In a study published today in Science, researchers report on their discovery of a molecule secreted by cells in the spinal cord that helps guide axons during a critical stage of central nervous system (CNS) development.
Investigators identified the new axon guidance factor, NELL2, and elucidated how it makes commissural axons creep toward the midline, and how the axons then depart from this area to reach their final destination.
Commissural neurons build circuits that connect the right and left sides of the CNS. A number of inborn diseases have been linked to early developmental failures in which commissural axons lose their way and make inappropriate connections.
Commissural neurons are able to get to the midline because they are attracted there by certain factors, including Netrins," author says. "But once they've crossed the midline, they need to move on, and to do so the neurons somehow switch off their sensitivity to the attractants. At the same time, the neurons become sensitive to repelling factors in the midline, such as Slits. This prevents them from backtracking and helps them move forward."
The researchers knew that a receptor protein called Robo3 is a key controller of the switch in which commissural neurons are initially attracted to the midline and then begin to avoid it.
In the current study, the researchers made the unexpected discovery that Robo3 has a third action that dovetails with the first two. By biochemically isolating proteins that bind to Robo3 from a vast pool of cell-secreted factors, they found that a protein called NELL2 binds to Robo3. In a series of mouse experiments, they were able to show that NELL2 is present in the developing spinal cord and directs the paths of commissural axons through repulsion by activating Robo3 receptors.
"We found that NELL2 is an axon-repulsion factor that helps the axon get to the midline," author says. "The Robo3 receptor therefore receives and coordinates input from not one but at least three diverse signaling molecules -- NELL2, Netrins, and Slits -- to fine tune an axon's journey across and away from the midline."