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Wnts are secreted proteins that are essential for a wide array of developmental and physiological processes. They signal across the plasma membrane by interacting with serpentine receptors of the Frizzled (Fz) family and members of the low-density-lipoprotein-related protein (LRP) family. Activation of Fz-LRP promotes the stability and nuclear localization of β-catenin by compromising the ability of a multiprotein complex containing axin, adenomatosis polyposis coli (APC) and glycogen synthase kinase 3 (GSK3) to target it for degradation and block its nuclear import. The Fz-LRP receptor complex probably accomplishes this by generating multiple signals in the cytoplasm. These involve activation of Dishevelled (Dsh), possibly through trimeric G proteins and LRP-mediated axin binding and/or degradation. However, individual Wnts and Fzs can activate both β-catenin-dependent and -independent pathways, and Fz co-receptors such as LRP probably provide some of this specificity. Additional, conflicting data concern the role of the atypical receptor tyrosine kinase Ryk, which might mediate Wnt signaling independently of Fz and/or function as a Fz co-receptor in some cells.

In Drosophila wing imaginal discs, the Wingless (Wg) protein acts as a morphogen, emanating from the dorsal/ventral (D/V) boundary of the disc to directly define cell identities along the D/V axis at short and long range. Here, we show that high levels of a Wg receptor, Drosophila frizzled 2 (Dfz2), stabilize Wg, allowing it to reach cells far from its site of synthesis. Wg signaling represses Dfz2 expression, creating a gradient of decreasing Wg stability moving toward the D/V boundary. This repression of Dfz2 is crucial for the normal shape of Wg morphogen gradient as well as the response of cells to the Wg signal. In contrast to other ligand-receptor relationships where the receptor limits diffusion of the ligand, Dfz2 broadens the range of Wg action by protecting it from degradation.

One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

Regulation of Wnt transcriptional targets is thought to occur by a transcriptional switch. In the absence of Wnt signaling, sequence‐specific DNA‐binding proteins of the TCF family repress Wnt target genes. Upon Wnt stimulation, stabilized β‐catenin binds to TCFs, converting them into transcriptional activators. C‐terminal‐binding protein (CtBP) is a transcriptional corepressor that has been reported to inhibit Wnt signaling by binding to TCFs or by preventing β‐catenin from binding to TCF. Here, we show that CtBP is also required for the activation of some Wnt targets in Drosophila. CtBP is recruited to Wnt‐regulated enhancers in a Wnt‐dependent manner, where it augments Armadillo (the fly β‐catenin) transcriptional activation. We also found that CtBP is required for repression of a subset of Wnt targets in the absence of Wnt stimulation, but in a manner distinct from previously reported mechanisms. CtBP binds to Wnt‐regulated enhancers in a TCF‐independent manner and represses target genes in parallel with TCF. Our data indicate dual roles for CtBP as a gene‐specific activator and repressor of Wnt target gene transcription.

Wnt/β-catenin signalling is known to play many roles in metazoan development and tissue homeostasis. Misregulation of the pathway has also been linked to many human diseases. In this review, specific aspects of the pathway's involvement in these processes are discussed, with an emphasis on how Wnt/β-catenin signalling regulates gene expression in a cell and temporally specific manner. The T-cell factor (TCF) family of transcription factors, which mediate a large portion of Wnt/β-catenin signalling, will be discussed in detail. Invertebrates contain a single TCF gene that contains two DNA-binding domains, the high mobility group (HMG) domain and the C-clamp, which increases the specificity of DNA binding. In vertebrates, the situation is more complex, with four TCF genes producing many isoforms that contain the HMG domain, but only some of which possess a C-clamp. Vertebrate TCFs have been reported to act in concert with many other transcription factors, which may explain how they obtain sufficient specificity for specific DNA sequences, as well as how they achieve a wide diversity of transcriptional outputs in different cells.

In Drosophila embryos the protein Naked cuticle (Nkd) limits the effects of the Wnt signal Wingless (Wg) during early segmentation. nkd loss of function results in segment polarity defects and embryonic death, but how nkd affects Wnt signaling is unknown. Using ectopic expression, we find that Nkd affects, in a cell-autonomous manner, a transduction step between the Wnt signaling components Dishevelled (Dsh) and Zeste-white 3 kinase (Zw3 Secreted Wnt proteins act as potent mitogens and cellfate regulators in organisms ranging from nematodes to humans. In vertebrates they specify cell fate and control growth in a variety of developmental processes, including brain development, limb formation, axis specification, and gastrulation (for review, see Cadigan and Nusse 1997). In the fruit fly Drosophila, the Wnt protein Wingless (Wg) establishes segment polarity during embryogenesis and is involved in multiple additional patterning events throughout later development (Cadigan and Nusse 1997). wg is first expressed in the developing epidermis in stripes just anterior to cells expressing the engrailed (en) gene and is necessary to maintain en transcription (DiNardo et al. 1988;Martinez Arias et al. 1988). hedgehog (hh) is expressed in the en-expressing cells and positively regulates wg expression in the anterior cells (Ingham et al. 1991;Lee et al. 1992). This positive-feedback loop establishes parasegmental boundaries, the first evidence of the metameric organization of the embryo, between wg-and en/hh-expressing cells. At later stages of embryonic development, a tight balance between Wg and other signaling pathways, such as the Drosophila epidermal growth factor receptor (EGFR), determines whether epidermal cells secrete either naked (smooth) cuticle or hair-like structures called denticles (Dougan and DiNardo 1992;O'Keefe et al. 1997;Szuts et al. 1997). In the absence of wg function, embryos are covered with a lawn of denticles, whereas otherwise wild-type embryos exposed to excess Wg produce a naked cuticle (Martinez Arias et al. 1988;Noordermeer et al. 1992).Genetic and biochemical studies have lead to the identification of the key components of the Wnt/Wg pathway and have uncovered some of the molecular events that are involved in signal transduction (Fig. 1A). Wg binds 7-pass transmembrane receptors of the frizzled family (Fz or Dfz2), which, in turn, activate the cytoplasmic protein Dishevelled (Dsh; Theisen et al. 1994;Bhanot et al. 1996). Dsh antagonizes the activity of a large protein complex that, in the absence of Wg signal, results in Armadillo (Arm)/␤-catenin phosphorylation and subsequent degradation by the ubiquitin-proteasome pathway (Yost et al. 1996;Aberle et al. 1997;Pai et al. 1997). This multiprotein complex includes Zw3/Glycogen synthase kinase 3␤ (Gsk3␤), Adenomatous Polyposis Coli (APC), Axin, and Arm/␤-catenin. Axin constitutes the core of this complex, al-