Turning of nerve growth cones induced by localized increases in intracellular calcium ions

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Abstract
Guidance of developing axons involves turning of the motile tip, the growth cone, in response to a variety of extracellular cues1,2. Little is known about the intracellular mechanism by which the directional signal is transduced. Ca2+ is a key second messenger in growth cone extension3,4 and has been implicated in growth-cone turning5,6. Here I report that a direct, spatially restricted elevation of intracellular Ca2+ concentration ([Ca2+]i) on one side of the growth cone by focal laser-induced photolysis (FLIP) of caged Ca2+ consistently induced turning of the growth cone to the side with elevated [Ca2+]i (attraction). Furthermore, when the resting [Ca2+]i at the growth cone was decreased by the removal of extracellular Ca2+, the same focal elevation of [Ca2+]i by FLIP induced repulsion. These results provide direct evidence that a localized Ca2+ signal in the growth cone can provide the intracellular directional cue for extension and is sufficient to initiate both attraction and repulsion. By integrating local and global Ca2+ signals, a growth cone could thus generate different turning responses under different environmental conditions during guidance.