Ryk regulates Wnt5a repulsion of mouse corticospinal tract through modulating planar cell polarity signaling

It was previously reported a role for Ryk in mediating Wnt5a repulsion of the corticospinal tract (CST) in mice. Recent evidence has shown that Ryk regulates planar cell polarity (PCP) signaling through interacting with Vangl2. Here, in vivo, in vitro and biochemical analyses were applied to investigate the molecular cross-talk between the Ryk and PCP signaling pathways, revealing that PCP pathway components play important roles in CST anterior-posterior guidance. Ryk-Vangl2 interactions are crucial for PCP signaling to mediate Wnt5a repulsion of CST axons. Cytoplasmic distribution of Ryk is increased under high concentrations of Wnt5a and facilitates the cytoplasmic distribution of Vangl2, leading to inhibition of Frizzled3 translocation to cytoplasm. Alternatively, Ryk stabilizes Vangl2 in the plasma membrane under low Wnt5a concentrations, which promotes cytoplasmic translocation of Frizzled3. We propose that Ryk regulates PCP signaling through asymmetric modulation of Vangl2 distribution in the cytoplasm and plasma membrane, which leads to repulsion of CST axons in response to the Wnt gradient.