Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain
Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain
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DOI：
10.1073/pnas.051628498
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发表时间：
2001-02-27
影响因子：
11.1
通讯作者：
Mikoshiba, K
中科院分区：
文献类型：
--
作者：
Ohshima, T;Ogawa, M;Mikoshiba, K
细胞周期蛋白依赖性激酶 (Cdk) 5 是 Cdk 家族的独特成员，因为仅在神经组织中检测到 Cdk5 激酶活性。 tdk5 的两个神经元特异性激活亚基 p35 和 p39 已被鉴定。这些亚型在胚胎小鼠脑中的重叠表达模式和p35-/-小鼠脑匀浆中显着残留的Cdk5激酶活性表明体内Cdk5激活剂的冗余功能。 p35-/-Cdk5 +/- 小鼠中的严重神经元迁移缺陷进一步支持了以下观点：与 Cdk5-/- 小鼠相比，Cdk5 激活剂的冗余表达可能导致 p35-/- 小鼠中的表型更温和。缺乏 Cdk5 或 p35 的突变小鼠在大脑皮质层状结构的混乱方面与 Reelin/Dab1 突变小鼠表现出一定的相似性。为了阐明 Cdk5/p35 和 Reelin/Dab1 信号传导之间的关系，我们生成了具有这些基因组合缺陷的小鼠品系。 p35-/- 中添加 Dab1 或 Reelin 突变的杂合性会导致小脑皮质神经元的广泛迁移缺陷。在 p35 和 Dab1 或 Reelin 的双无效小鼠中，小脑的浦肯野细胞和海马的锥体神经元中出现了额外的迁移缺陷。同时缺乏 Cdk5/p35 和 Reelin/Dab1 的小鼠神经元迁移的这些额外缺陷表明，Cdk5/p35 可能对发育中小鼠大脑中皮层神经元的定位产生协同作用。
Cyclin-dependent kinase (Cdk) 5 is a unique member of the Cdk family, because Cdk5 kinase activity is detected only in the nervous tissue. Two neuron-specific activating subunits of tdk5, p35 and p39, have been identified. Overlapping expression pattern of these isoforms in the embryonic mouse brain and the significant residual Cdk5 kinase activity in brain homogenate of the p35-/- mice indicate the redundant functions of the Cdk5 activators in vivo. Severe neuronal migration defects in p35-/-Cdk5 +/- mice further support the idea that the redundant expression of the Cdk5 activators may cause a milder phenotype in p35-/- mice compared with Cdk5-/- mice. Mutant mice lacking either Cdk5 or p35 exhibit certain similarities with Reelin/Dab1-mutant mice in the disorganization of cortical laminar structure in the brain. To elucidate the relationship between Cdk5/p35 and Reelin/Dab1 signaling, we generated mouse lines that have combined defects of these genes. The addition of heterozygosity of either Dab1 or Reelin mutation to p35-/- causes the extensive migration defects of cortical neurons in the cerebellum. In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus. These additional defects in neuronal migration in mice lacking both Cdk5/p35 and Reelin/Dab1 indicate that Cdk5/p35 may contribute synergistically to the positioning of the cortical neurons in the developing mouse brain.