Ko J, Humbert S, Bronson R T, Takahashi S, Kulkarni A B, Li E, Tsai L H
Department of Pathology and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2001 Sep 1;21(17):6758-71. doi: 10.1523/JNEUROSCI.21-17-06758.2001.
Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in brain development and neuronal migration. Cdk5 is abundant in postmitotic, terminally differentiated neurons. The ability of Cdk5 to phosphorylate substrates is dependent on activation by its neuronal-specific activators p35 and p39. There exist striking differences in the phenotypic severity of Cdk5-deficient mice and p35-deficient mice. Cdk5-null mutants show a more severe disruption of lamination in the cerebral cortex, hippocampus, and cerebellum. In addition, Cdk5-null mice display perinatal lethality, whereas p35-null mice are viable. These discrepancies have been attributed to the function of other Cdk5 activators, such as p39. To understand the roles of p39 and p35, we created p39-null mice and p35/p39 compound-mutant mice. Interestingly, p39-null mice show no obvious detectable abnormalities, whereas p35(-/-)p39(-/-) double-null mutants are perinatal lethal. We show here that the p35(-/-)p39(-/-) mutants exhibit phenotypes identical to those of the Cdk5-null mutant mice. Other compound-mutant mice with intermediate phenotypes allow us to determine the distinct and redundant functions between p35 and p39. Our data strongly suggest that p35 and p39 are essential for Cdk5 activity during the development of the nervous system. Thus, p35 and p39 are likely to be the principal, if not the only, activators of Cdk5.
细胞周期蛋白依赖性激酶5（Cdk5）在大脑发育和神经元迁移中起关键作用。Cdk5在有丝分裂后、终末分化的神经元中含量丰富。Cdk5磷酸化底物的能力取决于其神经元特异性激活剂p35和p39的激活。Cdk5缺陷小鼠和p35缺陷小鼠的表型严重程度存在显著差异。Cdk5基因敲除突变体在大脑皮层、海马体和小脑中表现出更严重的分层破坏。此外，Cdk5基因敲除小鼠表现出围产期致死性，而p35基因敲除小鼠是存活的。这些差异归因于其他Cdk5激活剂的功能，如p39。为了了解p39和p35的作用，我们创建了p39基因敲除小鼠和p35/p39复合突变小鼠。有趣的是，p39基因敲除小鼠没有明显可检测到的异常，而p35（-/-）p39（-/-）双基因敲除突变体是围产期致死的。我们在此表明，p35（-/-）p39（-/-）突变体表现出与Cdk5基因敲除突变小鼠相同的表型。其他具有中间表型的复合突变小鼠使我们能够确定p35和p39之间的不同和冗余功能。我们的数据强烈表明，p35和p39在神经系统发育过程中对Cdk5活性至关重要。因此，p35和p39可能是Cdk5的主要激活剂，如果不是唯一的激活剂的话。
