Nerve Navigation Findings Prompt New Direction for Spinal Cord Research

A piece of the puzzle of how nerves find their way across the midline of the brain and spinal cord in a developing embryo has been found by Medical College of Georgia researchers.

They have found that an enzyme called focal adhesion kinase tells the arm-like extension of a neuron to cross the midline of the spinal cord, says Dr. Wen-Cheng Xiong, developmental neurobiologist and lead author on the paper in the November issue of Nature Neuroscience. After crossing, the axon becomes part of the complex network that enables the right side of the brain to control the left side of the body and vice versa.

The finding helps explain normal development of the nervous systems and provides a new target in the search for ways to re-establish connections — and the movement and feeling they enable — lost to spinal cord injuries. “This kinase plays a role in helping direct axon movement across the spinal cord during development,” Dr. Xiong says. “How it does that is one of the questions we hope to answer next. We still have a lot of questions.” Among those is why this mechanism doesn’t seem to work after development is complete. “If the spinal cord is injured, why doesn’t it re-cross that boundary?” she says. “Why are these molecules not functioning well in the adult?”

Focal adhesion kinase already is a hot topic among scientists studying how cells migrate and how tumor cells spread. Now, Dr. Xiong and her collaborators have found the enzyme also plays an important role in central nervous system development. She explains that for axons to journey across the spinal cord, floor plate cells along this natural midline of the developing body secrete a guidance or cue factor called netrin-1. “If this molecule is deleted, this axon cannot cross. It just stays on this side” and the developing embryo will die, a testimony to netrin’s expansive role in getting cells where they need to be. “This factor plays a critical role for nearly all the neurons to cross the midline, even in the cortex or hippocampus of the brain,” Dr. Xiong says.

A receptor on the axon called DCC, or Deleted in Colon Cancer, responds to the signal from netrin. But why the axon knows to move in a certain direction once it sees that signal was an unknown, Dr. Xiong says. The researchers have now found that once this receptor binds to netrin, focal adhesion kinase is activated that tells the axon to reorganize its structure or cytoskeleton and the restructured axon knows how to move. When they delete the kinase, the axon doesn’t make the proper journey or the proper connection.

Developing axons can sense and navigate their environment but how the two functions work together to result in the axon getting where it needs to be is poorly understood, Dr. Xiong says. “Everybody in the developmental neurobiology field is wondering what is the mechanism, how the neuron, once it senses the environment, couples with the motor activity. This provides information for that kind of puzzle,” she says of the newly published work.

The researchers are looking for other molecules that also play a role in directing axonal growth. “We have lots of information about how this molecule talks with other molecules,” Dr. Xiong says. “We just need to get a system to figure out how they talk to each other.” She’s also moving toward an injury model to see what happens to this molecular talk after a spinal cord injury. “We know this factor can turn on but we don’t know how it turns on. If you sever the spinal cord, the important crossing of the axon is gone. Right now, we don’t know how to make it go back.”

Drs. Xiong’s MCG collaborators on the study include her husband, Dr. Lin Mei, also a developmental neurobiologist; research technician Zhu Feng and graduate student Qiang Wang as well as researchers at the University of Alabama at Birmingham; Johns Hopkins University School of Medicine; and Washington University School of Medicine.

Her research is funded by the National Institutes of Health.