Frizzled Receptors in Development and Disease

Abstract

Frizzled proteins are the principal receptors for the Wnt family of ligands. They mediate canonical Wnt signaling together with Lrp5 and Lrp6 coreceptors. In conjunction with Celsr, Vangl, and a small number of additional membrane and membrane-associated proteins, they also play a central role in tissue polarity/planar cell polarity (PCP) signaling. Targeted mutations in 9 of the 10 mammalian Frizzled genes have revealed their roles in an extraordinarily diverse set of developmental and homeostatic processes, including morphogenetic movements responsible for palate, ventricular septum, ocular furrow, and neural tube closure; survival of thalamic neurons; bone formation; central nervous system (CNS) angiogenesis and blood–brain barrier formation and maintenance; and a wide variety of processes that orient subcellular, cellular, and multicellular structures relative to the body axes. The last group likely reflects the mammalian equivalent of tissue polarity/PCP signaling, as defined in Drosophila, and it includes CNS axon guidance, hair follicle and tongue papilla orientation, and inner ear sensory hair bundle orientation. Frizzled receptors are ubiquitous among multicellular animals and, with other signaling molecules, they very likely evolved to permit the development of the complex tissue architectures that provide multicellular animals with their enormous selective advantage.

MicroRNA‑101 inhibits cell migration and invasion in bladder cancer via targeting FZD4

“…Among these putative target genes, FZD4, which encodes a seven-transmembrane domain protein and is associated with β-catenin canonical signalling pathway, was selected to be studied (Fig. 3A), as a tumour suppressor miR-493 was reported to inhibit bladder cancer cell growth and migration ability by targeting FZD4 (27)(28)(29). To verify this predication, luciferase reporter gene plasmids were generated with either WT or MT FZD4 3'-UTR (Fig.…”

Regulation of Wnt signaling by protocadherins

“…Mammals have 10 Fzd receptors [22]. The intracellular domain (ICD) of Fzd binds Dishevelled proteins (Dvls) through a conserved KTXXXW motif; Dvl interacts with a large number of Wnt co-receptors to activate the different Wnt pathways [23].…”

Planar cell polarity-dependent and independent functions in the emergence of tissue-scale hair follicle patterns

“…However, hair follicle refinement has not been observed in any other core PCP mutant to date, raising the question of whether this phenomenon is unique to the Fz6 allele. There are over 10 different Fz homologs present in the mouse genome, and deletion of Fz6 produces only mild defects compared to other PCP mutants (Wang et al, 2016). Thus, it is unclear whether redundant core PCP cues instruct the postnatal hair follicle pattern in Fz6 mutants, or whether a parallel PCP system, such as the Fat-Dachsous- Four-jointed system (Matis and Axelrod, 2013), functions postnatally to correct hair follicle alignment.…”