The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2012 Dec 6;76(5):931-44. doi: 10.1016/j.neuron.2012.10.009.
Precise patterning of axon guidance cue distribution is critical for nervous system development. Using a murine forward genetic screen for novel determinants of axon guidance, we identified B3gnt1 and ISPD as required for the glycosylation of dystroglycan in vivo. Analysis of B3gnt1, ISPD, and dystroglycan mutant mice revealed a critical role for glycosylated dystroglycan in the development of several longitudinal axon tracts. Remarkably, the axonal guidance defects observed in B3gnt1, ISPD, and dystroglycan mutants resemble several of the axon guidance defects found in mice lacking the axon guidance cue Slit and its receptor Robo. This similarity is explained by our observations that dystroglycan binds directly to Slit and is required for proper Slit localization within the basement membrane and floor plate in vivo. These findings establish a novel role for glycosylated dystroglycan as a key determinant of axon guidance cue distribution and function in the mammalian nervous system.
精确的轴突导向线索分布模式对于神经系统的发育至关重要。我们利用一种新型的小鼠正向遗传学筛选方法，用于寻找新的轴突导向决定因素，发现 B3gnt1 和 ISPD 是糖基化肌聚糖在体内所必需的。对 B3gnt1、ISPD 和肌聚糖突变小鼠的分析揭示了糖基化肌聚糖在几个长轴突束发育中的关键作用。值得注意的是，B3gnt1、ISPD 和肌聚糖突变体中观察到的轴突导向缺陷与缺乏轴突导向线索 Slit 和其受体 Robo 的小鼠中发现的几种轴突导向缺陷相似。我们的观察结果解释了这种相似性，即肌聚糖直接结合 Slit，并在体内对 Slit 在基底膜和基板内的正确定位是必需的。这些发现确立了糖基化肌聚糖作为哺乳动物神经系统中轴突导向线索分布和功能的关键决定因素的新作用。
