Disease relevance of Fzd1

• The morphogen retinoic acid promotes the formation of primitive endoderm in mouse F9 teratocarcinoma cells as does the stimulation of the Frizzled-1 pathway [1].
• Primitive endoderm formation stimulated by Wnt-8 acting on the rat Frizzled-1 receptor was blocked by treatment with pertussis toxin by depletion of either Galpha(o) or Galpha(q) via antisense oligodeoxynucleotides, as well as by inhibitors of protein kinase C (bisindoylmaleimide) and of mitogen-activated protein kinase kinase (PD98059) [2].
• Regarding these properties, we assess the hypothesis that Frizzled A could act in the healing process after myocardial infarction [3].

High impact information on Fzd1

• G protein signaling from activated rat frizzled-1 to the beta-catenin-Lef-Tcf pathway [4].
• The central effector of the Wnt pathway is beta-catenin, which undergoes stabilization upon binding of Wnt ligands to frizzled receptors [5].
• Biochemical analysis demonstrates that Wnt7b can bind to Fzd1 and -10 on the cell surface and cooperatively activate canonical Wnt signaling with these receptors in the presence of LRP5 [6].
• Fzd1, -4, and -7 are expressed primarily in the developing lung mesenchyme, and Fzd10 is expressed in airway epithelium [6].
• Identification and cloning of a secreted protein related to the cysteine-rich domain of frizzled. Evidence for a role in endothelial cell growth control [7].

Biological context of Fzd1

• In the course of the analysis of genes regulated by bone morphogenetic protein 2 in mesenchymal cells we found a significant induction of murine Frizzled-1 (mFz1) gene expression [8].
• Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals [9].
• WNT factors represent key mediators of many processes in animal development and homeostasis and act through a receptor complex comprised of members of the Frizzled and low density lipoprotein-related receptors (LRP) [10].
• Our results indicated that activated Fz1 increases stability of beta-catenin, inhibits apoptosis, induces osteoblastogenesis, and inhibits adipogenesis [11].
• The expression of eight murine Frizzled (1,3-9) genes was studied during mouse somitogenesis, in order to correlate the Wnt-dependent activation of myogenesis with the expression of specific Frizzled putative receptors [12].

Anatomical context of Fzd1

• We report comprehensive analysis of Wnt and Fz expression in whole liver as well as individual cell types: freshly isolated and plated hepatocytes, biliary epithelial cells, normal and activated stellate and Kupffer cells, and sinusoidal endothelial cells (SECs) [13].
• The same 14 Wnt and 7 Fz genes were expressed in both activated and normal stellate and Kupffer cells; only Fzb was expressed in their activated state [13].
• Although only 6 Wnt and 5 Fz genes were expressed in freshly isolated hepatocytes, 8 Wnt genes, 7 Fz genes, and Fzb were expressed in plated hepatocytes [13].
• We found that sFRP3 unexpectedly increased osteoblast differentiation, suggesting it may act through other mechanisms besides acting as a decoy receptor for Wnt's. INTRODUCTION: Secreted frizzled-related proteins (sFRPs) are a truncated form of frizzled receptor, missing both the transmembrane and cytosolic domains [14].
• Collectively these findings suggest (1) a functional role for Wnt-producing thymic epithelium in determining TCF/LEF-mediated transcriptional regulation in Fz-bearing thymocytes, and (2) a role for defined Wnt-Fz interactions at successive stages of thymocyte maturation [15].

Associations of Fzd1 with chemical compounds

• By using chimeric constructs in which N- and C-terminal segments of mFz1 were replaced by the corresponding parts of Xfz3 we demonstrated that the antagonistic activity resides in the cysteine-rich domain of the N-terminal part [8].
• Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions [16].
• The results show that the main families in the human genome, Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin, arose before the split of nematodes from the chordate lineage [17].

Physical interactions of Fzd1

• Our results in combination with work from Xenopus laevis (not shown) lead us to believe that Wnt-4 binds both canonical and noncanonical Frizzled receptors, thereby activating Wnt signaling pathways that may each contribute to kidney tubulogenesis [18].

Regulatory relationships of Fzd1

• Importantly microinjection of mFz1 transcript in Xenopus embryo inhibited the ability of Wnt1 to induce the expression of the Wnt/beta-catenin target gene Siamois in animal cap assay and secondary axis formation in whole embryo [8].
• Activation of Frizzled-1 by Wnts induces nuclear accumulation of beta-catenin and activation of Lef/Tcf-dependent gene expression [19].
• Multiple Wnt ligands and Frizzled receptors are expressed in the embryonic mouse pancreas, the surrounding mesenchyme, and have also been detected in the chicken endoderm during development [20].

Other interactions of Fzd1

• Wnts are extracellular ligands that bind to frizzled (Fz) receptors at the membrane, canonically inducing beta-catenin nuclear translocation and activation [13].
• Although 12 Wnt and 7 Fz genes were expressed in biliary tree, additional Fz9 and Fzb were only expressed in cultured biliary epithelial cells [13].
• Oligonucleotides for the 19 Wnt, 10 frizzled receptors genes, and secreted Frizzled-related protein-1 (sFRP or Fzb) were synthesized based on the available sequences [13].
• Thus, casein kinase 2 is shown to be regulated by Wnt3a and essential to stimulation of the Frizzled-1/beta-catenin/Lef-Tcf pathway [19].
• We ectopically expressed constitutively active chimeras between Wnt8 and Fz1 or Fz2 in preadipocytes and mesenchymal precursor cells [11].

Analytical, diagnostic and therapeutic context of Fzd1

• To begin to investigate these functions, we have used in situ hybridization to identify cells that express Frizzled (Fz) WNT receptor genes, and so are potentially receptive to WNT ligands [21].
• We used the T31 Mouse/Hamster radiation hybrid panel to map the mouse frizzled-1 to mouse chromosome 5 (5 cM from the centromere), and frizzled-9 to mouse chromosome 5 (74 cM from the centromere) [22].
• RT-PCR analysis showed that primary endothelial and smooth muscle cell cultures, of both mouse and human origin, express members of the Wnt and Wnt receptor (Frizzled) gene families [23].
• Involvement of FrzA/sFRP-1 and the Wnt/frizzled pathway in ischemic preconditioning [24].
• METHODS: To investigate the role of Frizzled A, we established a transgenic mouse line overexpressing the protein and developed a model of myocardial infarction by coronary artery ligation [3].

References