Macheda, M.L., Sun, W.W., Kugathasan, K., Hogan, B.M., Bower, N.I., Halford, M.M., Zhang, Y.F., Jacques, B.E., Lieschke, G.J., Dabdoub, A., and Stacker, S.A. (2012) The Wnt Receptor Ryk Plays a Role in Mammalian Planar Cell Polarity Signaling. The Journal of biological chemistry. 287(35):29312-29323.
Wnts are essential for a wide range of developmental processes including cell growth, division and differentiation. Some of
these processes signal via the planar cell polarity (PCP) pathway, which is a β-catenin-independent Wnt signaling pathway.
Previous studies have shown that Ryk, a member of the receptor tyrosine kinase family, can bind to Wnts. Ryk is required for
normal axon guidance and neuronal differentiation during development. Here we demonstrate that mammalian Ryk interacts with
the Wnt/PCP pathway. In vitro analysis showed that the Wnt inhibitory factor domain of Ryk was necessary for Wnt binding.
Detailed analysis of two vertebrate model organisms showed Ryk phenotypes consistent with PCP signaling. In zebrafish, gene
knockdown using morpholinos revealed a genetic interaction between Ryk and Wnt11 during the PCP pathway-regulated process
of embryo convergent extension. Ryk-deficient mouse embryos displayed disrupted polarity of stereociliary hair cells in the
cochlea, a characteristic of disturbed PCP signaling. This PCP defect was also observed in mouse embryos that were double
heterozygotes for Ryk and Looptail (containing a mutation in the core Wnt/PCP pathway gene Vangl2), but not in either of the
single heterozygotes, suggesting a genetic interaction between Ryk and Vangl2. Co-immunoprecipitation studies demonstrated
that RYK and VANGL2 proteins form a complex, while RYK also activated RhoA, a downstream effector of PCP signaling. Overall,
our data suggest an important role for Ryk in Wnt/planar cell polarity signaling during vertebrate development via the Vangl2
signaling pathway, as demonstrated in the mouse cochlea.