Pathfinding by growing axons in the developing nervous system is guided by
diffusible or bound factors that attract or repel the axonal growth cone(1,
2). The cytoplasmic signalling mechanisms that trigger the responses of the
growth cone to guidance factors are mostly unknown(3). Previous studies ha
ve shown that the level and temporal patterns of cytoplasmic Ca2+ can regul
ate the rate of growth-cone extension in vitro(4-8) and in vivo(9). Here we
report that Ca2+ also mediates the turning behaviour of the growth cones o
f cultured Xenopus neurons that are induced by an extracellular gradient of
netrin-1, an established diffusible guidance factor in vivo(1,10). The net
rin-1-induced turning response depends on Ca2+ influx through plasma membra
ne Ca2+ channels, as well as Ca2+-induced Ca2+ release from cytoplasmic sto
res(11). Reduction of Ca2+ signals by blocking either of these two Ca2+ sou
rces converted the netrin-1-induced response from attraction to repulsion.
Activation of Ca2+-induced Ca2+ release from internal stores with a gradien
t of ryanodine in the absence of netrin-1 was Sufficient to trigger either
attractive or repulsive responses, depending on the ryanodine concentration
used. These results support the model that cytoplasmic Ca2+ signals mediat
e growth-cone guidance by netrin-1, and different patterns of Ca2+ elevatio
n trigger attractive and repulsive turning responses.