title: The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling.
abstract: 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, whereas 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.
authors: Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors: Maria L
authors: ML
authors: Macheda
authors: Willy W
authors: WW
authors: Sun
authors: Kumudhini
authors: K
authors: Kugathasan
authors: Benjamin M
authors: BM
authors: Hogan
authors: Neil I
authors: NI
authors: Bower
authors: Michael M
authors: MM
authors: Halford
authors: You Fang
authors: YF
authors: Zhang
authors: Bonnie E
authors: BE
authors: Jacques
authors: Graham J
authors: GJ
authors: Lieschke
authors: Alain
authors: A
authors: Dabdoub
authors: Steven A
authors: SA
authors: Stacker
mesh_terms: D000818:Animals; D016466:CHO Cells; D016764:Cell Polarity / Q000502:physiology*; D003051:Cochlea / Q000166:cytology / Q000196:embryology; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431577:Ltap protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C468513:VANGL2 protein, human; D051153:Wnt Proteins; C540523:Wnt11 protein, human; C508957:Wnt11 protein, mouse; D029961:Zebrafish Proteins; C491759:vangl2 protein, zebrafish; C066737:RHOA protein, human; C080836:RYK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse; C551670:Ryk protein, zebrafish; D020559:Monomeric GTP-Binding Proteins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C549425:rhoab protein, zebrafish