Branching of sensory axons lacking cGKI (right) is biased to one side.

On page 489, Schmidt et al. identify a second messenger that helps to steer growth cones. Without this cGMP-directed guidance system, sensory axons lose their way during development.

Axonal pathfinding and cyclic nucleotide second messengers have been linked by recent in vitro studies showing that cGMP protects growth cones from collapse induced by repulsive cues. Now, Schmidt et al. show that cGMP is required for axon guidance in vivo, at least in sensory neurons.

To decipher cGMP function during axon growth in vivo, the group deleted the effector kinase cGKIα. This effector was expressed in embryonic sensory axons in wild-type mice, suggesting that sensory neurons might be affected in the deletion mice. Wild-type sensory axons traveled to the spinal cord, where they formed T-like branches and extended in both directions. Axons lacking cGKIα had difficulties performing this task.

Rather than splitting evenly at the branch point, axons in the mutant mice preferred to extend in one direction. They continued to grow toward the center of the spinal cord, but the branching defects resulted in fewer sensory axons there. The errors had significant physiological effects, including dampened pain reflexes, as measured by electrical stimulation of in vitro spinal cord preparations.

How cGMP signaling is transduced, both upstream and downstream of cGKIα, remains unknown. The kinase sits in lamellipodia and filopodia of the growth cone, well-placed to shift the trajectory of the growing axon when it encounters the appropriate guidance factors. The group is now looking for guidance factor receptors that activate adenylate cyclases (and thus increase cGMP levels). cGMP activation of cGKIα might change the growth cone direction by triggering remodeling of the actin cytoskeleton, by phosphorylating the actin-organizing protein VASP, for example. ▪