Axon formation in neocortical neurons depends on stage-specific regulation of microtubule stability by the dual leucine zipper kinase-c-Jun N-terminal kinase pathway.

Studies using cultured neurons have established the critical role of microtubule regulators in neuronal polarization. The c-Jun N-terminal kinase (JNK) pathway is one of the candidate signaling pathways driving microtubule regulation during neuronal polarization. However, the significance of the JNK pathway in axon formation, a fundamental step in neuronal polarization, in vivo, remains unclear. Here, we provide evidence supporting the notion that the JNK pathway contributes to axon formation, in vivo, by identifying the genetic interactions between mouse JNK1 and dual leucine zipper kinase (DLK). Double mutants exhibited severe defects in axon formation in the cerebral neocortex. Moreover, RNA interference rescue experiments, in vitro, showed that DLK and JNK1 function in a common pathway to support neuronal polarization by promoting short-neurite and axon formation. Defects in axon formation caused by perturbations of the DLK-JNK pathway were significantly improved by Taxol. However, defects in short-neurite formation caused by perturbations of the DLK-JNK pathway were enhanced by Taxol. Together, these in vivo and in vitro observations indicate that the DLK-JNK pathway facilitates axon formation in neocortical neurons via stage-specific regulation of microtubule stability.