title: The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2.
abstract: The Wnt signaling pathways control many critical developmental and adult physiological processes. In vertebrates, one fundamentally important function of Wnts is to provide directional information by regulating the evolutionarily conserved planar cell polarity (PCP) pathway during embryonic morphogenesis. However, despite the critical roles of Wnts and PCP in vertebrate development and disease, little is known about the molecular mechanisms underlying Wnt regulation of PCP. Here, we have found that the receptor-like tyrosine kinase (Ryk), a Wnt5a-binding protein required in axon guidance, regulates PCP signaling. We show that Ryk interacts with Vangl2 genetically and biochemically, and such interaction is potentiated by Wnt5a. Loss of Ryk in a Vangl2(+/-) background results in classic PCP defects, including open neural tube, misalignment of sensory hair cells in the inner ear, and shortened long bones in the limbs. Complete loss of both Ryk and Vangl2 results in more severe phenotypes that resemble the Wnt5a(-/-) mutant in many aspects such as shortened anterior-posterior body axis, limb, and frontonasal process. Our data identify the Wnt5a-binding protein Ryk as a general regulator of the mammalian Wnt/PCP signaling pathway. We show that Ryk transduces Wnt5a signaling by forming a complex with Vangl2 and that Ryk regulates PCP by at least in part promoting Vangl2 stability. As human mutations in WNT5A and VANGL2 are found to cause Robinow syndrome and neural tube defects, respectively, our results further suggest that human mutations in RYK may also be involved in these diseases.
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Andre
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Arielle
authors.initials: A
authors.lastname: Schilit
authors.forename: Michael M
authors.initials: MM
authors.lastname: Halford
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D019521:Body Patterning; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D016764:Cell Polarity; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development; D057809:HEK293 Cells; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse