ANALYSIS OF DISHEVELLED SIGNALING PATHWAYS DURING XENOPUS DEVELOPMENT

Background: Recent studies have demonstrated that the Wnt, Frizzled an d Notch proteins are involved in a variety of developmental processes in fly, worm, frog and mouse embryos. The Dishevelled (Dsh) protein is required for Drosophila cells to respond to Wingless, Notch and Frizz led signals, but the molecular mechanisms of its action are not well u nderstood. Using the ability of a mutant form of the Xenopus homologue of Dsh (Xdsh) to block Wnt and Dsh signalling in a model system, this work attempts to clarify the role of the endogenous Xdsh during the e arly stages of vertebrate development. Results: A mutant Xdsh (Xdd1) w ith an internal deletion of the conserved PDZ/DHR domain was construct ed. Overexpression of Xdd1 mRNA in ventral blastomeres of Xenopus embr yos strongly inhibited induction of secondary axes by the wild-type Xd sh and Xwnt8 mRNAs, but did not affect the axis-inducing ability of be ta-catenin mRNA. These observations suggest that Xdd1 acts as a domina nt-negative mutant. Dorsal expression of Xdd1 caused severe posterior truncations in the injected embryos, whereas wild-type Xdsh suppressed this phenotype, Xdd1 blocked convergent extension movements in ectode rmal explants stimulated with mesoderm-inducing factors and in dorsal marginal zone explants, but did not affect mesoderm induction and diff erentiation. Conclusions: A vertebrate homologue of Dsh is a necessary component of Wnt signal transduction and functions upstream of beta-c atenin. These findings also establish a requirement for the PDZ domain in signal transduction by Xdsh, and suggest that endogenous Xdsh cont rols morphogenetic movements in the embryo.