Ward Michael, McCann Corey, DeWulf Michael, Wu Jane Y, Rao Yi
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2003 Jun 15;23(12):5170-7. doi: 10.1523/JNEUROSCI.23-12-05170.2003.
Although neuronal migration is an essential process in development, how neural precursors reach their final destination in the nervous system is not well understood. Secreted molecules that are known to be involved in axon guidance are likely to play important roles in regulating neuronal migration, but an important issue that remains unclear is whether such molecules act as directional guidance cues or as motility regulators in neuronal migration. The secreted protein Slit was initially suggested to be a repellent for migrating neurons (Wu et al., 1999). However, it was concluded recently that Slit plays an inhibitory rather than a repulsive role in neuronal migration (Mason et al., 2001). We have developed a series of assays that allow us to differentiate between repulsive and inhibitory effects of secreted molecules, and we demonstrate that Slit is a repellent capable of reversing the direction of neurons migrating either in culture or in their native pathways. We also show that although Slit reduces migratory speed under certain conditions, it can function as a repellent without concurrent inhibition of neuronal migration. This is the first study to clearly demonstrate that migrating neurons can be directionally guided by secreted molecules. These findings provide a basis to understand the physiological roles of secreted molecules in the developing nervous system and have implications on how they could be applied therapeutically. Our results also indicate that it should be possible to determine the specific action of other molecules as directional guidance cues or as motility regulators of cell migration.
尽管神经元迁移是发育过程中的一个重要过程，但神经前体细胞如何在神经系统中到达其最终目的地仍未得到很好的理解。已知参与轴突导向的分泌分子可能在调节神经元迁移中发挥重要作用，但一个尚不清楚的重要问题是，这些分子在神经元迁移中是作为定向引导信号还是作为运动调节因子起作用。分泌蛋白Slit最初被认为是迁移神经元的排斥因子（Wu等人，1999年）。然而，最近得出的结论是，Slit在神经元迁移中起抑制作用而非排斥作用（Mason等人，2001年）。我们开发了一系列试验，使我们能够区分分泌分子的排斥和抑制作用，并且我们证明Slit是一种能够逆转在培养物中或在其天然路径中迁移的神经元方向的排斥因子。我们还表明，虽然Slit在某些条件下会降低迁移速度，但它可以作为一种排斥因子起作用，而不会同时抑制神经元迁移。这是第一项明确证明迁移神经元可以被分泌分子定向引导的研究。这些发现为理解分泌分子在发育中的神经系统中的生理作用提供了基础，并对它们如何用于治疗具有启示意义。我们的结果还表明，应该有可能确定其他分子作为定向引导信号或细胞迁移运动调节因子的具体作用。
