Wnt signaling is involved in a variety of developmental processes including cell fate determination, cell polarity, tissue patterning and control of cell proliferation. Members of the Frizzled family of proteins serve as receptors for the Wnt signaling pathway. The founding member of this family was identified in Drosophilia based on its role in tissue polarity in the adult cuticle and named for the disorganized appearance of bristle hairs on the mutant. Mouse Frizzled-8 (mFrz-8) was originally cloned in a PCR screen to identify additional Frizzled family members in vertebrates. There are nine murine Frizzled genes and 10 human Frizzled genes 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, a seven-pass transmembrane region, and a variable-length C-terminal tail. The most conserved regions of the Frizzled proteins are the extracellular cysteine-rich domain (CRD) which spans approximately 120 amino acid residues and contains 10 invariant cysteines, and the seven transmembrane domains. Mouse Frizzled-8 is 685 amino acid residues long and shows 95% and 82% amino acid identity to human and Xenopus Frizzled-8, respectively. Like other family members, Frizzled-8 has a complex expression pattern in the mouse embryo. It is expressed in the neural tube, brain, eye, somites, gut, and bronchial arches.
One of the best-characterized Wnt signal transduction pathways is the canonical Wnt/ beta -catenin pathway. It is involved in diverse biological mechanisms such as dorsal/ventral development in Xenopus embryos and mammalian tumor formation, acting via stabilization of beta -catenin. Frizzled-8 is implicated in this pathway based on its ability to bind Wnt ligands that stimulate beta -catenin stabilization and to influence the formation of secondary axes in Xenopus embryos. The mFrz-8 CRD has been demonstrated to bind cell surface Xenopus Wnt-8 (XWnt-8) protein, indicating that this region is sufficient for binding ligand. In addition, the CRD portion of Frizzled-8 has potent antagonizing activity of Wnt signaling as assayed by inhibition of secondary axes induced by Xwnt-8 mRNA. The crystal structure of mFrz-8 CRD exhibits a dimer interface that is also present in sFRP-3, and suggests that CRD dimerization may be important for Wnt signaling.
