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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >α2-chimaerin regulates a key axon guidance transition during development of the oculomotor projection
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α2-chimaerin regulates a key axon guidance transition during development of the oculomotor projection

机译：α2-chierererin在动眼神经投影发展过程中调节关键的轴突导向过渡

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摘要

The ocular motor system consists of three nerves which innervate six muscles to control eye movements. In humans, defective development of this system leads to eye movement disorders, such as Duane Retraction Syndrome, which can result from mutations in the α2-chimaerin signaling molecule. We have used the zebrafish to model the role of α2-chimaerin during development of the ocular motor system. We first mapped ocular motor spatiotemporal development, which occurs between 24 and 72 h postfertilization (hpf), with the oculomotor nerve following an invariant sequence of growth and branching to its muscle targets. We identified 52 hpf as a key axon guidance "transition," when oculomotor axons reach the orbit and select their muscle targets. Live imaging and quantitation showed that, at 52 hpf, axons undergo a switch in behavior, with striking changes in the dynamics of filopodia. We tested the role of α2-chimaerin in this guidance process and found that axons expressing gain-of-function α2-chimaerin isoforms failed to undergo the 52 hpf transition in filopodial dynamics, leading to axon stalling. α2-chimaerin loss of function led to ecotopic and misguided branching and hypoplasia of oculomotor axons; embryos had defective eye movements as measured by the optokinetic reflex. Manipulation of chimaerin signaling in oculomotor neurons in vitro led to changes in microtubule stability. These findings demonstrate that a correct level of α2-chimaerin signaling is required for key oculomotor axon guidance decisions, and provide a zebrafish model for Duane Retraction Syndrome.
机译：眼动系统由三个神经支配，其中六个神经支配着六块肌肉以控制眼睛的运动。在人类中，该系统发育不良会导致眼球运动障碍，例如Duane收缩综合症，这可能是由α2-chiererin信号分子的突变引起的。我们已经使用斑马鱼来模拟α2-chimaerin在眼运动系统发育过程中的作用。我们首先绘制了眼动时空发育图，其发生在受精后的24至72 h（hpf）之间，动眼神经遵循不变的生长顺序并分支到其肌肉目标。当动眼神经轴突到达轨道并选择其肌肉目标时，我们确定52 hpf是关键的轴突指导“过渡”。实时成像和定量分析显示，在52 hpf时，轴突的行为发生了变化，丝虫足的动力学发生了显着变化。我们测试了α2-chimaerin在该指导过程中的作用，发现表达功能增强的α2-chimaerin同工型的轴突未能通过52 hpf过渡态的动力学，导致轴突失速。 α2-chierererin功能丧失导致动眼神经轴突的异位和分支错误以及发育不全;视动反射测量表明，胚胎的眼球运动不良。体外动眼神经元中chimaerin信号的操纵导致微管稳定性的变化。这些发现表明关键的动眼神经轴突指导决策需要正确水平的α2-chimaerin信号传导，并为杜安回缩综合征提供了斑马鱼模型。

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