Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals
Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals
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DOI：
10.1016/j.isci.2020.100963
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发表时间：
2020-03-27
期刊：
影响因子：
5.8
通讯作者：
Kamiguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Chan, Carmen;Ooashi, Noriko;Kamiguchi, Hiroyuki
在神经发育过程中，生长锥通过信号放大从细胞外引导信号中破译呈现为浅浓度梯度的方向信息。然而，目前尚不清楚生长锥在基本线索浓度变化很大的环境中导航时是如何控制这种放大过程的。在这里，我们在体外和体内发现，肌醇1，4，5-三磷酸(IP3)受体3型是轴突对引导线索敏感性的调节因子。缺少3型亚基的生长锥对神经生长因子(NGF)高度敏感，NGF是一种依赖于IP3的诱人信号，并且不能转向野生型生长锥对NGF的正常浓度范围做出反应。这是由于全局的，但不是不对称的，激活了高度敏感的生长锥体中的钙信号。值得注意的是，如果IP3受体3型缺乏，较低的NGF浓度可以极化生长锥体以进行转向。这些数据表明，在轴突导航过程中，亚型特异的IP3受体在敏感度调节中发挥作用。
During neurodevelopment, the growth cone deciphers directional information from extracellular guidance cues presented as shallow concentration gradients via signal amplification. However, it remains unclear how the growth cone controls this amplification process during its navigation through an environment in which basal cue concentrations vary widely. Here, we identified inositol 1,4,5-trisphosphate (IP3) receptor type 3 as a regulator of axonal sensitivity to guidance cues in vitro and in vivo. Growth cones lacking the type 3 subunit are hypersensitive to nerve growth factor (NGF), an IP3-dependent attractive cue, and incapable of turning toward normal concentration ranges of NGF to which wild-type growth cones respond. This is due to globally, but not asymmetrically, activated Ca2+ signaling in the hypersensitive growth cones. Remarkably, lower NGF concentrations can polarize growth cones for turning if IP3 receptor type 3 is deficient. These data suggest a subtype-specific IP3 receptor function in sensitivity adjustment during axon navigation.