Reformation of the dopaminergic nigrostriatal pathway: a role of reeler gene product Reelin

reeler基因（Reln^<rl>，原rl）产物Reelin控制神经元的迁移和定位，因此在大脑发育中起关键作用。Reln的突变可导致脑干部分核的层状皮质区广泛破坏和异位。在正常小鼠的胚胎纹状体中，reelin mRNA的大量表达已被证实；然而，纺机小鼠基底神经节神经元的异常定位仍有待研究。我们为Reelin在黑质发育形成中的潜在作用提供了第一个证据。在缺乏Reelin的reeler突变小鼠中，通往黑质的多巴胺能神经元不能向外侧迁移，并在腹侧被盖区外侧异常聚集。它们的轴突似乎投射到纹状体斑块上，形成“多巴胺岛”。正常小鼠的研究结果显示，在胚胎中期，经CR-50鉴定的Reelin高度集中在腹侧脑膜，在那里，黑质多巴胺能神经元正在向外侧迁移到它们在成年大脑的最终位置。CR-50标记和顺行轴突示踪的结合提供了证据，证明胚胎纹状体神经元可能通过轴突投射向中脑腹侧提供Reelin。我们假设Reelin在黑质多巴胺能神经元的定位中起作用，并且它可以通过跨轴传递系统在远离其出生地的遥远位置作为环境线索。大脑皮层被组织成水平和垂直排列的神经元及其纤维连接，在解剖学和生理学上形成不同的层状和柱状隔室。然而，这种二分模式背后的发育机制仍然是个谜。我们提供的解剖学证据表明，Reelin（一种由Cajal-Retzius细胞产生和分泌的扩散蛋白）参与了小鼠丘下前皮层垂直细胞结构的发育形成，丘下前皮层是在出生后早期清晰识别皮层板神经元垂直柱状阵列及其树突状分支的独特部位。我们的研究结果还表明，Reelin在这些垂直结构的形成中发挥作用，作为皮层板神经元及其树突延伸的抑制或停止信号。除了水平层受到干扰外，缺乏Reelin的reeler突变小鼠还表现出这些垂直结构的破坏。基于目前的研究结果，我们假设Reelin和Cajal-Retzius细胞不仅调节大脑皮层水平层状结构的形成，还调节垂直柱状结构的形成。少

The reeler gene (Reln^<rl>, formerly rl) product Reelin controls neuronal migration and positioning and thereby plays a key role in brain development. Mutation of Reln leads to widespread disruption of laminar cortical regions and ectopia in some brainstem nuclei. In the embryonic striatum of normal mice, a substantial expression of reelin mRNA has been documented; however, the anomalous positioning of neurons in the basal ganglia of reeler mice remains to be studied. We provide first evidence for a potential role of Reelin in the developmental formation of the substantia nigra. In reeler mutant mice lacking Reelin, dopaminergic neurons destined for the substantia nigra fail to migrate laterally and become anomalously clustered just lateral to the ventral tegmental area. Their axons appear to project to striatal patches forming "dopamine islands". Results from the normal mice show that at the mid-embryonic stage, Reelin identified with CR-50 is highly concentrated in the ventral mesenc … More ephalon, where nigral dopaminergic neurons are in progress to migrate laterally to their eventual position of the adult brain. A combination of CR-50 labeling and anterograde axonal tracing provided evidence that embryonic striatal neurons may supply the ventral portion of the mesencephalon with Reelin through their axonal projections. We hypothesize that Reelin plays a role in the positioning of nigral dopaminergic neurons and that it can act as an environmental cue at a remote site far from its birthplace via a transaxonal delivery system.The cerebral cortex is organized into horizontal and vertical arrays of neurons and their fiber connections that form anatomically and physiologically distinct laminar and columnar compartments. However, the developmental mechanism(s) underlying this dichotomous pattern remains a mystery. We provide anatomical evidence suggesting that Reelin, a diffusible protein produced and secreted by Cajal-Retzius cells, is involved in the developmental formation of the vertical cell structures in the mouse presubicular cortex, the unique site where the vertical columnar arrays of cortical plate neurons and their dendritic branches are clearly identified during the early postnatal period. Our results also suggest that Reelin plays a role in the formation of these vertical structures by acting as an inhibitory or stop signal for cortical plate neurons and their dendritic extensions. In addition to having perturbed horizontal laminae, reeler mutant mice lacking of Reelin display disruption of these vertical structures. Based on the present findings, we hypothesize that Reelin and Cajal-Retzius cells regulate the developmental formation of not only horizontal laminations but also vertical columnar structures in the cerebral cortex. Less