Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
Dev Cell. 2015 Dec 7;35(5):537-552. doi: 10.1016/j.devcel.2015.11.008.
Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure.
许多导向受体通过 ADAM 家族的膜相关金属蛋白酶进行蛋白水解切割，导致其细胞外结构域脱落。细胞外结构域脱落对于受体信号转导和功能至关重要，但神经元中这一过程是如何控制的仍知之甚少。本文中，作者发现跨膜蛋白 Lrig2 负调控神经元中 ADAM 介导的导向受体蛋白水解。Lrig2 结合 Neogenin，一种排斥性导向分子（RGM）的受体，并通过 ADAM17（TACE）防止 Neogenin 的过早脱落。RGMa 减少了 Lrig2-Neogenin 相互作用，使 ADAM17 能够接触到 Neogenin，并允许该蛋白酶诱导细胞外结构域脱落。Lrig2 调控 ADAM17 介导的 Neogenin 切割对于 RGMa 在体外抑制神经突生长和体内皮质神经元迁移是必需的。此外，Lrig2 的敲低显著改善了中枢神经系统轴突再生。综上，这些数据确定了一种独特的配体门控机制来控制 ADAMs 的受体脱落，并揭示了 Lrig 在神经元迁移和再生失败中的作用。
