| Wnt family member 4 | OKDB#: 185 |
| Symbols: | WNT4 | Species: | human | ||
| Synonyms: | WNT-4, SERKAL | Locus: | 1p36.12 in Homo sapiens |
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| General Comment |
The WNT gene family consists of structurally related genes that encode cysteine-rich secreted glycoproteins that act as extracellular signaling factors. WNT genes are implicated in a wide variety of biologic processes including cell fate determination and patterning in early embryos and in cell growth and/or differentiation in certain adult mammalian tissues. Bergstein et al. (1997) stated that all WNT genes identified in mammals encode proteins of approximately 350 to 400 amino acids with an amino-terminal secretory signal peptide followed by a short domain of low sequence conservation and then by a large conserved domain that includes 22 cysteine residues, the relative spacing of which is exactly conserved in the majority of known WNT proteins.
NCBI Summary: The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome. [provided by RefSeq, Jul 2008] |
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| General function | Ligand, Growth factor | ||||
| Comment | |||||
| Cellular localization | Secreted | ||||
| Comment | |||||
| Ovarian function | Follicle endowment, Follicle development, Preantral follicle growth, Germ cell development | ||||
| Comment | JNK signaling regulates E-cadherin junctions in germline cysts and determines primordial follicle formation in mice. Niu W et al. (2016) Physiologically, the size of the primordial follicle pool determines the reproductive lifespan of female mammals, while its establishment largely depends on a proper process of germline cyst breakdown during the perinatal period. However, the mechanisms regulating this process are poorly understood. Here we demonstrate that c-Jun amino-terminal kinase (JNK) signaling is crucial for germline cyst breakdown and primordial follicle formation. JNK was specifically localized in oocytes and its activity was increased as germline cyst breakdown progressed. Importantly, the disruption of JNK signaling with its specific inhibitor (SP600125) or knock-down technology (Lenti-JNK-shRNAs) resulted in significantly suppressed cyst breakdown and primordial follicle formation in cultured mouse ovaries. Our results show that E-cadherin is intensely expressed in germline cysts, and that its decline is necessary for oocyte release from the cyst. However, the inhibition of JNK signaling leads to aberrantly enhanced localization of E-cadherin at oocyte-oocyte contact sites. Meanwhile, WNT4 expression is upregulated after SP600125 treatment. Additionally, similar to SP600125 treatment, WNT4 overexpression delays cyst breakdown; and is accompanied by abnormal E-cadherin expression patterns. In conclusion, our results suggest that JNK signaling, which is inversely correlated with WNT4, plays an important role in perinatal germline cyst breakdown and primordial follicle formation by regulating E-cadherin junctions between oocytes in mouse ovaries.////////////////// Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Naillat F et al. Germ cells are the foundation of an individual, since they generate the gametes and provide the unique genome established through meiosis. The sex-specific fate of the germ line in mammals is thought to be controlled by somatic signals, which are still poorly characterized. We demonstrate here that somatic Wnt signalling is crucial for the control of female germ line development. Wnt-4 maintains germ cell cysts, early follicular gene expression, and provides a female pattern of E-cadherin and ss-catenin expression within the germ cells. In addition, we find that Stra8 expression is down regulated and the Cyp26b1 gene is expressed ectopically in the partially masculinised Wnt-4-deficient ovary. Wnt-4 may control meiosis via these proteins since the Cyp26b1 enzyme is known to degrade retinoic acid and inhibit meiosis in the male embryo, and Stra8 induces meiosis in the female through retinoic acid. Reintroduction of a Wnt-4 signal to the partially masculinised embryonic ovary in fact rescues the female property to a certain degree, as seen by inhibition of Cyp26b1 and induction of Irx3 gene expression. Wnt-4 deficiency allows only 20% of the germ cells to initiate meiosis in the ovary, while meiosis is inhibited completely in the Wnt-4/Wnt-5a double mutant. These findings indicate a critical role for Wnt signalling in meiosis. Thus the Wnt signals are important somatic cell signals that coordinate presumptive female follicle development. WNT4 is Expressed in Human Fetal and Adult Ovaries, and Its Signaling Contributes to Ovarian Cell Survival. J?kel?en M et al. WNT4 plays an important role in female sexual development and ovarian function. WNT4- deficiency leads disturbed development of the internal genitalia in mouse and human, and to a dramatic reduction of mouse oocytes. However, the expression and role of WNT4 in human ovaries is yet unknown. The expression of WNT4 mRNA and protein was studied in human adult and fetal ovaries (gestational ages 12-41 weeks), and the role of Wnt4 in oocyte apoptosis was investigated in Wnt4-deficient mice. WNT4 mRNA and protein were present in human ovaries throughout fetal development and in different follicular stages in adult ovaries. Compared with wild-type mice, Wnt4-deficient mice had a markedly enhanced rate of oocyte apoptosis, with the highest values at gestational ages of 14.5 and 16.5 days post-coitum. The current results support a view that WNT4 may have a role in oocyte selection and follicle formation and maturation in human ovaries. 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. The signalling molecule Wnt-4 is crucial for female sexual development. Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells (Vainio et al., 1999). Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome. Canto P et al. Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism. The etiology of this entity remains unknown. It has been suggested that genomic variants in genes related to the regulation of androgen biosynthesis and function could be involved in genetic predisposition to PCOS. WNT-4 is a member of the WNT family of secreted molecules. Studies on female Wnt-4 knockout mice have suggested that this gene suppresses gonadal androgen synthesis in normal females. We investigated if 25 women with PCOS presented mutations in WNT-4 as the cause of their disorder. Direct sequencing of all five exons demonstrated no mutant alleles in any patient. This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS. However, the present data do not rule out the possible existence of causative mutations in the WNT-4 gene promoter region.Loss of Wnt4 and Foxl2 leads to Female-To-Male Sex Reversal Extending to Germ Cells. Ottolenghi C et al. The discovery that the SRY gene induces male sex in humans and other mammals led to speculation about a possible equivalent for female sex. However, only partial effects have been reported for candidate genes experimentally tested so far. Here we demonstrate that inactivation of two ovarian somatic factors, Wnt4 and Foxl2, produces testis differentiation in XX mice, resulting in the formation of testis tubules and spermatogonia. These genes are thus required to initiate or maintain all major aspects of female sex determination in mammals. The two genes are independently expressed and show complementary roles in ovary morphogenesis. In addition, forced expression of Foxl2 impairs testis tubule differentiation in XY transgenic mice, and germ cell-depleted XX mice lacking Foxl2 and harboring a kit mutation undergo partial female-to-male sex reversal. The results are all consistent with an anti-testis role for Foxl2. The data suggest that the relative autonomy of the action of Foxl2, Wnt4 and additional ovarian factor(s) in the mouse should facilitate the dissection of their respective contributions to female sex determination. Wnt4 Is Associated with the Development of Ovarian Tissue in the Protandrous Black Porgy, Acanthopagrus schlegeli. Wu GC et al. The protandrous black porgy, Acanthopagrus schlegeli, has a striking life cycle, with sex differentiation at the juvenile stage, mono-male development, and male-to-female sex change (with vitellogenic oocytes) at 3 yr of age. In the present study, we investigated the possible roles of wnt4 in gonadal development in a nonmammalian model organism (protandrous black porgy fish), especially in relation to sex differentiation, ovarian growth and sex change. Fish of various ages were treated with estradiol (E2) or aromatase inhibitor (AI) to determine whether manipulation of the hormonal environment had an impact on these processes. Furthermore, a natural sex change (2(+)-yr-old) and a nonchemical method to induce an early sex change (1(+)-yr-old) via the removal of testicular tissue were also examined in this study. We present herein an integrative immunohistochemical, cellular and molecular data set describing these phenomena. During gonadal sex differentiation, no increase in wnt4 expression was detected. A profile of increased wnt4 and decreased cyp19a1a expression was associated with the ovarian growth (proliferation of oogonia/development of ovarian lamellae) in 1(+)-yr-old fish. Both E2 and AI induced an increase in wnt4 transcripts and resulted in ovarian development in 0(+)- and 1(+)-yr-old fish. Increased wnt4 transcripts were found in ovarian tissue undergoing development from primary oocytes to vitellogenic oocytes during the natural sex change in 2(+)-yr-old fish. Removal of testicular tissue in 1(+)-yr-old fish resulted in a successful early sex change (with vitellogenic oocytes) at 6 mo after the excision. During the process of the early sex change (3 mo after testis excision), the fish ovary became active and had increased diameter of the primary oocytes; this was in accordance with increased ovarian wnt4 expression but not with sf1, foxl2, and genes in the steroidogenic pathway, including cyp19a1a. Wnt4 staining further confirmed the profile of wnt4 expression associated with ovarian development. The present study suggests that wnt4 plays important roles in late ovarian growth (e.g., oogonia proliferation, structure of ovarian lamellae) and the natural sex change (vitellogenic oocytes), in the protandrous black porgy. WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary. Liu CF et al. Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or beta-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of beta-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing beta-catenin downstream of WNT4. In the absence of Wnt4 or beta-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin betaB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and beta-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via beta-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and beta-catenin) and negative (activin betaB) regulators derived from the somatic cells in the fetal ovary. | ||||
| Expression regulated by | |||||
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| Ovarian localization | Oocyte, Granulosa, Luteal cells, mesenchymal layer | ||||
| Comment | WNT4-like protein is a cortical granule component in mouse oocytes and functions in regulating preimplantation embryogenesis. Liu M et al. (2015) Mammalian cortical granules (CG) are membrane-bound organelles located in the cortex of the unfertilized oocytes. Upon fertilization, CG undergo exocytosis to function in blocking polyspermy. While cortical granules are important in fertilization, their exact biochemical composition and reproductive function have not been fully defined. In the present study, a 66 kDa wingless-type MMTV integration site family, member 4 (WNT4)-like protein, with mouse CG origin was identified. Oocytes that were double labeled with lectin Lens culinaris agglutinin (LCA) and WNT4 antibody showed colocalization of the WNT4 molecules and cortical granules. The disappearance of WNT4 molecules in the artificially activated oocytes that were devoid of cortical granules confirmed their granule origin. Following fertilization, WNT4 remained associated with zygotes and blastomeres of 2-cell and 8-cell embryos; however the amount of protein present was reduced more than 2-fold as embryos developed. Prior to implantation, WNT4 appeared to be detectable only in the trophoblast cells. Our functional study revealed that WNT4 molecules were involved in regulating zygotic cleavage and early embryogenesis. To our knowledge, this is the first study demonstrating mammalian cortical granules contain signaling molecules that are involved in the regulation of the first phase of embryonic development.////////////////// The WNT/-catenin signaling pathway and expression of survival promoting genes in luteinized granulosa cells: endometriosis as a paradigm for a dysregulated apoptosis pathway. Sanchez AM 2014 et al. OBJECTIVE To analyze the WNT/-catenin signaling pathway in luteinized granulosa cells from women with and without endometriosis in relation to cellular apoptosis. DESIGN Basic. SETTING University hospital. PATIENT(S) Patients with a laparoscopic diagnosis of endometriosis (n=30) and women undergoing intracytoplasmic sperm injection for male infertility (control group n=39). INTERVENTION(S) Isolation of luteinized granulosa cells. MAIN OUTCOME MEASURE(S) Gene expression analysis of components of the WNT/-catenin pathway, protein expression levels of -catenin, and cell cycle studies in luteinized granulosa cells. RESULT(S) Compared with luteinized granulosa cells from control women, cells derived from endometriosis patients had significantly higher transcript levels of the -catenin-independent molecules WNT4 and WNT5a and lower levels of the -catenin-dependent molecule WNT1. A decrease of total -catenin as well as of its dephosphorylated active form, together with an aberrant gene expression of the downstream targets survivin and BMP4, was detected in cells from affected women. Flow cytometry analysis confirmed an enhanced apoptosis of luteinized granulosa cells from patients with endometriosis. CONCLUSION(S) The concomitant dysregulation of specific members of the WNT pathway and of its pivot molecule -catenin in granulosa cells characterized by an increased apoptosis suggests that the WNT/-catenin signaling pathway might be involved in leading to granulosa cell atresia. ///////////////////////// Kidney development is initiated by the ingrowth of the Wolffian duct-derived ureteric bud into the presumptive kidney mesenchyme. In response to a signal from the ureter, mesenchymal cells condense, aggregate into pretubular clusters, and undergo an epithelial conversion generating a simple tubule. This then undergoes morphogenesis and is transformed into the excretory system of the kidney, the nephron. Stark et al. (1994) studied the expression of 12 mouse Wnt genes by in situ hybridization and found high expression of Wnt4 in kidney mesenchyme and its derivatives. Wnt4 transcripts were detected in condensed mesenchymal cells on both sides of the stalk of the ureter at 11.5 days postcoitum and were in the site where the first pretubular cell aggregates form. Miller et al. (1998) describe the expression patterns of Wnt genes in the developing and adult female reproductive tract. Wnt gene expression patterns are regulated by the presence of epithelium in tissue graft experiments, suggesting that Wnt genes may play roles in the mesenchymal-epithelial interactions critical for female reproductive tract development and function. 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. Members of the WNT signaling pathways are widely expressed in mouse ovaries, oocytes, and cleavage stage embryos. Harwood BN et al. The mammalian oocyte-to-embryo transition, characterized by a period of transcriptional silence, is dependent on maternal RNAs and proteins produced during the growth phase of the oocyte. Signaling pathways control timely transcription and translation of RNA, as well as post-translational modification of proteins. The WNT/beta-catenin pathway is clearly not active during preimplantation embryo development. However, alternative Wnt signaling pathways may play a role during early embryo development. This study describes the extensive expression, at the transcript and protein level, of receptors, ligands, and intracellular molecules known to play a role in WNT signaling, as well as those known to negatively regulate the canonical WNT/beta-catenin pathway in developing oocytes and preimplantation embryos. This expression of a wide array of molecules involved in WNT signaling suggests that the alternative WNT pathways may be active during oogenesis and the oocyte-to-embryo transition. Developmental Dynamics 237:1099-1111, 2008. (c) 2008 Wiley-Liss, Inc. Ovary-predominant wnt4 expression during gonadal differentiation is not conserved in the rainbow trout (Oncorhynchus mykiss). Nicol B et al. The Wnt/?catenin pathway is crucial for ovarian differentiation in mammals, and WNT4 is an important protein that regulates this process. While the role of Wnt4 in gonadal differentiation is relatively well characterized in mammals, little is known regarding its role in teleost fish. Therefore, we investigated the potential activity of wnt4 in gonadal differentiation in rainbow trout (Oncorhynchus mykiss), focusing on the teleost and salmonid gene duplications. Phylogenetic and synteny analyses demonstrated that teleost fish possess two wnt4 genes, wnt4a and wnt4b, as a consequence of the teleost-specific whole-genome duplication (3R). In rainbow trout, we also identified an additional wnt4 gene, which is a wnt4a paralog that likely resulted from the salmonid-specific whole-genome duplication (4R). These two Wnt4a proteins (Wnt4a1 and Wnt4a2) share a high identity (>80%) with other vertebrate Wnt4 proteins, whereas Wnt4b is clearly more divergent (60% identity). During embryogenesis and adulthood, the wnt4a1/2 transcripts were expressed in various tissues, including the ovaries and testes. In contrast, wnt4b expression was restricted to the nervous system, suggesting a sub- or a neo-functionalization of this divergent paralog. During early gonadal differentiation in both males and females, the wnt4a1/2 transcripts were detected in the somatic cells surrounding the germ cells, with a slight sexual dimorphism in favor of males. These results demonstrate that, unlike mammals, rainbow trout do not display an ovary-predominant wnt4 expression profile during early gonadal differentiation. Mol. Reprod. Dev. ? 2011 Wiley Periodicals, Inc. | ||||
| Follicle stages | Primary, Secondary | ||||
| Comment | Minnie Hsieh et al 2002 reported regulated Expression of Wnts and Frizzleds at Specific Stages of Follicular Development in the Rodent Ovary. Wnt ligands and Frizzled (Fz) G protein-coupled receptors impact cell fate, including embryonic development of the ovary. Because the role of these regulatory molecules during follicular development in the adult is not known, an RT-PCR survey was done. Wnt-4, Fz-4, and Fz-1 were among the transcripts detected, and each exhibited a specific pattern of expression. Fz-1 mRNA was low in preovulatory follicles of PMSG-treated mice but was increased within 4-12 h after an ovulatory surge of human CG. By in situ analysis, Fz-1 transcripts increased first in the theca cells and then in the granulosa cells of ovulating follicles but were low in corpora lutea. In contrast, Wnt-4, a critical factor in early ovarian development, was expressed in small preantral follicles. In addition, Wnt-4 was detected in preovulatory follicles and exhibited high levels in corpora lutea. A potential receptor for Wnt-4 in corpora lutea is Fz-4 that was also elevated in this tissue. Although Wnt-4 has been shown to function downstream of the PR in other tissues, Wnt-4 was not altered in follicles of PR-null mice that fail to ovulate. Rather expression of Fz-1 was lower in ovaries of PR knockout mice, compared with normal littermates. Thus, specific Wnt/Fz are expressed at distinct stages of follicular development, suggesting multiple functions for this signaling pathway in the ovary. | ||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
6 mutations
Species: mouse
Species: human
Species: mouse
Species: mouse
Species: mouse
Species: None
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Nov. 1, 1999, midnight | by: |
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| last update: | March 12, 2020, 2:23 p.m. | by: | hsueh email: |
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