Cdk5 phosphorylation of ErbB4 is crucial for cortical interneuron migration

Abstract

Interneuron dysfunction is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia and autism. Some of these disorders arise during brain formation, at the time of interneuron specification, migration and synapse formation. Here, we showed that the signalling molecule cyclin-dependent kinase 5 (Cdk5), and its activator p35, control the migration of interneurons towards and within the cerebral cortex by modulating the motogenic ErbB4/phosphatidylinositol (PI) 3-kinase signalling pathway. We first identified ErbB4 as a novel p35/Cdk5 kinase substrate. We then demonstrated that Cdk5-dependent ErbB4/PI3-kinase signalling cascade regulates interneuron leading process dynamics (morphology) and directionality. Finally, we showed that lack of Cdk5 activity in p35 mutants leads to permanent reduction in the final number of a subtype of interneurons that may affect formation of neuronal circuits, thus increasing the risk of neurodevelopmental disorders. Together, these findings identify Cdk5 as a crucial signalling factor in cortical interneuron development.