The Class F of the superfamily of G protein-coupled receptors (GPCRs) consists of Smoothened (SMO) and 10 FZD isoforms, FZD1–10. FZDs are ubiquitously expressed seven transmembrane (7TM) receptors that tightly regulate biological processes in multicellular organisms, ranging from embryonic development, stem cell regulation, organogenesis, cellular, and tissue polarity to tissue homeostasis. FZD signaling lies at the root of numerous pathologies for which treatments are limited. As cell-surface receptors, FZDs mediate responses induced by binding of secreted ligands of the Wingless/Int1 (WNT) family of proteins, of which 19 isoforms exist in mammals. In addition to WNTs, other proteins and structures have been identified as FZD ligands, such as Clostridium difficile toxin B and Norrin – the latter being selective for FZD4. 
In mouse primary microglial cultures, WNT-5A induced GDP/GTP exchange on heterotrimeric G proteins, reduced cAMP levels, and induced G protein-mediated responses such as the mobilization of intracellular calcium, phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), microglial proliferation, invasion, and proinflammatory transformation. Interestingly, WNT-3A induced the expression of cyclooxygenase 2 (COX2), a classical target gene of the WNT/b-catenin pathway, through a pertussis toxin (PTX)-sensitive and ERK1/2-dependent pathway. FZDs and WNTs for the specification of intracellular signaling pathways in diverse cellular models and in vivo systems, but there is still a lack of understanding regarding the detailed mechanisms that govern ligand interaction, FZD activation, signal initiation, and signal specification.


1.Schulte G, et al. Trends Pharmacol Sci. 2018;39(9):828–842.