Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
J Neurosci. 2011 Apr 20;31(16):6174-87. doi: 10.1523/JNEUROSCI.5464-10.2011.
Cortical interneurons, generated predominantly in the medial ganglionic eminence, migrate around and avoid the developing striatum in the subpallium en route to the cortex. This is attributable to the chemorepulsive cues of class 3 semaphorins expressed in the striatal mantle and acting through neuropilin (Nrp1 and Nrp2) receptors expressed in these cells. Cortical interneurons also express Robo receptors, and we show here that in mice lacking Robo1, but not Robo2, these cells migrate aberrantly through the striatum. In vitro experiments demonstrated that interneurons lacking Robo1 function are significantly less responsive to the effects of semaphorins. Failure to respond to semaphorin appears to be attributable to a reduction in Nrp1 and PlexinA1 receptors within these cells. Biochemical studies further demonstrated that Robo1 binds directly to Nrp1, but not to semaphorins, and this interaction is mediated by a region contained within its first two Ig domains. Thus, we show for the first time that Robo1 interacts with Nrp1 to modulate semaphorin signaling in the developing forebrain and direct the migration of interneurons through the subpallium and into the cortex.
皮质中间神经元主要在前内侧神经节隆起产生，在迁移到皮质的过程中，它们会在到达皮质前，在靠近边缘层的地方绕过并避开发育中的纹状体。这归因于在纹状体外壳中表达的 class 3 神经导向分子 semaphorin 所产生的化学排斥信号，这些信号通过在这些细胞中表达的神经纤毛蛋白（Nrp1 和 Nrp2）受体起作用。皮质中间神经元也表达 Robo 受体，我们在这里表明，在缺乏 Robo1 但不缺乏 Robo2 的小鼠中，这些细胞会异常地通过纹状体迁移。体外实验表明，缺乏 Robo1 功能的中间神经元对 semaphorin 的作用的反应明显降低。对 semaphorin 无反应似乎归因于这些细胞内 Nrp1 和 PlexinA1 受体的减少。生化研究进一步表明，Robo1 直接与 Nrp1 结合，而不是与 semaphorin 结合，这种相互作用是由其前两个 Ig 结构域内的一个区域介导的。因此，我们首次表明 Robo1 通过与 Nrp1 相互作用来调节发育中的前脑的 semaphorin 信号，并指导中间神经元通过侧脑皮质迁移到皮质。
