Phosphorylation of Connexin 43 by Cdk5 Modulates Neuronal Migration During Embryonic Brain Development

The gap junction protein, connexin 43 (Cx43), is only present and abundantly expressed in astrocytes but is absent in neurons in the mature brain tissues. However, both the expression and function of Cx43 in neurons during brain embryonic development remain largely unexplored. In the present study, we confirmed that Cx43 is expressed in the migrating neurons in the embryonic stage of the brain. Neuron-specific Cx43 conditional knockout (cKO) using Cre-loxP technique impairs neuronal migration and formation of laminar structure in cerebral cortex during brain embryonic development. The animal behavior tests demonstrated that, at the adult stage, neuronal Cx43 cKO mice exhibit normal learning and memory functions but increased anxiety-like behavior. We also found that during the embryonic development, the gradually decreased Cx43 expression in the cortex is closely correlated with the upregulation of cyclin-dependent kinase 5 (Cdk5) activity. Cdk5 directly phosphorylates Cx43 at Ser279 and Ser282, which, in consequence, inhibits the membrane targeting of Cx43 and promotes its proteasome-dependent degradation. In summary, our findings revealed that the embryonic expression of Cx43 in neurons regulates processes of neuronal migration and positioning in the developing brain by controlling astrocyte-neuron interactions during brain embryonic development, and Cdk5 directly phosphorylates Cx43, which regulates the membrane localization and degradation of Cx43 in neurons.