Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos.
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.
Shao
Ming
M
Institute of Developmental Biology, Shandong University, Jinan 250100, China.
Liu
Zhong-Zhen
ZZ
Wang
Cheng-Dong
CD
Li
Hong-Yan
HY
Carron
Clémence
C
Zhang
Hong-Wei
HW
Shi
De-Li
DL
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*
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