C-Jun N-terminal kinase (JNK) cooperates with Gsk3β to regulate Dishevelled-mediated microtubule stability

Background: Wnt factors are a large family of signaling molecules that play important roles in the regulation of cell fate specification, tissue polarity and cell movement. In the nervous system, Wnts also regulates the formation of neuronal connection acting as retrograde signals that regulate the remodeling of the axons prior to the assembly of the presynaptic apparatus. The scaffold protein Dishevelled (Dvl) mimics the effect of Wnt on the neuronal cytoskeleton by increasing the number of stable microtubule along the axon shaft and inducing the formation of looped microtubules (MT) at enlarged growth cones. A divergent Wnt-Dvl canonical pathway which bifurcates downstream of Gsk3 beta regulates MT dynamics. Results: Here we show that the Wnt pathway also activates c-Jun N-terminal kinase (JNK) to regulate MT stabilization. Although in the Wnt planar cell polarity (PCP) pathway, JNK lays downstream of Rho GTPases, these GTPases are not required for Wnt-mediated MTs stability. Epistatic analyses and pharmacological studies suggest that the Wnt-Dvl signalling regulates the dynamic of the cytoskeleton through two different pathways that lead to inhibition of Gsk3 beta and activation of JNK in the same cell. Conclusion: We demonstrate a novel role for JNK in Wnt-mediated MT stability. Wnt-Dvl pathway increases MT stability through a transcription independent mechanism that requires the concomitant inhibition of Gsk3 beta and activation of JNK. These studies demonstrate that Wnts can simultaneously activate different signalling pathways to modulate cytoskeleton dynamics.