Calcium signalling in the guidance of nerve growth by netrin-1
Calcium signalling in the guidance of nerve growth by netrin-1
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作者：
Hong, K;Nishiyama, M;Poo, MM
在发育中的神经系统中，生长轴突的寻路是由吸引或排斥轴突生长锥的扩散或结合因子引导的（1,2）。引发生长锥对引导因子反应的细胞质信号机制大多是未知的(3)。先前的研究表明，细胞质Ca2+的水平和时间模式可以调节生长锥在体外（4-8）和体内(9)的延伸速度。在这里，我们报道Ca2+也介导了培养的爪蟾神经元生长锥的转向行为，这是由netrin-1的细胞外梯度诱导的，netrin-1是一种在体内建立的扩散引导因子（1,10）。netrin-1诱导的转向反应依赖于Ca2+通过质膜Ca2+通道的内流，以及Ca2+诱导的Ca2+从细胞质储存中释放（11）。通过阻断这两个Ca2+源中的任何一个来减少Ca2+信号，将netrin-1诱导的反应从吸引转化为排斥。在没有netrin-1的情况下，激活Ca2+诱导的Ca2+释放从内部储存中释放，足以触发吸引或排斥反应，这取决于所使用的ryanodine浓度。这些结果支持细胞质Ca2+信号介导netrin-1的生长锥引导的模型，以及不同模式的Ca2+升高触发吸引和排斥转向反应。
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 have shown that the level and temporal patterns of cytoplasmic Ca2+ can regulate 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 of cultured Xenopus neurons that are induced by an extracellular gradient of netrin-1, an established diffusible guidance factor in vivo(1,10). The netrin-1-induced turning response depends on Ca2+ influx through plasma membrane Ca2+ channels, as well as Ca2+-induced Ca2+ release from cytoplasmic stores(11). Reduction of Ca2+ signals by blocking either of these two Ca2+ sources converted the netrin-1-induced response from attraction to repulsion. Activation of Ca2+-induced Ca2+ release from internal stores with a gradient 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 mediate growth-cone guidance by netrin-1, and different patterns of Ca2+ elevation trigger attractive and repulsive turning responses.