The Nitric Oxide–cGMP Pathway Controls the Directional Polarity of Growth Cone Guidance via Modulating Cytosolic Ca2+ Signals
The Nitric Oxide–cGMP Pathway Controls the Directional Polarity of Growth Cone Guidance via Modulating Cytosolic Ca2+ Signals
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DOI：
10.1523/jneurosci.0087-09.2009
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发表时间：
2009-06
期刊：
影响因子：
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通讯作者：
T. Tojima;Rurika Itofusa;H. Kamiguchi
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文献类型：
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作者：
T. Tojima;Rurika Itofusa;H. Kamiguchi
生长锥上的不对称Ca 2+信号介导吸引或排斥轴突导向，这取决于通过兰尼碱受体（RyRs）发生Ca 2+诱导的Ca 2+释放（CICR）。虽然一氧化氮合酶（nNOS）的神经亚型在发育中的背根神经节（DRG）神经元中高度表达，但NO在轴突导向中的作用仍然是未知的。在这里，我们报告，NO-cGMP途径负调控CICR控制DRG轴突导向的方向极性。NO和cGMP的细胞内水平取决于细胞外底物：层粘连蛋白激活NO-cGMP途径，而粘附分子L1不激活。NO和cGMP的活性决定了生长锥相对于由光解笼状Ca 2+产生的不对称Ca 2+信号的转向。Ca 2+信号引起生长锥对层粘连蛋白底物的排斥，其通过NO-cGMP途径的药理学阻断或nNOS的遗传缺失转化为吸引。相反，Ca 2+诱导的生长锥上的L1基板的吸引力转化为排斥通过增加NO水平。这种NO介导的转向转换涉及通过RyR调节CICR。此外，生长锥排斥诱导的细胞外梯度的生理线索，神经营养素-4，是依赖于Ca 2+信号和转化为吸引力通过抑制NO-cGMP途径。这些结果表明，在接触不同的粘附环境，生长锥可以通过调节CICR通过内源性NO和cGMP来改变它们的转向反应轴突的指导线索。
Asymmetric Ca2+ signals across the growth cone mediate attractive or repulsive axon guidance depending on the occurrence of Ca2+-induced Ca2+ release (CICR) through ryanodine receptors (RyRs). Although the neuronal isoform of nitric oxide (NO) synthase (nNOS) is highly expressed in developing dorsal root ganglion (DRG) neurons, the role of NO in axon guidance remains essentially unknown. Here we report that the NO–cGMP pathway negatively regulates CICR to control the directional polarity of DRG axon guidance. Intracellular levels of NO and cGMP depend on extracellular substrates: laminin activates the NO–cGMP pathway, whereas the adhesion molecule L1 does not. The activity of NO and cGMP determines the turning direction of growth cones with respect to asymmetric Ca2+ signals that are produced by photolysing caged Ca2+. The Ca2+ signals cause growth cone repulsion on a laminin substrate, which is converted to attraction by pharmacological blockade of the NO–cGMP pathway or genetic deletion of nNOS. Conversely, Ca2+-induced growth cone attraction on an L1 substrate is converted to repulsion by increasing NO levels. Such NO-mediated switching of turning direction involves the regulation of CICR through RyRs. Furthermore, growth cone repulsion induced by an extracellular gradient of a physiological cue, neurotrophin-4, is dependent on Ca2+ signals and converted to attraction by inhibiting the NO–cGMP pathway. These results suggest that, on contact with different adhesive environments, growth cones can change their turning responses to axon guidance cues by modulating CICR via endogenous NO and cGMP.