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The recent discovery that Frizzled proteins are receptor for Wnts has been quickly followed by the identification of a secreted protein, Frzb, that is related to Frizzled, expressed by the Spemann organizer in frog embryos and can bind to and antagonize Wnt developmental signalling molecules.
Figure 1. Frzb is structurally related to the cysteine-rich extracellular domain (CRD) of Frizzled, the putative Wnt receptor. The structures of mouse Frzb (Mfrzb), Xenopus Frzb (Xfrzb), rat Frizzled-1 (Rfz-1) and Drosophila Frizzled-2 (Dfz2) are shown schematically, and the sequence identities of the CRDs (red) relative to that of Mfrzb are given. Frzb lacks the seven transmembrane spanning regions (green) found in Frizzled proteins, but contains a signal sequence (blue) indicating that it is secreted. The predicted number of amino acids for each protein is indicated to the right.
Figure 2. Frzb can antagonize Wnt signalling. (a) Frzb may bind Wnt and prevent its interaction with a Frizzled-like Wnt receptor. In the absence of Wnt signalling, the serine/threonine protein kinase GSK-3β(Zw-3 in Drosophila) phosphorylates cytoplasmic β-catenin (β, armadillo in Drosophila) and, with cooperation of the tumour-suppressor protein APC, causes the degradation of β-catenin. Low β-catenin levels are maintained and the cells do not respond. (b) When cells are stimulated by a Wnt ligand interacting with a Frizzled-like receptor, cytoplasmic Dishevelled protein (Dsh) is activated, which inactivates GSK-3β. There is a rise in β-catenin levels, and β-catenin accumulates in the nucleus in association with the HMG-box DNA-binding protein TCF (also known as LEF or Pangolin). The β-catenin–TCF complex acts as a potent transcriptional activator, stimulating Wnt-responsive genes which ultimately influence the fate or behaviour of cells.
Figure 3. A model of mesodermal patterning in Xenopus. The Spemann organizer (red) secretes the dorsal antagonists Frzb, noggin and chordin, which antagonize ventralizing Xwnt-8 and BMP-4 signals in the ventral–lateral mesoderm (pink). This interaction ultimately influences the patterning and formation of dorsal–lateral cell types, such as somite and kidney. Interactions between BMP-4 and noggin or chordin are also involved in cell-fate decisions between the ectoderm (blue) and neural tissue (white). It is not know if Frzb functions in neural induction or if these signalling systems are involved in patterning of the endoderm (yellow).
