Gradient Guides Nerve Growth Down Spinal Cord

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

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

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

"This is remarkable example of the efficiency of nature," saidYimin Zou, Ph.D., assistant professor of neurobiology, pharmacology andphysiology at the University of Chicago. "The nervous system is using asimilar set of chemical signals to regulate axon traffic in bothdirections along the length of the spinal cord."

It may also prove a boon to clinicians, offering clues abouthow to grow new connections among neurons to repair or replace damagednerves. Unlike many other body components, damaged axons in the adultspinal cord cannot adequately repair themselves. An estimated 250,000people 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 controlvoluntary movements and fine-motor skills. These are some of thelongest cells in the body. The corticospinal neurons connect to groupsof neurons along the length of spinal cord, some of which reach out ofthe spinal cord. They pass out of the cord between each pair ofvertebrae and extend to different parts of the body, for example thehand or foot.

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

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

From previous studies, Zou and colleagues knew that a gradientof various Wnt proteins, including Wnt4, formed along the spinal cordaround the time of birth. Here they show that two other proteins, Wnt1and Wnt5a are produced at high concentrations at the top of the cordand at consecutively lower levels farther down.

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

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

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

"Understanding how the brain and the spinal cord are connectedduring embryonic development could give us clues about how to repairdamaged connections in adults with traumatic injury or degenerativedisorders," Zou added.

The National Institute of Neurological Disorders and Stroke,the Schweppe Foundation, the Robert Packard ALS Center at JohnsHopkins, the University of Chicago Brain Research Foundation and theJack 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 Wangand Xuejun Song of the Parker College Research Institute in DallasTexas.