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Development June 1, 2009; 136 (12): 2121-31.
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Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos.

Shao M , Liu ZZ , Wang CD , Li HY , Carron C , Zhang HW , Shi DL .

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.

PubMed ID: 19465602
Article link: Development

Species referenced: Xenopus laevis
Genes referenced: ctnnb1 dlx3 dvl1 dvl2 evx1 fzd7 gpc1 gpc4 gpi mapk8 mmut myc myod1 pcdh8.2 pigp ptch1 tac1 tbxt wnt11

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