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

Abstract

Studiesusingculturedneuronshaveestablished thecriticalroleofmicrotubuleregulatorsinneuronalpolarization.Thec-JunN-terminal kinase (JNK) pathwayisone ofthe 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 functioninacommon pathway to support neuronal polarizationby promoting short-neurite and axon formation. Defectsin axon formation caused byperturbations of the DLK-JNK pathway were significantlyimprovedbyTaxol. However, defectsinshort-neurite formation causedbyperturbationsofthe 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. © 2011 the authors.