The Wnt genes encode a large family of glycoproteins that are essential in development and tissue maintenance (1). Members of the Frizzled family of proteins serve as receptors for the Wnt signaling pathway (2). Ten mouse and human Frizzled genes have been identified to date. The predicted structure of Frizzled proteins is similar among all family members, containing a divergent N-terminal signal peptide, a highly conserved extracellular cysteine-rich domain (CRD), a variable-length linker region, a seven-pass transmembrane region, and a variable-length C-terminal cytoplasmic domain. The CRD, which comprises 642 amino acid residues and shares 95% identity with the human orthologue in the CRD. Frizzled-1 mRNA has been detected in relatively large amounts in adult heart, placenta, lung, kidney, pancreas, prostate, and ovary, and in fetal lung and kidney (3).
Several Frizzled-dependent signaling pathways exist (2). Their activation depends on the Wnt ligand and the cell context. Members of the low density lipoprotein receptor-related protein (LRP) are co-receptors for the Wnt ligands. LRP5/6 serve as co-receptors in the Wnt/Frizzled canonical pathway that alters gene expression via the stabilization of beta -catenin (4, 5). LRP1 may down regulate Wnt-3a/Frizzled-1 signaling in the canonical pathway by sequestering Frizzled-1 (6). Frizzled-1 is one of the purported Wnt-10b receptors whose signaling inhibits adipogenesis in preadipocytes (7). Frizzled-1 may be part of a feedback mechanism to modulate the effects of BMP-2 in mesenchymal cells since upregulation of its expression by BMP-2 counteracts the effects of BMP-2 and Wnt-3a in inducing the expression of the osteoblast differentiation marker, alkaline phosphatase (8).
