Wnt proteins are now recognized as one of the major families of developmentally important signaling molecules, with mutations in Wnt genes displaying remarkable phenotypes in the mouse, Caenorhabditis elegans, and Drosophila. Among functions provided by Wnt proteins are such intriguing processes as embryonic induction, the generation of cell polarity, and the specification of cell fate. Until recently, our knowledge of the molecular mechanism of Wnt signaling was very limited, but over the past year, several major gaps have been filled. These include the identification of cell-surface receptors and a novel mechanism of relaying the signal to the cell nucleus. In addition, several components of Wnt signaling are implicated in the genesis of human cancer. These insights have come from different corners of the animal kingdom and have converged on a common pathway. At this junction in this rapidly evolving field, we review our current understanding of Wnt function and signaling mechanisms, doing so in a comparative approach. We have put emphasis on the latest findings, highlighting novelty and underscoring questions that remain. For additional literature, we refer to several previous reviews (McMahon 1992; Nusse and Varmus 1992; Klingensmith and Nusse 1994; Miller and Moon 1996; Moon et al. 1997). We have limited the number of references, particularly in the tables. Fully referenced forms of these tables can be found on the Wnt homepage (http://wwwleland.stanford.edu/∼rnusse/wntwindow.html).

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Wnt signaling: a common theme in animal development

Wnt genes encode a large family of secreted, cysteine-rich proteins that play key roles as intercellular signaling molecules in development. Genetic studies in Drosophila and Caenorhabditis elegans, ectopic gene expression in Xenopus, and gene knockouts in the mouse have demonstrated the involvement of Wnts in processes as diverse as segmentation, CNS patterning, and control of asymmetric cell divisions. The transduction of Wnt signals between cells proceeds in a complex series of events including post-translational modification and secretion of Wnts, binding to transmembrane receptors, activation of cytoplasmic effectors, and, finally, transcriptional regulation of target genes. Over the past two years our understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator. Here we review recent data that have started to unravel the mechanisms of Wnt signaling.

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Mechanisms of wnt signaling in development

Receptors for Wingless and other signalling molecules of the Wnt gene family have yet to be identified We show here that cultured Drosophila cells transfected with a novel member of the frizzled gene family in Drosophila, Dfz2, respond to added Wingless protein by elevating the level of the Armadillo protein Moreover, Wingless binds to Drosophila or human cells expressing Dfz2 These data demonstrate that Dfz2 functions as a Wingless receptor, and they imply, in general, that Frizzled proteins are receptors for the Wnt signalling molecules

A new member of the frizzled family from Drosophila functions as a Wingless receptor.

http://www-leland.stanford.edu/%7Ernusse/reviews/GordonNusseJBC.pdf

Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors

G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.

Structural diversity of G protein-coupled receptors and significance for drug discovery

The function of the frizzled (fz) locus in Drosophilia melanogaster is required to coordinate the cytoskeletons of epidermal cells to produce a parallel array of cuticular hairs and bristles (for example on the wild-type wing all hairs point towards the distal tip). In fz mutants it is not the structure of individual hairs and bristles that is altered, but their orientation with respect to their neighbours and the organism as a whole. Mitotic clone analysis indicates that fz has two functions in the developing wing. It is required for the proximal-distal transmission of an intercellular polarity signal, a process that is expected to be at least partly extracellular. It is also required for cells to respond to the polarity signal, which is expected to be a cytoplasmic function. The fz locus could encode either one bifunctional or two single-function proteins. We report here that, in pupae, fz produces a messenger RNA that encodes a protein with seven putative transmembrane domains. Thus, the Fz protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information, respectively. This is the first reported sequence for the protein product of a tissue polarity gene.

Sharon Conover

Papers

A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains