Disease relevance of fz

• Here, we report that overexpression of Dfz2, but not Fz, rescues the mutant phenotype of wgPE2, an allele that produces denticle diversity but no naked cuticle [1].
• This suggests that fz2 is involved in the spatial control of cardiac wound repair after infarction, possibly through intra- and intercellular transmission of polarity signals as in developing Drosophila [2].
• A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23 [3].
• We have isolated from a UMR 106 rat osteosarcoma cell library a cDNA (fz-1) encoding a predicted 641-residue protein (Fz-1) with 46% homology with Drosophila Fz [4].
• Increased expression of a homologue of drosophila tissue polarity gene "frizzled" in left ventricular hypertrophy in the rat, as identified by subtractive hybridization [5].

High impact information on fz

• The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye [6].
• Thus, Go is likely part of a trimeric G protein complex that directly transduces Fz signals from the membrane to downstream components [7].
• The authors propose that a component of the apical Crumbs complex regulates the phosphorylation of the Frizzled (Fz) PCP receptor, thus modulating PCP in the Drosophila eye [8].
• This process requires that the R3 photoreceptor precursor of each ommatidium have a higher level of Frizzled signaling than its neighboring R4 precursor [9].
• Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled [10].

Biological context of fz

• While these defects are partially penetrant in embryos lacking either fz or Dfz2, the penetrance is significantly enhanced in embryos lacking both [11].
• In this study, we make use of a fz transgene and a hypomorphic fz allele as genetic tools in an attempt to order these genes in a genetic hierarchy [12].
• In addition, this screen yielded a set of missense mutations that identify amino acids specifically required for fz signaling function [13].
• Thus, asymmetric localization of Fz, Stbm and Pk define two opposite cortical domains prior to mitosis of the pI cell [14].
• However, null mutations of the fz gene have little effect on Wg signal transduction and the lack of mutations in the fz2 gene has thus far prevented a rigorous examination of its role in vivo [15].

Anatomical context of fz

• Planar cell polarity (PCP) in the Drosophila eye is established by the distinct fate specifications of photoreceptors R3 and R4, and is regulated by the Frizzled (Fz)/PCP signaling pathway [16].
• The function of the frizzled (fz) locus in Drosophilia melanogaster is required to coordinate the cytoskeletons of epidermal cells to produce a parallel array of cuticular hairs and bristles (for example on the wild-type wing all hairs point towards the distal tip) [17].
• We found that myofibroblasts express a homologue of Drosophila tissue polarity gene frizzled (fz2) when migrating into the granulation tissue [2].
• In Drosophila, members of the frizzled family of tissue-polarity genes encode proteins that are likely to function as cell-surface receptors of the type known as Wnt receptors, and to initiate signal transduction across the cell membrane, although how they do this is unclear [18].
• However, the founding member of the Frizzled family, Drosophila Frizzled (FZ), was cloned almost a decade ago because of its role in regulating cell polarity within the plane of an epithelium [19].

Associations of fz with chemical compounds

• The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling [20].
• The Wingless morphogen gradient is established by the cooperative action of Frizzled and Heparan Sulfate Proteoglycan receptors [21].
• ROR1, ROR2 and MUSK are receptor-type tyrosine kinases with extracellular Fz domain, while MFRP is type II transmembrane protein with extracellular Fz domain [22].
• The results show that the main families in the human genome, Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin, arose before the split of nematodes from the chordate lineage [23].

Physical interactions of fz

• In an extension of these experiments, we tested whether two different subdomains of the Wg protein would by themselves bind to Frizzled and generate a biological response [24].
• The smo gene encodes an integral membrane protein with characteristics of G protein-coupled receptors and shows homology to the Drosophila Frizzled protein [25].
• Dishevelled can also be bound by the Frizzled PCP antagonist Prickle [26].

Regulatory relationships of fz

• Genetic evidence that Drosophila frizzled controls planar cell polarity and Armadillo signaling by a common mechanism [13].
• However, a truncated form of Fz also blocks Wg signaling in embryo and wing margin development, and the truncated form of DFz2 affects ommatidial polarity during eye development [27].
• Interestingly, both increasing and decreasing the activity of frizzled and other upstream genes enhanced the phenotypes of hypomorphic inturned and fuzzy mutants [28].
• This is because expression of Frizzled is repressed by the Engrailed transcription factor, whereas that of Frizzled2 is repressed by Wingless signaling [29].
• Except for Dl upregulation in R3, the mechanism of how Fz/PCP signaling regulates Notch in this context is not understood [30].

Other interactions of fz

• While previous results indicate that loss of function for fz has tissue polarity defects, loss-of-function effects of Dfz2 are not known [11].
• The PCP signal may selectively result in focal Fz activation and asymmetric relocalization of Dsh to the membrane, where Dsh effects cytoskeletal reorganization to orient prehair initiation [31].
• Pathway specificity by the bifunctional receptor frizzled is determined by affinity for wingless [32].
• These interactions suggest a positive feedback loop initiated by Fz that results in the apical maintenance of other PCP factors through Fmi [16].
• Genetic interactions and epistasis analysis suggest that fz, ds, and fat (ft) act together in the long-range propagation of polarity signals in the eye and wing [33].

Analytical, diagnostic and therapeutic context of fz

• None of the mutants was functional in cell culture or could fully replace fz in vivo [20].
• We report here the molecular cloning and characterization of the fz locus [34].
• Go is required for transduction of both pathways, and epistasis experiments suggest that it is an immediate transducer of Fz [7].
• Expression of Wnts and of their putative receptors encoded by murine homologs of the Drosophila frizzled gene in hematopoietic tissues was examined by reverse transcriptase-polymerase chain reaction [35].
• We have examined these and other alleles by Western blot analysis and found that most fz mutations result in altered amounts of Fz protein, and many also result in a Fz protein that migrates aberrantly in SDS-PAGE [36].

References