San Raffaele Scientific Institute, Division of Neuroscience, via Olgettina 60, 20132 Milan, Italy; CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
San Raffaele Scientific Institute, Division of Neuroscience, via Olgettina 60, 20132 Milan, Italy.
Neuron. 2022 Dec 21;110(24):4090-4107.e11. doi: 10.1016/j.neuron.2022.09.021. Epub 2022 Oct 13.
The nervous system requires metabolites and oxygen supplied by the neurovascular network, but this necessitates close apposition of neurons and endothelial cells. We find motor neurons attract vessels with long-range VEGF signaling, but endothelial cells in the axonal pathway are an obstacle for establishing connections with muscles. It is unclear how this paradoxical interference from heterotypic neurovascular contacts is averted. Through a mouse mutagenesis screen, we show that Plexin-D1 receptor is required in endothelial cells for development of neuromuscular connectivity. Motor neurons release Sema3C to elicit short-range repulsion via Plexin-D1, thus displacing endothelial cells that obstruct axon growth. When this signaling pathway is disrupted, epaxial motor neurons are blocked from reaching their muscle targets and concomitantly vascular patterning in the spinal cord is altered. Thus, an integrative system of opposing push-pull cues ensures detrimental axon-endothelial encounters are avoided while enabling vascularization within the nervous system and along peripheral nerves.
神经系统需要由神经血管网络提供的代谢物和氧气，但这需要神经元和内皮细胞紧密相邻。我们发现运动神经元通过长程 VEGF 信号吸引血管，但轴突途径中的内皮细胞是与肌肉建立连接的障碍。目前尚不清楚如何避免这种来自异型神经血管接触的矛盾干扰。通过小鼠诱变筛选，我们表明 Plexin-D1 受体在内皮细胞中对于神经肌肉连接的发育是必需的。运动神经元释放 Sema3C，通过 Plexin-D1 引发短程排斥，从而排斥阻碍轴突生长的内皮细胞。当这种信号通路被破坏时，背侧运动神经元无法到达其肌肉靶标，同时脊髓中的血管模式也发生改变。因此，一个相互矛盾的推拉线索的综合系统确保了避免有害的轴突-内皮接触，同时允许神经系统内和周围神经内的血管化。
