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Reelin在中枢神经系统进化过程中的作用
Role of Reelin in the evolution of the central nervous system
目的 探讨Reelin在中枢神经系统进化过程中所起的作用及其调节机制。 方法 取Reelin基因缺失小鼠（Reeler）和野生小鼠（WT），胚龄16d（E16）至出生30d（P30）各年龄点，共192例。利用免疫荧光技术与5’-溴脱氧尿嘧啶核苷（BrdU）法，检测两组小鼠中大脑皮质、海马、脊髓发育过程中放射状胶质细胞、神经干细胞、增殖细胞及星形胶质细胞的表达，并使用 Nissl 染色技术，分别对脊髓、海马、大脑皮质的组织学特征进行观察。 结果 脊髓发育过程中，神经细胞仅发生1次迁移，并形成套层，套层进而衍变成呈H型脊髓灰质。与野生型小鼠相比，同年龄Reelin基因缺失小鼠（Reeler小鼠）在形态结构、细胞迁移方面与野生型小鼠基本类似，但增殖的神经细胞数目明显减少。在第1次迁移的基础上，海马的形成还需经历第2次神经细胞迁移，最终形成了双“C”字型结构的锥体细胞层和颗粒细胞层；与野生型小鼠相比，在形态上Reeler小鼠锥体细胞层明显扩散劈裂为两层，齿状回颗粒层细胞明显增殖并向门区迁移以致颗粒层与门区的界限消失，形成鼓槌状结构；同时，增殖的神经细胞数目减少，放射状胶质细胞排列紊乱。新皮质的形成也需经历两次迁移，但第2次神经细胞迁移所形成的皮质板按照由内向外的迁移方式继续发育为界限清晰的6层结构；与野生型小鼠相比，同年龄点Reeler小鼠新皮质片层化结构紊乱，增殖的神经细胞和放射状胶质细胞数目均有所减少，并且放射状胶质细胞排列紊乱。 结论 脊髓、海马和新皮质分别代表了进化过程中的管状神经、古皮质和新皮质，Reelin可能是皮质进化的关键分子。Reelin参与了第2次迁移以及新皮质皮质板的继续分层，Reelin缺失可以引起上述皮质形态和结构的变化，尤其是古皮质和新皮质。
Objective To investigate Reelin’s role in the evolution of the central nervous system and the relevant regulatory mechanisms. Methods A total of 192 wild-type (WT) and reeler mice from embryonic day 16 (E16) to postnatal day 30(P30) were used for this study. The neuronal migration, radial glial cells and neuroproliferation in the cerebral cortex, hippocampus and spinal cord were visualized by immunofluorescent labeling, 5-bromodeoxyuridine immunofluorescence (BrdU method). Nissl staining was also used to observe the histogenesis of the spinal cord, the cerebral cortex and hippocampus. Results During the development of spinal cord, the first neuronal migrate occurred from neuroepithelium to form “H”-like gray matter. Compared WT mice with reeler mice, only nuance was found in histogenesis, cell migration, radial glia and neuropliferation. On the other hand, the development of hippocampus required second neural migrations to eventually form the pyramidal cell layer and granule cell layer with double “C”-like shape. Compared with WT mouse, pyramidal layer in the reeler mouse was splitting into two layers with the disorder of migration and proliferation. In addition, the limitation of granule layer and hilus gradually disappeared to form drumstick-like structure. In the meantime, the number of proliferative neural stem cells reduced and the radial glial cells were arranged in disorder. The formation of the neocortex also required second neural migration to form six-layer cortex with inside-out migration manner. Compared with WT mouse, lamination of neocortex in the reeler mouse was in disorder. The neuroproliferation and radial glial cells reduced, and the radial glials were arranged in disorder. Conclusion Spinal cord, hippocampus and neocortex represent the tubular nervous system, archicortex and neocortex, respectively, in the evolution of the central nervous system(CNS). Reelin may be a key molecule during CNS evolution. Reelin’s important function probably is involved in second migration to affect the formation of cortical plate. Lack of Reelin will induce the changes of cortical structure, especially in the archicortex and neocortex.
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