title: Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos.
abstract: The Glypican family of heparan sulfate proteoglycans regulates Wnt signaling and convergent extension (CE) in vertebrate embryos. They are predicted to be glycosylphosphatidylinositol (GPI)-tethered membrane-bound proteins, but there is no functional evidence of their regulation by the GPI synthesis complex. Down syndrome critical region protein 5 (Dscr5, also known as Pigp) is a component of the GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex, and is associated with specific features of Down syndrome. Here we report that Dscr5 regulates CE movements through the non-canonical Wnt pathway. Both dscr5 overexpression and knockdown impaired convergence and extension movements. Dscr5 functionally interacted with Knypek/Glypican 4 and was required for its localization at the cell surface. Knockdown of dscr5 disrupted Knypek membrane localization and caused an enhanced Frizzled 7 receptor endocytosis in a Caveolin-dependent manner. Furthermore, dscr5 knockdown promoted specific Dishevelled degradation by the ubiquitin-proteosome pathway. These results reveal a functional link between Knypek/Glypican 4 and the GPI synthesis complex in the non-canonical Wnt pathway, and provide the new mechanistic insight that Dscr5 regulates CE in vertebrate embryos by anchoring different Wnt receptors at the cell surface and maintaining Dishevelled stability.
authors.affiliation: Institute of Developmental Biology, Shandong University, Jinan 250100, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shao
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Liu
authors.forename: Cheng-Dong
authors.initials: CD
authors.lastname: Wang
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Li
authors.forename: Clémence
authors.initials: C
authors.lastname: Carron
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhang
authors.forename: De-Li
authors.initials: DL
authors.lastname: Shi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D022461:Caveolins / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000502:physiology; D004705:Endocytosis; D053673:Glypicans / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014982:Xenopus laevis; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022461:Caveolins; D000072261:Dishevelled Proteins; C492040:Fzd7 protein, Xenopus; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C470289:fzd7a protein, zebrafish; C440207:gpc4 protein, zebrafish; D017351:N-Acetylglucosaminyltransferases; C543974:PigP protein, Xenopus; C543973:PigP protein, zebrafish