Dscr 5 Regulates Convergent Extensionin Vertebrate Embryos Development

Gastrulation of vertebrate embryos is the fundamental morphogenetic movement through which the three germ layers form:ectoderm, mesoderm and endoderm. Gastrulation includes three kinds of movements:epiboly, internalization and convergent extension (CE) movement.Convergence and extension are defined as the narrowing of embryonic tissues mediolaterally (convergence) and their elongation anteroposteriorly (extension). These movements are driven by a number of directed and cooperated cell movements. CE movement is one of the fundamental cell movements, and is important to the elongation of the embryonic anterior-posterior axis.The Wnt/PCP signaling, one of the non-canonical Wnt signaling plays an important role in regulating the CE movement. It is triggered by Wnt-11 through interaction with its seven-pass transmembrane Frizzled receptor and coreceptor of the Glypican family, which includes zebrafish Knypek protein and its orthologue Xenopus Glypican 4. The signal is then relayed to the cytoplasmic protein Dishevelled and further activates downstream components-GTPase Rho and Rac, followed the activation of Rho-associated coiled-coil containing protein kinase (ROCK) and Myosin. The PCP signaling finally induces the modification of actin and the recomposition of the cytoskeleton.Down syndrome is one of the most frequent human birth defects, occurring in 1 out of 600 to 1000 births. It is caused by trisomy of chromosome 21 and is associated with mental retardation and various facial and physical anomalies. Phenotypic and molecular analyses of patients have led to the identification of a region in chromosome 21, critical for the pathogenesis of Down syndrome. This region is called Down syndrome critical region (DSCR), in which several genes have been identified, including dscr5. However, the function of most of them in key early developmental events remains largely unexplored. Thus, functional analysis of these genes during early development represents an essential step in understanding the pathogenesis of the birth defects in Down syndrome patients.The human dscr5 encodes the protein phosphatidylinositol-glycan-class P(PIG-P), which is a component of GPI-GnT complex required for the first step of glycosylphosphatidylinositol (GPI) biosynthesis. The GPI is a glycolipid complex which acts as the anchor of many membrane proteins. The GPI-anchored proteins belong to the heparan sulfate proteoglycans (HSPG), which have been found in Drosophila and vertebrates and play an important role in regulating the Wnt signaling. Although Knypek and Glypican 4 are potential GPI-anchored proteins, it is unknown if their anchoring on the membrane and the activation are regulated by GPI-GnT. Thus, it remains to be determined if there is a functional link between these potential GPI-anchored proteins and the GPI biosynthesis complex.In this study, we report that Dscr5 is involved in the CE movement. Overexpression and knockdown of dscr5 can both induce the disturbance of CE movement in zebrafish embryos. Further we find that Dscr5 regulates the CE movement through the Wnt/PCP pathway. The Wnt/PCP signaling requires the anchoring of Knypek and Frizzled 7 on the membrane, while knockdown of dscr5 leads to the endocytosis of Frizzled 7 receptor through the Caveolin-dependent pathway and the degradation of Dishevelled through the ubiquitin-proteasome pathway (UPP). These results suggest a new mechanism that regulates the Wnt/PCP signaling and CE movement.