Abstract
BackgroundWnt 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 Gsk3β regulates MT dynamics.ResultsHere 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 Gsk3β and activation of JNK in the same cell.ConclusionWe 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 Gsk3β and activation of JNK. These studies demonstrate that Wnts can simultaneously activate different signalling pathways to modulate cytoskeleton dynamics.
Highlights
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
To begin to understand how Dvl signals through Jun N-terminal kinase (JNK), we have examined the contribution of the different domains of Dvl on JNK-mediated MT stability
To examine if JNK is upstream of Gsk3β, we investigated whether JNK affects the levels of Gsk3β-mediated phosphorylation of MAP1B, which is correlated with MT stability and more importantly with the level of Gsk3β activity [11]
Summary
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. 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. Wnts can function as molecules that guide axons to their appropriate targets [6,7,8] but they can function as target-derived signals to regulate the terminal arborisation of axons [9,10] In the latter case, Wnt proteins act retrogradely to inhibit axon extension and to induce the terminal remodelling of incoming presynaptic axons. Initial characterization demonstrated a role for Gsk3β, a serine/threonine kinase [4], the mechanism by which Wnt signalling regulates the organization and stability of MTs remains poorly understood
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