title: Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2.
abstract: It is fundamentally important that signaling gradients provide positional information to govern morphogenesis of multicellular organisms. Morphogen gradients can generate different cell types in specific spatial order at distinct threshold concentrations. However, it is largely unknown whether and how signaling gradients also control cell polarities by acting as global cues. Here, we show that Wnt signaling gradient provides directional information to a field of cells. Vangl2, a core component in planar cell polarity, forms Wnt-induced receptor complex with Ror2 to sense Wnt dosages. Wnts dose-dependently induce Vangl2 phosphorylation of serine/threonine residues and Vangl2 activities depend on its levels of phosphorylation. In the limb bud, Wnt5a signaling gradient controls limb elongation by establishing PCP in chondrocytes along the proximal-distal axis through regulating Vangl2 phosphorylation. Our studies have provided new insight to Robinow syndrome, Brachydactyly Type B1, and spinal bifida which are caused by mutations in human ROR2, WNT5A, or VANGL.
authors.affiliation: National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Hai
authors.initials: H
authors.lastname: Song
authors.forename: Kevin
authors.initials: K
authors.lastname: Bishop
authors.forename: Gene
authors.initials: G
authors.lastname: Elliot
authors.forename: Lisa
authors.initials: L
authors.lastname: Garrett
authors.forename: Milton A
authors.initials: MA
authors.lastname: English
authors.forename: Philipp
authors.initials: P
authors.lastname: Andre
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D016764:Cell Polarity; D047108:Embryonic Development; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse