Wnt7b Promotes Axon Differentiation and Extension by Regulating JNK-Mediated Cytoskeletal Dynamics

Abstract

Neuronal polarization and axon growth are critical processes underlying neuronal differentiation and maturation. Wnt proteins have been implicated as key regulators of neuronal development; however, the cellular mechanisms through which they influence axon growth remain poorly understood. In this study, we investigated the role of Wnt7b in axon differentiation and elongation in hippocampal neurons, and aimed to characterize the underlying molecular mechanisms involved. Our results show that Wnt7b accelerates neuronal polarization and promotes axon elongation. In the presence of Wnt7b, most undifferentiated neurons polarized and subsequently developed longer axons compared to controls. Further analysis revealed that this effect is mediated by the JNK signaling pathway, as both pharmacological inhibition and expression of a dominant-negative JNK construct blocked Wnt7b-induced axonal elongation. Additionally, Wnt7b triggered local activation of JNK in growing axons and induced cytoskeletal rearrangements. Specially, Wnt stimulation promoted microtubule stabilization along newly formed axons and enhanced the protrusion of dynamic microtubules into the growth cones, a process that may facilitate axon extension. Together, these findings identify Wnt7b as a crucial modulator of axon differentiation and elongation, acting through activation of the JNK pathway.