In vivo regulation of axon extension and pathfinding by growth-cone calcium transients

Growth cones at the tips of extending neurites migrate through complex environments in the developing nervous system and guide axons to appropriate target regions using local cues 1 , 2 . The intracellular calcium concentration ([Ca 2+ ] i ) of growth cones correlates with motility in vitro 3 , 4 , 5 , 6 , 7 , but the physiological links between environmental cues and axon growth in vivo are unknown. Here we report that growth cones generate transient elevations of [Ca 2+ ] i as they migrate within the embryonic spinal cord and that the rate of axon outgrowth is inversely proportional to the frequency of transients. Suppressing Ca 2+ transients by photorelease of a Ca 2+ chelator accelerates axon extension, whereas mimicking transients with photorelease of Ca 2+ slows otherwise rapid axonal growth. The frequency of Ca 2+ transients is cell-type specific and depends on the position of growth cones along their pathway. Furthermore, growth-cone stalling and axon retraction, which are two important aspects of pathfinding 8 , 9 , 10 , are associated with high frequencies of Ca 2+ transients. Our results indicate that environmentally regulated growth-cone Ca 2+ transients control axon growth in the developing spinal cord.