The Wnt/Frizzled pathway is a major pathway implicated in the specification of cell and tissue polarity and operating in different developmental processes, including heart and neural tissue development, kidney morphogenesis, limb polarity and sex determination. The canonical beta-catenin-dependent Wnt pathway controls cell fates via transcriptional activation of target genes. During this process, signals provided by secreted Wnt ligands are transduced through Frizzled receptors, Dishevelled (Dsh) and beta-catenin to the nucleus. In the absence of Wnt signals, a cytoplasmic protein complex, consisting of glycogen synthase kinase 3 (GSK3), adenomatous polyposis coli (APC) and Axin, marks beta-catenin for ubiquitin-dependent degradation. In response to a Wnt ligand, this degradation complex is inactivated and stabilized beta-catenin translocates to the nucleus, where in complex with the TCF transcription factors it stimulates target gene expression.

In vertebrates, the canonical Wnt pathway is responsible for dorsoventral axis specification (Sokol, 1999). One of the earliest indicators of dorsal development is the accumulation of beta-catenin in dorsal nuclei followed by activation of Wnt target genes, such as Siamois, in the Spemann organizer. Antisense depletion of beta-catenin in Xenopus embryos and its genetic knockout in mice result in abnormal axial development, demonstrating a critical role for beta-catenin in axis specification. Activation of several organizer-specific genes depends on functional TCF sites in their promoters, indicating that beta-catenin cooperates with TCF during dorsal development. Taken together, available data establish a key role for Wnt signaling in early dorsoventral asymmetries and axis specification. As discussed above, the same signaling pathway is thought to be involved in neural induction and anteroposterior neural patterning later in development.








Besides the canonical pathway mediated by beta-catenin and TCF, noncanonical Wnt signals are transduced to the cytoskeleton through the activation of small Rho GTPases, intracellular Ca release and c-Jun-N-terminal kinase. During gastrulation and organogenesis, noncanonical Wnt signaling regulates many morphogenetic processes that involve changes in cell shape and motility (Sokol, 1996; Sokol, 2000). The abundance of intracellular targets indicates the existence of a complex network of protein interactions underlying the control of cell division, cell fate, shape and polarity by Wnt signaling.

In Drosophila , Frizzled and Dishevelled are required for the establishment of polarity in the plane of the epithelial tissue, commonly referred to as planar cell polarity (PCP). The PCP pathway requires a number of conserved proteins, including Flamingo, Strabismus, Diego, Prickle, and Fat, rather than beta-catenin and TCF, yet their detailed protein interactions have not been defined. In vertebrate embryos, similar molecular requirements have been established for the pathway that regulates convergent extension (CE) movements and neural tube closure. The CE movements involve convergence of cells towards the dorsal midline and mediolateral cell intercalations in the notochord and neural tube leading to the extension of the body axis. The same Dsh domains that are required for fly PCP are essential for vertebrate CE, suggesting that the same molecular mechanisms are involved. This view has been further supported by reports demonstrating that the vertebrate counterparts of Strabismus and Prickle regulate morphogenetic movements in frog and fish embryos. Both the PCP pathway and regulation of CE involve polarized cell alignment, which may explain the similarity of molecular mechanisms (Sokol, 2000) . Despite the discovery of many gene products regulating noncanonical Wnt signaling, the mechanisms underlying their specific roles in this signaling process remain unclear.

In the past few years, we have identified several molecular antagonists and agonists of the Wnt pathway and currently investigating molecular mechanisms underlying their effects (Krupnik et al., 1999; Gloy et al., 2002; Brott and Sokol, 2005; Itoh et al., 2005). These proteins are relevant for the design of efficient cancer therapies, as many components of the canonical Wnt pathway are mutated in colon carcinomas, melanomas, liver, breast and skin tumors . Besides the effect on cell proliferation, Wnt signaling regulates morphogenetic cell movements and accompanying cytoskeletal changes during gastrulation (Sokol, 2000).  Since this pathway is distinct from the canonical beta-catenin pathway, we want to learn how different proteins relay Wnt signals to different targets and how Wnt signaling contributes to the control of epithelial-mesenchymal transformation. This discovery of the connection between the Wnt pathway and the control of cell movements should contribute to the understanding of morphogenetic processes in normal embryonic development as well as malignant cell transformation in cancer.






Wnt signaling