Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Curr Top Dev Biol. 2021;142:147-196. doi: 10.1016/bs.ctdb.2020.11.008. Epub 2021 Jan 18.
As the nervous system develops, newly differentiated neurons need to extend their axons toward their synaptic targets to form functional neural circuits. During this highly dynamic process of axon pathfinding, guidance receptors expressed at the tips of motile axons interact with soluble guidance cues or membrane tethered molecules present in the environment to be either attracted toward or repelled away from the source of these cues. As competing cues are often present at the same location and during the same developmental period, guidance receptors need to be both spatially and temporally regulated in order for the navigating axons to make appropriate guidance decisions. This regulation is exerted by a diverse array of molecular mechanisms that have come into focus over the past several decades and these mechanisms ensure that the correct complement of surface receptors is present on the growth cone, a fan-shaped expansion at the tip of the axon. This dynamic, highly motile structure is defined by a lamellipodial network lining the periphery of the growth cone interspersed with finger-like filopodial projections that serve to explore the surrounding environment. Once axon guidance receptors are deployed at the right place and time at the growth cone surface, they respond to their respective ligands by initiating a complex set of signaling events that serve to rearrange the growth cone membrane and the actin and microtubule cytoskeleton to affect axon growth and guidance. In this review, we highlight recent advances that shed light on the rich complexity of mechanisms that regulate axon guidance receptor distribution, activation and downstream signaling.
随着神经系统的发育，新分化的神经元需要将轴突延伸到其突触靶标，以形成功能性神经回路。在这个轴突寻路的高度动态过程中，运动轴突尖端表达的导向受体与环境中存在的可溶性导向线索或膜锚定分子相互作用，被吸引或排斥远离这些线索的来源。由于竞争线索通常存在于同一位置并在同一发育时期，因此导向受体需要在空间和时间上受到调节，以便导航轴突做出适当的导向决策。这种调节是通过过去几十年中关注的一系列不同的分子机制来实现的，这些机制确保了生长锥上存在正确的表面受体复合物，生长锥是轴突尖端的扇形扩展。这个动态的、高度活跃的结构由生长锥边缘排列的片状伪足网络定义，其中散布着指状的丝状伪足突起，用于探索周围环境。一旦轴突导向受体在生长锥表面的正确位置和时间被部署，它们就会通过启动一系列复杂的信号事件来响应各自的配体，这些信号事件用于重排生长锥膜以及肌动蛋白和微管细胞骨架，从而影响轴突生长和导向。在这篇综述中，我们强调了最近的进展，这些进展揭示了调节轴突导向受体分布、激活和下游信号的丰富而复杂的机制。
