help physicians restore function to people with paralyzing spinal cord injuries.

Growing nerve cells send out axons, long narrow processes that search out and connect with other nerve cells. Axons are tipped with growth cones, bearing specific receptors, which detect chemical signals and then grow toward or away from the source.

In 2003, University of Chicago researchers reported that a gradient of biochemical signals known as the Wnt proteins acted as a guide for sensory nerves. These nerves have a receptor on the tips of their growth cones, known as Frizzled3, which responds to Wnts.

In this paper, the researchers show that the nerves growing in the opposite direction are driven down the cord, away from the brain, under the guidance of a receptor, known as Ryk, with very different tastes. Ryk sees Wnts as repulsive signals.

"This is remarkable example of the efficiency of nature," said Yimin Zou, Ph.D., assistant professor of neurobiology, pharmacology and physiology at the University of Chicago. "The nervous system is using a similar set of chemical signals to regulate axon traffic in both directions along the length of the spinal cord."

It may also prove a boon to clinicians, offering clues about how to grow new connections among neurons to repair or replace damaged nerves. Unlike many other body components, damaged axons in the adult spinal cord cannot adequately repair themselves. An estimated 250,000 people in the United States suffer from permanent spinal cord injuries, with about 11,000 new cases each year.

This study focused on corticospinal neurons, which control voluntary movements and fine-motor skills. These are some of the longest cells in the body. The corticospinal neurons connect to groups of neurons along the length of spinal cord, some of which reach out of the spinal cord. They pass out of the cord between each pair of vertebrae and extend to different parts of the body, for example the hand or foot.

Zou and colleagues studied the guidance system used to assemble this complex network in newborn mice, where corticospinal axon growth is still underway. Before birth, axons grow out from the cell body of a nerve cell in the motor cortex. The axons follow a path back through the brain to the spinal cord.

By the time of birth, the axons are just growing into the cord. During the first week after birth they grow down the cervical and thoracic spinal cord until they reach their proper position, usually after seven to ten days.

From previous studies, Zou and colleagues knew that a gradient of various Wnt proteins, including Wnt4, formed along the spinal cord around the time of birth. Here they show that two other proteins, Wnt1 and Wnt5a are produced at high concentrations at the top of the cord and at consecutively lower levels farther down.

They also found that motor nerves are guided by Wnts through a different receptor, called Ryk, that mediates repulsion by Wnts. Antibodies that blocked the Wnt-Ryk interaction blocked the downward growth of corticospinal axons when injected into the space between the dura and spinal cord in newborn mice.

This knowledge, coupled with emerging stem cell technologies, may provide the most promising current approach to nervous system regeneration. If Wnt proteins could be used to guide transplanted nerve cells - or someday, embryonic stem cells - to restore the connections between the body and the brain, "it could revolutionize treatment of patients with paralyzing injuries to these nerves," Zou suggests.

"Although half the battle is acquiring the right cells to repair the nervous system," he said, "the other half is guiding them to their targets where they can make the right connections."

"Understanding how the brain and the spinal cord are connected during embryonic development could give us clues about how to repair damaged connections in adults with traumatic injury or degenerative disorders," Zou added.

The National Institute of Neurological Disorders and Stroke, the Schweppe Foundation, the Robert Packard ALS Center at Johns Hopkins, the University of Chicago Brain Research Foundation and the Jack Miller Peripheral Neuropathy Center supported this study.

Additional authors include Yaobu Liu, Jun Shi. Chin-Chun Lu, and Anna Lyuksyutova of the University of Chicago, and Zheng-Bei Wang and Xuejun Song of the Parker College Research Institute in Dallas Texas.

University of Chicago Medical Center