Ohshima T, Ogawa M, Hirasawa M, Longenecker G, Ishiguro K, Pant H C, Brady R O, Kulkarni A B, Mikoshiba K
Laboratory for Developmental Neurobiology, Cell Culture Development, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0198, Japan.
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2764-9. doi: 10.1073/pnas.051628498. Epub 2001 Feb 13.
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 Cdk5, 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.
细胞周期蛋白依赖性激酶（Cdk）5是Cdk家族的一个独特成员，因为仅在神经组织中检测到Cdk5激酶活性。已鉴定出Cdk5的两个神经元特异性激活亚基，即p35和p39。这些异构体在胚胎小鼠脑中的重叠表达模式以及p35基因敲除小鼠脑匀浆中显著的残余Cdk5激酶活性表明，Cdk5激活剂在体内具有冗余功能。p35基因敲除/Cdk5杂合小鼠中严重的神经元迁移缺陷进一步支持了这样一种观点，即与Cdk5基因敲除小鼠相比，Cdk5激活剂的冗余表达可能在p35基因敲除小鼠中导致较轻的表型。缺乏Cdk5或p35的突变小鼠在大脑皮质层状结构紊乱方面与Reelin/Dab1突变小鼠表现出某些相似之处。为了阐明Cdk5/p35与Reelin/Dab1信号通路之间的关系，我们构建了具有这些基因联合缺陷的小鼠品系。在p35基因敲除小鼠中添加Dab1或Reelin突变的杂合性会导致小脑皮质神经元广泛的迁移缺陷。在p35与Dab1或Reelin的双基因敲除小鼠中，小脑浦肯野细胞和海马锥体神经元出现额外的迁移缺陷。缺乏Cdk5/p35和Reelin/Dab1的小鼠中神经元迁移的这些额外缺陷表明，Cdk5/p35可能协同作用于发育中小鼠大脑皮质神经元的定位。
