Extensive information on Wingless homologs and their receptors, including Frizzled, is to be found at Roel Nusse's World Wide Web Wnt Window (WWWWW).

FZ2, a putative receptor for Wingless

See Drosophila Fz2 for more information about Frizzled homologs.

FZ2, a putative receptor for Wingless resembles all other members of the frizzled family in having the following structural motifs (beginning at the N terminus): a signal sequence, a domain of 120 amino acids with an invariant pattern of ten cysteine residues, a highly divergent region of 40-100 largely hydrophilic amino acids that is predicted to be flexible, and seven putative transmembrane segments. The C terminus resembles that of most mammalian frizzled proteins in ending with the sequence S/T-X-V. FZ2 most closely resembles human fz5 and mouse fz8 with which it shares 49% and 45% amino acid identity, respectively. FZ and FZ2 share 33% amino-acid identity (Bhanot, 1996).

In a four-cell-stage Caenorhabditis elegans embryo, Wnt signaling polarizes an endoderm precursor called EMS. The polarization of this cell orients its mitotic spindle in addition to inducing endodermal fate in one daughter cell. Reducing the function of Wnt pathway genes, including a newly identified GSK-3beta homolog called gsk-3, disrupts endoderm induction, whereas only a subset of these genes (mom-1/porcupine, mom-5/frizzled and the Wnt pathway component gsk-3) are required to orient the EMS mitotic spindle. mom-1/porcupine is required specifically in the signaling cell P2. Wnt pathway genes thought to act downstream of gsk-3, including the Armadillo and APC homologs, appear not to be required for spindle orientation, suggesting that gsk-3 represents a branch point in the control of endoderm induction and spindle orientation. Orientation of the mitotic spindle does not require gene transcription in EMS, suggesting that Wnt signaling may directly target the cytoskeleton in a responding cell (Schlesinger, 1999).

Because rotational positioning of the EMS centrosomes appears to not require gene transcription, it is suggested that P2 to EMS signaling directly targets the cytoskeleton in EMS. Microtubules are the primary structural component of the mitotic spindle and are thought to interact with cortical microfilaments during rotation of the nucleus/centrosome complex in EMS. Either microtubules or microfilaments could be targets of Wnt signaling, as both are required for correct orientation of the mitotic spindle in EMS. Wnt pathway genes have been implicated in cytoskeleton-related processes in other systems. Mammalian GSK-3beta can phosphorylate the microtubule-associated protein tau, and this activity is regulated by Dishevelled, another Wnt pathway component (Wagner, 1997). Therefore P2 signaling might influence microtubule dynamics directly through gsk-3. Alternatively, P2 signaling might influence spindle orientation in EMS by locally activating microtubule motor complexes that directly interact with astral microtubules to orient the nucleus/centrosome complex before cell division. It seems likely that Wnt signaling directly targets the cytoskeleton to control other developmental processes. For example, the polarized organization of hair cells in the Drosophila epithelium appears to be controlled by the orientation of actin microfilaments, which in turn are regulated by tissue polarity genes including fz and dsh. Wnt signaling in C. elegans may also target the cytoskeleton to polarize endoderm potential in EMS, as the polarization of endoderm potential appears to require functional microfilaments and microtubules. Alternatively, P2 signaling may simply cause a localized activation of downstream Wnt pathway components, resulting in an asymmetric segregation of their activity to the daughters of EMS. In conclusion, it is emphasized that some developmental signals may influence cell fate by directly targeting cytoplasmic components in a responding cell and only indirectly regulate gene transcription. As the Wnt pathway is widely conserved, it will be interesting to learn if direct targeting of the cytoskeleton in cells responding to Wnt signaling proves to be of general importance during animal development (Schlesinger, 1999 and references).

The N-terminal ends of mouse collagen type XVIII contain sequences homologous to Frizzled. It appears that the Frizzled motif is found in otherwise unrelated proteins (Rehn, 1995). Two human homologs of Frizzled have been identified (Chan, 1992). The structure of human FZD-2 suggests that it has a role in transmembrane signal transmission (Zhao, 1995).

Six novel frizzled homologs from mammals have been identified, as well as 11 from zebrafish, several from chicken and sea urchin and one from C. elegans. The mammalian and nematode homologs share with Drosophila Frizzled a conserved N-terminal cysteine-rich domain and seven transmembrane segments. The mammalian homologues are expressed in distinctive sets of tissues in the adult, and at least three are expressed during embryogenesis (Wang, 1996).

Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling

Wnt proteins (see Drosophila Wingless) modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD; see Drosophila Frizzled) and the co-receptors LRP5 and LRP6 (see Drosophila Arrow) to regulate cell fate decisions and the growth and repair of several tissues. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation. This study develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. These Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion and enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine (Janda, 2017).

A context-dependent combination of Wnt receptors controls axis elongation and leg development in a short germ insect

Short germ embryos elongate their primary body axis by consecutively adding segments from a posteriorly located growth zone. Wnt signalling is required for axis elongation in short germ arthropods, including Tribolium castaneum, but the precise functions of the different Wnt receptors involved in this process are unclear. This study analysed the individual and combinatorial functions of the three Wnt receptors, Frizzled-1 (Tc-Fz1), Frizzled-2 (Tc-Fz2) and Frizzled-4 (Tc-Fz4), and their co-receptor Arrow (Tc-Arr) in the beetle Tribolium. Knockdown of gene function and expression analyses revealed that Frizzled-dependent Wnt signalling occurs anteriorly in the growth zone in the presegmental region (PSR). Simultaneous functional knockdown of the Wnt receptors Tc-fz1 and Tc-fz2 via RNAi resulted in collapse of the growth zone and impairment of embryonic axis elongation. Although posterior cells of the growth zone were not completely abolished, Wnt signalling within the PSR controls axial elongation at the level of pair-rule patterning, Wnt5 signalling and FGF signalling. These results identify the PSR in Tribolium as an integral tissue required for the axial elongation process, reminiscent of the presomitic mesoderm in vertebrates. Knockdown of Tc-fz1 alone interfered with the formation of the proximo-distal and the dorso-ventral axes during leg development, whereas no effect was observed with single Tc-fz2 or Tc-fz4 RNAi knockdowns. Tc-Arr was identied as an obligatory Wnt co-receptor for axis elongation, leg distalisation and segmentation (Beermann, 2012).

The Tc-fz2 expression pattern and the Tc-fz1/2 double RNAi phenotype identify the region between the posterior growth zone and the new segments as crucial for axial elongation (AE). This tissue develops in a similar position to the presomitic mesoderm (PSM) in vertebrates and is called the presegmental region (PSR) in Tribolium. In both Drosophila and Tribolium, Fz1 and Fz2 function redundantly: in Drosophila during segmentation and in Tribolium within the PSR, the axis elongation phenotype was only seen when Tc-Fz1 and Tc-Fz2 were depleted simultaneously. Since Wnt signalling drives segmentation from within the PSR, reception of the Wnt signal in this tissue by the Tc-Fz1 and Tc-Fz2 receptors is necessary for this process (Beermann, 2012).

Marker gene analysis showed that the posterior growth zone is not completely abolished in Tc-fz1/2RNAi embryos, as was previously shown for Tc-arrowRNAi embryos. The markers Eve, odd and wnt8 are still expressed in posterior cells of the growth zone. The persistent expression of the marker gene caudal proves the identity of these cells as posterior cells. Because the complete wild-type expression pattern of caudal is not retained in Tc-fz1/2RNAi embryos, the terminal-most tissues could still contribute to axis elongation. The absence of the hindgut marker brachyenteron in strongly affected Tc-fz1/2RNAi embryos is in accordance with the loss of the hindgut in fz1/2RNAi larval cuticles. In less strongly affected Tc-fz1/2RNAi embryos, byn expression is still detectable. The results show that the transition of the pair-rule genes from the primary to the segmental phase depends on Wnt signalling. As a consequence of this loss of Wnt signalling, AE does not occur. In contrast to Tc-wnt8, Tc-wnt5 expression is completely abolished in strong Tc-fz1/2RNAi embryos. This finding could be explained by an autoregulatory loop in the PSR involving Frizzled and Wnt5 (Beermann, 2012).

In vertebrates, coordinated cell movements in the PSM under the control of FGF signalling are responsible for AE. Because signalling pathways are connected to other signalling pathways, it is hypothesised that FGF signalling might be involved in AE in Tribolium as well. Indeed, the prominent wild-type FGF expression domain is missing in Tc-fz1/2RNAi embryos, indicating that FGF signalling depends on Wnt signalling in Tribolium and might itself be crucially required for AE. It is striking that in both vertebrates and insects, a tissue immediately posterior to the last somites or segment formed - the PSM and the PSR, respectively - fulfils analogous functions in the axial elongation process (Beermann, 2012).

In Drosophila and Tribolium, wingless is required for segmentation as well as for distalisation and dorso-ventral patterning of the appendages. For Tribolium, it was argued that the leg patterning function of wingless is only required during later embryonic stages (Beermann, 2012).

This study shows that Tc-fz1 function is required for both proximo-distal (PD) and dorso-ventral (DV) axis formation in the leg. Because both the PD and the DV leg phenotypes are the result of parental RNAi, a distinct time-dependency for Tc-fz1 function could not be verified. Rather, the data support concentration-dependent regulation of the PD and DV axes during leg development. The Tc-fz1RNAi leg phenotype strongly resembles the winglessRNAi phenotypes described for Tribolium and Drosophila. Based on bristle mapping, it is proposed that the best candidate ligand for Tc-Fz1 in appendage formation is Tc-Wnt1 (Beermann, 2012).

Remarkably, Tc-fz1/2RNAi larvae lacking most of the abdominal segments develop normal legs. Here, the reduced Tc-fz1 function seems to be partially compensated. This result is in contrast to Tc-arrowRNAi, in which leg formation is severely affected in larvae with a mild AE defect. Why does the knockdown of Tc-fz1 in the Tc-fz1/2 double RNAi experiment interfere only mildly with leg formation? AE is apparently very sensitive to depletion of Tc-fz1/2 function. The dose of dsRNA required for an AE phenotype hardly affects Tc-Fz1-dependent leg patterning at all. Presumably, in the double knockdown embryos, the concentration of Tc-fz1 transcripts does not sink below a critical threshold. In contrast, AE and leg patterning require similar amounts of the co-receptor Arrow. These results support a dosage dependency of Wnt receptors and co-receptors during embryogenesis (Beermann, 2012).

In larvae with weak Tc-fz1 RNAi phenotypes, lesions occur in the proximal leg, affecting the joints of the trochanter - sites of Tc-fz4 expression - and leading to a fusion of coxa and trochanter. Tc-Fz4, therefore, supports Tc-Fz1 in transducing the Wnt signal in the proximal leg. This assumption is corroborated by the finding that Tc-fz1/4 double RNAi enhances the frequency and the phenotype of this leg phenotype. However, Tc-Fz4 on its own is dispensable in the leg; Tc-Fz1 appears to be the crucial partner. At present, the precise function of Tc-Fz1/Fz4 in the dorso-proximal leg is speculative. The hypothesised leg differentiation center at the coxa/trochanter boundary, postulated for Tenebrio, is an intriguing possibility. Larvae with the strongest Tc-fz1RNAi phenotype display loss of distal structures, including the pretarsal claw. Because Tc-fz4 is not expressed distal to the tibiotarsal region, Tc-Fz1 seems to be the single primary Wnt transducer in the distal appendage. The ligand for this signal is probably distal Wnt1, based on the leg phenotype of wgRNAi larvae. Depending on their conformation, Frizzled receptor proteins have been proposed to signal via different downstream signalling pathways and could thus serve as multifunctional signal transducers depending on, e.g. ligand availability. In this way, a variety of different biological outcomes can be controlled by a small number of Wnt receptors (Beermann, 2012).

Frzb(s), proteins that bind to Wnt receptors and interfere with Wnt signaling

Fritz, a mouse (mfiz) and human (hfiz) gene, codes for a secreted protein that is structurally related to the extracellular cysteine-rich portion of the frizzled genes from Drosophila and vertebrates. The overall identity between the extracellular domains of various frizzled-like proteins and hfiz is only in the range of 10-38%. The Fritz protein antagonizes Wnt function when both proteins are ectopically expressed in Xenopus embryos. In early gastrulation, mouse fiz mRNA is expressed in all three germ layers. Later in embryogenesis fiz mRNA is found in the central and peripheral nervous systems, nephrogenic mesenchyme and several other tissues, all of which are sites where Wnt proteins have been implicated in tissue patterning. A model is proposed in which Fritz protein can interfere with the activity of Wnt proteins via their cognate frizzled receptors and thereby modulate the biological responses to Wnt activity in a multitude of tissue sites (Mayr, 1997).

The primary mouth forms from ectoderm and endoderm at the extreme anterior of the embryo, a conserved mesoderm-free region. In Xenopus, a very early step in primary mouth formation is loss of the basement membrane between the ectoderm and endoderm. In an unbiased microarray screen, genes encoding the sFRPs Frzb-1 and Crescent were defined as transiently and locally expressed in the primary mouth anlage. Using antisense oligonucleotides and 'face transplants', it was shown that frzb-1 and crescent expression is specifically required in the primary mouth region at the time this organ begins to form. Several assays indicate that Frzb-1 and Crescent modulate primary mouth formation by suppressing Wnt signaling, which is likely to be mediated by β-catenin. First, a similar phenotype (no primary mouth) is seen after loss of Frzb-1/Crescent function to that seen after temporally and spatially restricted overexpression of Wnt-8. Second, overexpression of either Frzb-1 or Dkk-1 results in an enlarged primary mouth anlage. Third, overexpression of Dkk-1 can restore a primary mouth to embryos in which Frzb-1/Crescent expression has been inhibited. Frzb-1/Crescent function locally promotes basement membrane dissolution in the primary mouth primordium. Consistently, Frzb-1 overexpression decreases RNA levels of the essential basement membrane genes fibronectin and laminin, whereas Wnt-8 overexpression increases the levels of these RNAs. These data are the first to connect Wnt signaling and basement membrane integrity during primary mouth development, and suggest a general paradigm for the regulation of basement membrane remodeling (Dickinson, 2009).

Other Frizzled homologs

The C. elegans gene lin-17 codes for a Frizzled homolog that affects asymmetric division of a variety of cells including ectodermal, gonadal and neuronal lineages. In most cases, the affected cell divisions are asymmetric in wild-type animals but symmetric in lin-17 animals, producing sister cells with similar fates. In addition, lin-17 mutations cause divisions that would normally produce sister cells on unequal size to instead generate cells of equal size. LIN-17 protein is 25-30% identical to Frizzled and its vertebrate homologs. Similarity is found in the putative amino-terminal extracellular domain, as well as between the transmembrane domains. Like mutations in lin-17, mutations in lin-44 affect a number of asymmetric cell divisions. In lin-44, the polarities of certain asymmetric cell divisions are reversed, i.e., the fates of anterior daughter cells are transformed to those of the corresponding posterior daughters and vice versa. lin-44 encodes a putative signaling protein that is a member of the Wnt gene family. It is suggested that LIN-44 is the ligand of LIN-17 (Sawa, 1996).

The amino acid sequence of Xfz3, a Xenopus frizzled family member, is 89% identical to the product of the murine gene Mfz3, and is predicted to be a serpentine receptor with seven transmembrane domains. Xfz3 is a maternal mRNA with low levels of expression until the end of gastrulation. The expression level increase significantly from neurulation onward. Whole-mount in situ hybridization analysis shows that expression of Xfz3 is highly restricted to the central nervous system. High levels of expression are detected in the anterior neural folds. Low levels of expression are also detected in the optic and otic vesicles, as well as in the pronephros anlage. In addition, Xfz3 mRNA is concentrated in a large band in the midbrain. Overexpression of Xfz3 blocks neural tube closure, resulting in embryos with either bent and strongly reduced anteroposterior axis in a dose-dependent manner. However, it affects neither gastrulation nor the expression and localization of organizer-specific genes, such as goosecoid, chordin and noggin. Therefore, Xfz3 is not involved in early mesodermal patterning. Injection of RNA encoding GFP-tagged Xfz3 shows that overexpressed proteins can be detected on the cell surface until at least late neurula stage, suggesting that they can exert an effect after gastrulation. The expression data and functional analyses suggest that the Xfz3 gene product has an antagonizing activity in the morphogenesis during Xenopus development (Shi, 1998).

Wnts are secreted signaling molecules implicated in a large number of developmental processes. Frizzled proteins have been identified as the likely receptors for Wnt ligands in vertebrates and invertebrates, but a functional role for vertebrate frizzleds has not yet been defined. To assess the endogenous role of frizzled proteins during vertebrate development, a Xenopus frizzled gene (xfz8) has been identified and characterized. It is highly expressed in the deep cells of the Spemann organizer prior to dorsal lip formation and in the early involuting marginal zone. Ectopic expression of xfz8 in ventral cells leads to complete secondary axis formation and can synergize with Xwnt-8, while an inhibitory form of xfz8 (Nxfz8) blocks axis duplication by Xwnt-8, consistent with a role for xfz8 in Wnt signal transduction. Expression of Nxfz8 in dorsal cells has profound effects on morphogenesis during gastrulation and neurulation that result in dramatic shortening of the anterior-posterior axis. These results suggest a role for xfz8 in morphogenesis during the gastrula stage of embryogenesis (Deardorff, 1998).

The presence of multiple domains in Dsh suggests that it may interact with different signaling pathways via different domains. Several structural motifs are conserved in Dsh. The N-terminal DIX domain (DIX named after Dishevelled and axin) can interact physically with and has homologies to the C-terminal region of axin, a negative regulator of Wnt signaling. The medial PDZ domain of Dsh represents a globular protein-protein interaction domain contained in many adaptor molecules found in cellular junctional complexes. PDZ domains bind C-terminal ends of membrane receptors and/or interact with other PDZ domains. Finally, the C-terminal DEP domain (named after Dishevelled, Egl-10 and plekstrin) is found in several molecules that regulate G-protein functions. Xenopus Dishevelled (Dsh) induces a secondary axis and can translocate to the membrane when activated by Frizzleds; however, dominant-negative approaches have not supported a role for Dsh in primary axis formation. The Dsh protein is post-translationally modified at the dorsal side of the embryo: timing and position of this regulation suggest a role for Dsh in dorsal-ventral patterning. To create functional links between these properties of Dsh the influence of endogenous Frizzleds and the Dsh domain dependency for these characteristics were examined. Xenopus Frizzleds phosphorylate and translocate Xdsh to the membrane irrespective of their differential ectopic axes inducing abilities, showing that translocation is insufficient for axis induction. Dsh deletion analysis has revealed that axis inducing abilities do not segregate with Xdsh membrane association. The DIX region and a short stretch at the N-terminus of the DEP domain are necessary for axis induction while the DEP region is required for Dsh membrane association and its phosphorylation. In addition, Dsh forms homomeric complexes in embryos, suggesting that multimerization is important for its proper function (Rothbacker, 2000).

Only one Dsh molecule has been found so far in Xenopus, and Xdsh may represent the obligatory component through which Frizzled molecules mediate their function(s) in Xenopus. During embryogenesis, distinct Frizzled molecules may instruct Xdsh to activate either a beta-catenin-dependent or beta-independent pathway, or both. So far, three maternally expressed Xenopus Frizzled proteins (Xfz-3, -7 and -8) have been identified in Xenopus. They all can translocate Xdsh to the membrane; in contrast, only Xfz-8 can induce a secondary axis. Xfz-7 is expressed most abundantly in early cleavage stages and thus may function as a primary anchor to recruit endogenous Xdsh to the membrane. Initial phosphorylation of Xdsh soon after fertilization may reflect such membrane association events. At present, it is unclear how differential Xdsh phosphorylation is achieved in the embryo One possibility is that as yet unidentified Wnt-like growth factors activate the Frizzled receptor system. A recent study in zebrafish supports this hypothesis, since a dominant-negative Fz blocks endogenous D/V signaling. Alternatively, Xdsh in early embryos might be activated de novo by a dorsally activated kinase in a Frizzled-independent manner (Rothbacker, 2000 and references therein).

Eye development in both invertebrates and vertebrates is regulated by a network of highly conserved transcription factors. However, it is not known what controls the expression of these factors to regulate early eye formation and whether transmembrane signaling events are involved. A role for signaling via a member of the frizzled family of receptors has been established in regulating early eye development. Overexpression of Xenopus frizzled 3 (Xfz3), a receptor expressed during normal eye development, functions cell autonomously to promote ectopic eye formation and can perturb endogenous eye development. Ectopic eyes obtained with Xfz3 overexpression have a laminar organization similar to that of endogenous eyes and contain differentiated retinal cell types. Ectopic eye formation is preceded by ectopic expression of transcription factors involved in early eye development, including Pax6, Rx, and Otx2. Conversely, targeted overexpression of a dominant-negative form of Xfz3 (Nxfz3), consisting of the soluble extracellular domain of the receptor, results in suppression of endogenous Pax6, Rx, and Otx2 expression and suppression of endogenous eye development. This effect can be rescued by coexpression of Xfz3. Finally, overexpression of Kermit, a protein that interacts with the C-terminal intracellular domain of Xfz3, also blocks endogenous eye development, suggesting that signaling through Xfz3 or a related receptor is required for normal eye development. In summary, frizzled signaling is both necessary and sufficient to regulate eye development in Xenopus (Rasmussen, 2001).

The observation that Xfz3 can initiate ectopic eye formation identifies wnt signaling as the first identified extracellular signaling pathway that regulates eye formation. Several wnts, including Xwnt-1, Xwnt-3A, and Xwnt-8, are expressed in the anterior neural plate in a region that overlaps the eye fields. In addition, Xwnt-1 is much more potent than any other wnt ligand in synergizing with Xfz3 to promote both axis duplication and neural crest induction. However, given the relative promiscuity of binding and the number of wnts present in the developing nervous system, it remains to be determined which wnt regulates eye development in vivo (Rasmussen, 2001).

Frizzled activation can lead to signaling either through a canonical pathway involving ß-catenin or noncanonical pathways that regulate planar cell polarity in Drosophila and possibly vertebrates, as well as calcium mobilization and protein kinase C activation in Xenopus and zebrafish. The signaling pathway used by Xfz3 to promote eye development has not yet been defined, although limited evidence points to the noncanonical planar cell polarity pathway. Overexpression of Xfz3 alone (unlike that of Xfz8) does not lead to axis duplication, a phenotype linked to activation of the canonical signaling pathway, although coexpression of Xfz3 with Xwnt1 can promote efficient axis duplication. Expression of the closely related homolog Mfz3 in Xenopus embryos results in protein kinase C activation but not expression of siamois and Xnr3, which are downstream effectors in the canonical pathway. In addition, activation of the canonical wnt signaling pathway represses anterior neural development, arguing against mediation of the regulation of eye development by this pathway, although localized activation of the canonical pathway at later stages of development has not been examined (Rasmussen, 2001).

Eight-cell RNA injection was used to overexpress a truncated form of Dsh (Dsh-DeltaN), which preferentially activates the noncanonical planar cell polarity pathway. It was found that 28% of the embryos (31/110) had dense ectopic pigment at or near the midline in the region of the hindbrain, reminiscent of the phenotype observed with Xfz3 overexpression. Conversely, injection of RNA encoding a truncated form of Dsh (Dsh-DEP+), which preferentially inhibits the noncanonical planar cell polarity pathway, resulted in reduced or missing eyes in 51% of injected embryos (52/101), similar to what was observed with Nxfz3 overexpression. These findings implicate the noncanonical planar cell polarity signaling pathway in the regulation of eye development, although this has yet to be confirmed (Rasmussen, 2001).

Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles

Mammalian body hairs align along the anterior-posterior (A-P) axis and offer a striking but poorly understood example of global cell polarization, a phenomenon known as planar cell polarity (PCP). This study has discovered that during embryogenesis, marked changes in cell shape and cytoskeletal polarization occur as nascent hair follicles become anteriorly angled, morphologically polarized and molecularly compartmentalized along the A-P axis. Hair follicle initiation coincides with asymmetric redistribution of Vangl2, Celsr1 and Fzd6 within the embryonic epidermal basal layer. Moreover, loss-of-function mutations in Vangl2 and Celsr1 show that they have an essential role in hair follicle polarization and orientation, which develop in part through non-autonomous mechanisms. Vangl2 and Celsr1 are both required for their planar localization in vivo, and physically associate in a complex in vitro. Finally, in vitro evidence is provided that homotypic intracellular interactions of Celsr1 are required to recruit Vangl2 and Fzd6 to sites of cell-cell contact (Devenport, 2008).

Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance

In mammals, a set of anatomically diverse polarity processes - including axon growth and guidance, hair follicle orientation, and stereociliary bundle orientation in inner ear sensory hair cells - appear to be mechanistically related, as judged by their dependence on vertebrate homologues of core tissue polarity/planar cell polarity (PCP) genes in Drosophila. To explore more deeply the mechanistic similarities between different polarity processes, this study has determined the extent to which frizzled 3 (Fz3) can rescue the hair follicle and Merkel cell polarity defects in frizzled 6-null (Fz6-/-) mice, and, reciprocally, the extent to which Fz6 can rescue the axon growth and guidance defects in Fz3-/- mice. These experiments reveal full rescue of the Fz6-/- phenotype by Fz3 and partial rescue of the Fz3-/- phenotype by Fz6, implying that these two proteins are likely to act in a conserved manner in these two contexts. Stimulated by these observations, additional anatomical structures were sought that exhibit macroscopic polarity and that might plausibly use Fz3 and/or Fz6 signaling. This search has revealed a hitherto unappreciated pattern of papillae on the dorsal surface of the tongue that depends, at least in part, on redundant signaling by Fz3 and Fz6. Taken together, these experiments provide compelling evidence for a close mechanistic relationship between multiple anatomically diverse polarity processes (Hua, 2014).

A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis

Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. This study found that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b (see Drosophila Wingless) are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3 (see Drosophila Src42A and Stat92E). A gene signature regulated by this pathway predicts metastasis and overall survival in patients. An antibody was developed to Fzd2 that reduces cell migration and invasion and inhibits tumor growth and metastasis in xenografts. It is proposed that targeting this pathway could provide benefit for patients with tumors expressing high levels of Fzd2 and Wnt5a/b (Gujral, 2014).

frizzled: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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