Role of neuronal migration for the formation of neuronal connections

苔藓纤维突起的小脑前神经元（PCN）的发育是切向神经元迁移的一个经典例子。在PCN中，脑桥神经元遵循典型的前腹侧定向通路在脑桥内形成脑桥核。决定PCN边缘迁移和脑桥神经元前向迁移的引导机制尚不清楚。在这里，我们报道了来自脑膜组织的趋化因子SDF1调节PCN的迁移途径。PCN受到脑膜组织的化学吸引，这是SDF1源所模拟的效果。对Sdf1受体Cxcr4敲除小鼠的分析表明，PCN的边缘迁移和脑桥神经元的前向迁移均被破坏。我们进一步发现SDF1/CXCR4信号可以细胞自主调节这两个过程。由于神经元迁移中断，脑桥核形成高度异常，后侧出现多个异位脑桥簇。异位脑桥簇导致皮质脊髓束形成异位侧支。我们的研究结果共同证明了SDF1/CXCR4在PCN迁移的多个方面的关键作用，并强调了偏离迁移对正常细胞核形成的有害后果。此外，我们提供了第一个活体证据，证明脑桥神经元本身诱导皮层脊髓轴突的侧支。

The development of mossy-fibre projecting precerebellar neurons (PCN) presents a classical example of tangential neuronal migration. Among the PCN, the pontine neurons follow a stereotypic anteroventral-directed pathway to form the pontine nuclei in the pons. The guidance mechanisms that determine the marginal migration of PCN and the anterior migration of pontine neurons are poorly understood. Here, we report that a chemokine SDF1 derived from the meningeal tissue regulates the migratory pathways of PCN. PCN are chemoattracted by the meningeal tissue, an effect that is mimicked by an SDF1 source. Analysis of knockout mice for the Sdf1 receptor Cxcr4 shows that both the marginal migration of PCN and the anterior migration of pontine neurons are disrupted. We further find that SDF1/CXCR4 signalling regulates these two processes cell-autonomously. As a result of disrupted neuronal migration, pontine nuclei formation was highly abnormal, with the presence of multiple ectopic pontine clusters posteriorly. The ectopic pontine clusters led to ectopic collateral branch formation from the corticospinal tract. Our results together demonstrate crucial roles for SDF1/CXCR4 in multiple aspects of PCN migration and highlight the deleterious consequence of derailed migration on proper nuclei formation. Furthermore, we provide the first in vivo evidence that pontine neurons themselves induce collateral branching from the corticospinal axons.