The WNT receptors, encoded by the Frizzled genes, are implicated in a variety of cellular processes such as cell fate determination, cell polarity control, and malignant transformation. Human Frizzled-4 (FZD4) cDNAs have been cloned and characterized by Kirikoshi et al. (1999) FZD4 spans a total of 7392 nucleotides and encodes a 537-amino-acid protein with the N-terminal cysteine-rich domain, seven transmembrane domains, and the C-terminal S/T-X-V motif.
NCBI Summary:
This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Comment
WNT signaling in ovarian follicle biology and tumorigenesis. Boyer A et al. The WNTS are an expansive family of glycoprotein signaling molecules known mostly for the roles they play in embryonic development. WNT signaling first caught the attention of ovarian biologists when it was reported that the inactivation of Wnt4 in mice results in partial female-to-male sex reversal and oocyte depletion. More recently, studies using loss- and gain-of-function transgenic mouse models demonstrated the requirement for Wnt4, Fzd4 and Ctnnb1, components of the WNT pathway, for normal folliculogenesis, luteogenesis and steroidogenesis, and showed that dysregulated WNT signaling can cause granulosa cell tumor development. This review covers our current knowledge of WNT signaling in ovarian follicles, highlighting both the great promise and the many unresolved questions of this emerging field of research.
Expression regulated by
SMAD4
Comment
SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis. Du X et al. (2020) The TGF-β and Wnt signaling pathways are interrelated in many cell types and tissues, and control cell functions in coordination. Here, we report that SMAD4, a downstream effector of the TGF-β signaling pathway, induces FZD4, a receptor of the Wnt signaling pathway, establishing a novel route of communication between these two pathways in granulosa cells (GCs). We found that SMAD4 is a strong inducer of FZD4, not only initiating FZD4 transcription but also activating FZD4-dependent Wnt signaling and GC apoptosis. Furthermore, we identified the direct and indirect mechanisms by which SMAD4 promotes expression of FZD4 in GCs. First, SMAD4 functions as a transcription factor to directly bind to the FZD4 promoter region to increase its transcriptional activity. Second, SMAD4 promotes production of SDNOR, a novel lncRNA that acts as a sponge for miR-29c, providing another mean to block miR-29c from degenerating FZD4 mRNA. Overall, our findings not only reveal a new channel of crosstalk between the TGF-β and Wnt signaling pathways, SMAD4-FZD4 axis, but also provide new insights into the regulatory network of GC apoptosis and follicular atresia. These RNA molecules, such as miR-29c and lnc-SDNOR, represent potential targets for treatment of reproductive diseases and improvement of female fertility.//////////////////
Ovarian localization
Granulosa, Luteal cells
Comment
Kirikoshi et al. (1999) reported that the FZD4 mRNA of 7.7 kb in size were detected almost ubiquitously in normal human tissues and larger amounts in fetal kidney, adult heart, skeletal muscle, and ovary. Richards et al 2002 reported that
the adult ovary of rodents expresses several members of the Wnt/Frizzled signaling pathway in a cell- and
stage- specific manner (M. Hsieh & J.S. Richards, submitted for publication). For example, Wnt4 is expressed in small,
primary follicles in ovaries of immature and adult mice, which suggests that Wnt4 impacts early stages of follicle
growth/formation (M. Hsieh & J.S. Richards, submitted for publication) as well as the initial development of the female
gonad . In addition, Wnt4 is expressed at elevated levels in corpora lutea following the LH surge. At this same time, the
Frizzled 4 receptor is also highly expressed, which suggests that it may be a preferred receptor for Wnt4 in this tissue.
Albert Ricken et al reported the
Wnt Signaling in the Ovary and the identification and Compartmentalized Expression of wnt-2, wnt-2b, and Frizzled-4 mRNAs .
Using RT-PCR with degenerate primers on RNA from ovaries of hormone-stimulated immature rats, the authors identified transcripts for wnt-2 and wnt-2b. RT-PCR and in situ hybridization (ISH) demonstrated that granulosa cells express wnt-2 mRNA.. RT-PCR analysis, using primers designed from this wnt-2b cDNA sequence, failed to detect transcripts in the ovarian follicular compartment (granulosa and oocyte). ISH revealed that the ovarian surface epithelium expresses wnt-2b mRNA.
Using a similar degenerate RT-PCR approach, the authors detected expression of a putative wnt receptor, frizzled-4 (fzd-4), and a cytoplasmic component of the wnt signaling cascade, disheveled-2 (dsh-2), in the rat ovary. Further analyses using both RT-PCR and ISH indicated that granulosa cells express fzd-4 mRNA.
Follicle stages
Corpus luteum
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Mice Null for Frizzled4 (Fzd4-/-) Are Infertile and Exhibit Impaired Corpora Lutea Formation and FunctionHsieh M, et al .
Previous studies showed that transcripts encoding specific Wnt ligands and Frizzled receptors including Wnt4, Frizzed 1 (Fzd1) and Frizzled4 (Fzd4) were expressed in a cell specific manner in the adult mouse ovary. Overlapping expression of Wnt4 and Fzd4 mRNA in small follicles and corpora lutea led us to hypothesize that the infertility of mice null for Fzd4 (Fzd4(-/-)) might involve impaired follicular growth or corpus luteum formation. Analyses at defined stages of reproductive function indicate that immature Fzd4(-/-) mouse ovaries contain follicles at many stages of development and respond to exogenous hormone treatments in a manner similar to their wildtype litter-mates indicating that the processes controlling follicular development and follicular cell responses to gonadotropins are intact. Adult Fzd4(-/-) mice also exhibit normal mating behavior and ovulate indicating that endocrine events controlling these processes occur. However, Fzd4(-/-) mice fail to become pregnant and do not produce offspring. Histological and functional analyses of ovaries from timed mating pairs at d1.5 to d7.5 post-coitus (p.c.) indicate that the corpora lutea of the Fzd4(-/-) mice do not develop normally. Expression of luteal cell specific mRNAs (Lhcgr, Prlr, Cyp11a1 and Sfrp4) is reduced, luteal cell morphology is altered and markers of angiogenesis and vascular formation (Efnb1, Efnb2, Ephb4, Vegfa, Vegfc) are low in the Fzd4(-/-) mice. Although a recently identified, high affinity FZD4 ligand Norrin (Norrie disease pseudoglima homolog; NDPH) is expressed in the ovary, adult Ndph-/- mice contain functional corpora lutea and do not phenocopy Fzd4(-/-) mice. Thus, Fzd4 appears to impact the formation of the corpus luteum by mechanisms that more closely phenocopy Prlr null mice.
Species: human
Mutation name: type: naturally occurring fertility: None Comment: A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy. Yang L et al. (2018) Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. In this study, a Chinese autosomal dominant FEVR pedigree was recruited. Ophthalmic examinations were performed, targeted next-generation sequencing was used to identify the causative gene, and Sanger sequencing was conducted to verify the candidate mutation. Co-segregation analysis was performed to evaluate pathogenicity. Semi-quantitative reverse transcription-PCR was applied to investigate the spatial and temporal expression patterns of the frizzled class receptor 4 (FZD4) gene in the mouse. A novel heterozygous, deleterious variant of the FZD4 gene, c.A749G (p.Y250C), was identified in this FEVR pedigree, which co-segregated with the clinical phenotype. The amino acid tyrosine (Y) is highly conserved both orthologously and paralogously. The FZD4 gene was highly expressed in the retina, sclera of the eye, ovary, kidney, and liver; ubiquitously expressed in other tissues; and highly expressed in 6 different developmental stages/times of retinal tissue. Our study is the first to identify that the novel heterozygous variant c.A749G (p.Y250C) in the FZD4 gene may be the disease-causing mutation in this FEVR family, extending its mutation spectrum. These findings further our understanding of the molecular pathogenesis of FEVR and will facilitate the development of methods for the diagnosis, prevention, and genetic counseling of this disease.//////////////////