Fig. 7. Working model.

It has been widely demonstrated that when the axon grows in the absence of Wnt5a, cadherins are constantly being recycled from the plasma membrane. Our results support a model in which midline-expressed Wnt5a triggers local accumulation of βcatenin in contralateral axons. It has been shown that βcatenin links cadherins and actin microtubules. Thus, Wnt5a-dependent accumulation of βcatenin would facilitate midline crossing by promoting the stabilization of the cytoskeleton at the tip of the growth cone. In contrast, our results demonstrate that Zic2 activates a different set of Wnt receptors and other intracellular Wnt proteins in ipsilaterally projecting neurons, such as Fzd1, Fzd8, Lgr5, or Apc2, to favor the accumulation of βcatenin. We also show that EphB1 phosphorylates βcatenin in Y654, and previous reports have demonstrated that phosphorylated Y654-βcatenin has low affinity for cadherins. Taking all these observations together, we propose that phosphorylation of βcatenin induced by the binding of EphB1 to ephrinB2 prevents the formation of cadherin/actin complexes facilitating axon steering.