The formation and remodeling of neuronal connections during nervous system development is a highly dynamic process and is influenced by neuronal activity. The regulation of gene expression by neuronal activity is crucial to fine-tune neuronal connections, but how neuronal activity sends signals to the nucleus to regulate gene transcription remains unclear. Our laboratory has demonstrated that the proline-directed serine/threonine kinase Cdk5 is crucial for the growth of dendrites in cultured hippocampal neurons. Interestingly, we found that Cdk5 and its activators p35 and p39 were localized not only in the cytoplasm but also in the nucleus in neurons. These observations prompt us to hypothesize that Cdk5 might have an important role in the nucleus by regulating activity-dependen...[ Read more ]

The formation and remodeling of neuronal connections during nervous system development is a highly dynamic process and is influenced by neuronal activity. The regulation of gene expression by neuronal activity is crucial to fine-tune neuronal connections, but how neuronal activity sends signals to the nucleus to regulate gene transcription remains unclear. Our laboratory has demonstrated that the proline-directed serine/threonine kinase Cdk5 is crucial for the growth of dendrites in cultured hippocampal neurons. Interestingly, we found that Cdk5 and its activators p35 and p39 were localized not only in the cytoplasm but also in the nucleus in neurons. These observations prompt us to hypothesize that Cdk5 might have an important role in the nucleus by regulating activity-dependent gene transcription during dendrite development. Consistent with the hypothesis, the defects in dendritic growth upon knockdown of Cdk5 in cultured hippocampal neurons can be rescued by wild-type Cdk5, but not the nuclear-localization deficient mutant, indicating that the nuclear localization of Cdk5 is required for dendrite development. Biochemical fractionation revealed the increased accumulation of Cdk5 in the nucleus after neuronal depolarization. In addition, the depolarization-induced mRNA expression of the neurotrophin bdnf was greatly attenuated by the Cdk5 inhibitor roscovitine. Finally, the induction of dendritic growth after neuronal depolarization was abolished in the presence of roscovitine, as well as in Cdk5 knockout hippocampal neurons. Together these observations suggest a novel function of Cdk5 in activity-dependent dendritic growth by regulating gene transcription in the nucleus.