Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex
Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex
复制标题
DOI：
10.1242/dev.02854
复制
发表时间：
2007-06-15
期刊：
影响因子：
4.6
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Ohshima, Toshio;Hirasawa, Motoyuki;Mikoshiba, Katsuhiko
哺乳动物大脑皮层由六层组成，在胚胎期通过协调神经元迁移产生。最近的研究确定了皮质神经元径向迁移的特定阶段。最后分裂后，神经元在室管膜下区-中间区（SVZ-IZ）内从多极形状转变为双极形状，然后沿着放射状胶质纤维迁移。缺乏Cdk 5的小鼠表现出异常的皮质生成，由于神经元迁移缺陷。当我们在E14.5通过子宫内电穿孔将GFP引入迁移神经元时，我们在野生型胚胎中观察到迁移神经元，但在3-4天后在Cdk 5（-/-）胚胎中没有观察到。将显性负性形式的Cdk 5引入野生型迁移神经元证实了SVZ-IZ内以细胞自主方式的多极到双极转换的特定损伤。皮质特异性Cdk 5条件性敲除小鼠显示大脑皮质的倒置分层，V层和胼胝体神经元（但不是VI层神经元）的树突形态严重受损。Cdk 5缺陷小鼠大脑皮层中树突状蛋白Map 2的量减少，皮层内皮层神经元的轴突轨迹也异常。这些结果表明，Cdk 5是所需的适当的多极双极转换，和Cdk 5的缺陷导致锥体神经元的异常形态。此外，适当的放射状神经元迁移产生了大脑皮层形成的由内而外的模式和皮层锥体神经元的正常轴突轨迹。
The mammalian cerebral cortex consists of six layers that are generated via coordinated neuronal migration during the embryonic period. Recent studies identified specific phases of radial migration of cortical neurons. After the final division, neurons transform from a multipolar to a bipolar shape within the subventricular zone-intermediate zone (SVZ-IZ) and then migrate along radial glial fibres. Mice lacking Cdk5 exhibit abnormal corticogenesis owing to neuronal migration defects. When we introduced GFP into migrating neurons at E14.5 by in utero electroporation, we observed migrating neurons in wild-type but not in Cdk5(-/-) embryos after 3-4 days. Introduction of the dominant-negative form of Cdk5 into the wild-type migrating neurons confirmed specific impairment of the multipolar-to-bipolar transition within the SVZ-IZ in a cell-autonomous manner. Cortex-specific Cdk5 conditional knockout mice showed inverted layering of the cerebral cortex and the layer V and callosal neurons, but not layer VI neurons, had severely impaired dendritic morphology. The amount of the dendritic protein Map2 was decreased in the cerebral cortex of Cdk5-deficient mice, and the axonal trajectory of cortical neurons within the cortex was also abnormal. These results indicate that Cdk5 is required for proper multipolar-to-bipolar transition, and a deficiency of Cdk5 results in abnormal morphology of pyramidal neurons. In addition, proper radial neuronal migration generates an inside-out pattern of cerebral cortex formation and normal axonal trajectories of cortical pyramidal neurons.