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First published online May 22, 2009
doi: 10.1242/10.1242/dev.032649

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Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos

Ming Shao¹, Zhong-Zhen Liu^1,*, Cheng-Dong Wang^1,*, Hong-Yan Li², Clémence Carron², Hong-Wei Zhang^1, and De-Li Shi^1,2,

¹ Institute of Developmental Biology, Life Science College, and Key Lab of Experimental Teratology of the Ministry of Education, Shandong University, Jinan 250100, China.
² Groupe de Biologie Expérimentale, Laboratoire de Biologie du Développement, CNRS UMR 7622, Université Pierre et Marie Curie, 9 quai Saint-Bernard, 75005 Paris, France.

Authors for correspondence (e-mails: zhw{at}sdu.edu.cn; de-li.shi{at}upmc.fr)

Accepted 20 April 2009

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.

Key words: Zebrafish, Wnt signaling, Convergent extension, Dscr5, Glypicans, Frizzled, Dishevelled

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