Migration defects of cdk5-/- neurons in the developing cerebellum is cell autonomous
Migration defects of cdk5-/- neurons in the developing cerebellum is cell autonomous
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DOI：
10.1523/jneurosci.19-14-06017.1999
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发表时间：
1999-07-15
影响因子：
5.3
通讯作者：
Kulkarni, AB
中科院分区：
文献类型：
--
作者：
Ohshima, T;Gilmore, EC;Kulkarni, AB
细胞周期蛋白依赖性激酶 5 (Cdk5) 是细胞周期相关激酶家族的成员。先前对cdk5(-/-)小鼠的神经病理学分析显示，从大脑皮层到脑干区域的中枢神经系统发育发生了显着变化。在这些动物的缺陷中，小脑细胞迁移正常模式的破坏尤其明显，包括小脑浦肯野细胞位置的明显异常。在突变体中对该大脑区域的完整分析受到阻碍，因为大多数小脑形态发生发生在出生后，并且 cdk5(-/-) 小鼠在围产期死亡。为了克服这个缺点，我们通过将cdk5(-/-)胚胎干细胞注射到宿主囊胚中来产生嵌合小鼠。对所得cdk5(-/-) cdk5(+/+)嵌合小鼠的小脑进行分析表明，突变浦肯野细胞的异常位置是一种细胞自主缺陷。此外，大量颗粒细胞仍然位于分子层中，表明未能完成从外部颗粒细胞层到内部颗粒细胞层的迁移。与浦肯野细胞和颗粒细胞群相反，所有三种小脑深部核细胞群均正确形成，并且由突变型和野生型基因型的细胞组成。尽管 cdk5(-/-) 表型与 reeler 和 mdab-1(-/-) (scrambler/yotari) 突变大脑中报道的相似，但发现 cdk5(-/-) 大脑中的 reelin 和disabled-1 mRNA 是正常的。总之，这些数据进一步支持了这样的假设：Cdk5 活性是神经元迁移的特定成分所必需的，不同的神经元细胞类型甚至不同发育阶段的单一神经元细胞类型对这些特定成分的需求不同。
Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-related kinases. Previous neuropathological analysis of cdk5(-/-) mice showed significant changes in CNS development in regions from cerebral cortex to brainstem. Among the defects in these animals, a disruption of the normal pattern of cell migrations in cerebellum was particularly apparent, including a pronounced abnormality in the location of cerebellar Purkinje cells. Complete analysis of this brain region is hampered in the mutant because most of cerebellar morphogenesis occurs after birth and the cdk5(-/-) mice die in the perinatal period. To overcome this disadvantage, we have generated chimeric mice by injection of cdk5(-/-) embryonic stem cells into host blastocysts. Analysis of the cerebellum from the resulting cdk5(-/-) cdk5(+/+) chimeric mice shows that the abnormal location of the mutant Purkinje cells is a cell-autonomous defect. In addition, significant numbers of granule cells remain located in the molecular layer, suggesting a failure to complete migration from the external to the internal granule cell layer. In contrast to the Purkinje and granule cell populations, all three of the deep cerebellar nuclear cell groupings form correctly and are composed of cells of both mutant and wild-type genotypes. Despite similarities of the cdk5(-/-) phenotype to that reported in reeler and mdab-1(-/-) (scrambler/yotari) mutant brains, reelin and disabled-1 mRNA were found to be normal in cdk5(-/-) brain. Together, the data further support the hypothesis that Cdk5 activity is required for specific components of neuronal migration that are differentially required by different neuronal cell types and by even a single neuronal cell type at different developmental stages.