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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, Z.Z., Wang, C.D., Li, H.Y., Carron, C., Zhang, H.W., and Shi, D.L.
Date:
2009
Source:
Development (Cambridge, England)
136(12):
2121-31 (Journal)
Shao, M., Liu, Z.Z., Wang, C.D., Li, H.Y., Carron, C., Zhang, H.W., and Shi, D.L. (2009) Down syndrome critical region protein 5 regulates membrane localization of Wnt receptors, Dishevelled stability and convergent extension in vertebrate embryos. Development (Cambridge, England). 136(12):2121-31.
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.
