ECM communicates with MMP

In This Issue In This Issue cGMP steers axons home n 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 cGKI ␣. This effector O Branching of sensory axons lacking cGKI (right) is biased to one side. he extracellular matrix (ECM) orchestrates its own destruction, according to results by Gálvez et al. (page 509). Many different proteins, such as collagen (COL), fibronectin (FN), and gelatin T (GEL), make up the basement membranes and connective tissues of ECM-rich tissues. Their degradation by membrane-type matrix metalloprotease 1 (MT1-MMP) is required for cell migration. But it now appears that ECM proteins are not passive victims in this process—they influence the location and activity of the MT1-MMP (green) is inactive when associated with ␤1 integrin (red, left) between static cells, but active when associated with ␣ v ␤ 3 integrin (red, right) in migrating cells. protease by recruiting the help of cell adhesion receptors. Using MT1-MMP fused to GFP in endothelial cells, Gálvez et al. noted that the protease had an unusual association with ␤ 1 integrin at cell–cell contact sites on ␤ 1 integrin–dependent substrates 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 cGKI ␣ 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 cGKI ␣ , remains unknown. The kinase sits in lamellipodia and filopodia of the growth cone, well-placed to shift the trajectory …