Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, the Netherlands.
Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany; Center for Biostructural Imaging of Neurodegeneration, 37075 Göttingen, Germany.
Prog Neurobiol. 2021 Mar;198:101916. doi: 10.1016/j.pneurobio.2020.101916. Epub 2020 Sep 28.
During the development of the nervous system, axons extend through complex environments. Growth cones at the axon tip allow axons to find and innervate their appropriate targets and form functional synapses. Axon pathfinding requires axons to respond to guidance signals and these cues need to be detected by specialized receptors followed by intracellular signal integration and translation. Several downstream signaling pathways have been identified for axon guidance receptors and it has become evident that these pathways are often initiated from intracellular vesicles called endosomes. Endosomes allow receptors to traffic intracellularly, re-locating receptors from one cellular region to another. The localization of axon guidance receptors to endosomal compartments is crucial for their function, signaling output and expression levels. For example, active receptors within endosomes can recruit downstream proteins to the endosomal membrane and facilitate signaling. Also, endosomal trafficking can re-locate receptors back to the plasma membrane to allow re-activation or mediate downregulation of receptor signaling via degradation. Accumulating evidence suggests that axon guidance receptors do not follow a pre-set default trafficking route but may change their localization within endosomes. This re-routing appears to be spatially and temporally regulated, either by expression of adaptor proteins or co-receptors. These findings shed light on how signaling in axon guidance is regulated and diversified - a mechanism which explains how a limited set of guidance cues can help to establish billions of neuronal connections. In this review, we summarize and discuss our current knowledge of axon guidance receptor trafficking and provide directions for future research.
在神经系统发育过程中，轴突在复杂的环境中延伸。轴突尖端的生长锥允许轴突找到并支配其适当的靶标，并形成功能性突触。轴突导向需要轴突对导向信号做出反应，这些线索需要被专门的受体检测到，然后进行细胞内信号整合和翻译。已经确定了几种用于轴突导向受体的下游信号通路，并且很明显，这些通路通常是从称为内体的细胞内小泡开始的。内体允许受体在细胞内运输，将受体从一个细胞区域重新定位到另一个区域。轴突导向受体在内体区室中的定位对于它们的功能、信号输出和表达水平至关重要。例如，内体中的活性受体可以招募下游蛋白到内体膜上，并促进信号转导。此外，内体运输可以将受体重新定位到质膜上，允许受体重新激活或通过降解来调节受体信号的下调。越来越多的证据表明，轴突导向受体不会遵循预设的默认运输途径，而是可能在内体内改变其定位。这种重新路由似乎受到空间和时间的调节，要么通过衔接蛋白或共受体的表达，要么通过衔接蛋白或共受体的表达。这些发现揭示了轴突导向中的信号转导是如何被调节和多样化的——这一机制解释了为什么有限数量的导向线索可以帮助建立数十亿个神经元连接。在这篇综述中，我们总结并讨论了我们目前对内体运输的了解，并为未来的研究提供了方向。
