State Key Laboratory of Neurobiology, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21353-8. doi: 10.1073/pnas.0812872106. Epub 2009 Nov 24.
Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here, we show that PKCdelta, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKCdelta attenuated the degradation of p35 but not its mutant derivative, which could not be phosphorylated by PKCdelta. Down-regulation of PKCdelta by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by down-regulation of p35 and could be prevented by cotransfection with the wild-type but not the mutant p35. Furthermore, PKCdelta could be activated by the promigratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCdelta and p35 were required for the promigratory effect of BDNF on cultured newborn neurons. Thus, PKCdelta may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.
周期蛋白依赖性激酶 5（Cdk5）及其激活剂 p35 对于皮质神经元的放射状迁移和分层至关重要。然而，在皮质形态发生过程中，这种激酶如何被细胞外和细胞内信号调节仍不清楚。在这里，我们表明 PKCdelta，一种在皮质神经元中表达的新型 PKC 成员，可以通过直接磷酸化稳定 p35。PKCdelta 减弱了 p35 的降解，但不能减弱其突变衍生物的降解，因为突变衍生物不能被 PKCdelta 磷酸化。通过特定的小干扰 RNA（siRNA）在子宫内电穿孔进行 PKCdelta 的下调严重损害了皮质神经元的放射状迁移。这种迁移缺陷与 p35 下调引起的缺陷相似，并且可以通过与野生型而非突变型 p35 的共转染来预防。此外，PKCdelta 可以被促迁移因子脑源性神经营养因子（BDNF）激活，并且是 BDNF 激活 Cdk5 所必需的。PKCdelta 和 p35 对于 BDNF 对培养的新生神经元的促迁移作用都是必需的。因此，PKCdelta 可能通过在新生神经元中维持 p35 的适当水平来促进皮质的放射状迁移。
