Affinage

WNT4

Protein Wnt-4 · UniProt P56705

Length
351 aa
Mass
39.1 kDa
Annotated
2026-06-11
100 papers in source corpus 52 papers cited in narrative 52 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT4 is a secreted Wnt-family ligand that orchestrates tissue patterning, cell-fate transitions, and hormonal responses across the urogenital, skeletal, hematopoietic, and reproductive systems, signaling through both canonical β-catenin/TCF-dependent and several β-catenin-independent routes depending on cellular context (PMID:9753677, PMID:16700629, PMID:25108526). In its canonical mode WNT4 stabilizes cytosolic β-catenin and drives TCF/LEF transcription in epithelial cells, signaling through Frizzled-1 in vascular smooth muscle and engaging LRP5/LRP6 co-receptors with Frizzled selectivity distinct from prototypical WNT3a (PMID:11832423, PMID:15265686, PMID:21193738, PMID:24269653). WNT4 also acts non-canonically: it activates p38 MAPK via Axin to promote osteogenesis, drives Rac1/JNK signaling through Frizzled-6 to expand hematopoietic progenitors, signals through RhoA to enforce muscle satellite-cell quiescence, and inhibits NF-κB by targeting TAK1 to suppress osteoclastogenesis (PMID:17720811, PMID:21541287, PMID:25108526, PMID:31495781); it can additionally redirect β-catenin to the membrane to suppress rather than activate transcription (PMID:17976036). In development, WNT4 is required to trigger mesenchymal-to-epithelial transition during nephron tubulogenesis, a function conserved in the Xenopus pronephros and acting in parallel with Notch (PMID:9753677, PMID:21852398, PMID:12142017). In sex determination WNT4 functions as an anti-testis factor: it antagonizes the FGF9/SOX9 testis program, cooperates with FOXL2 and RSPO1, and maintains female germ cells by activating β-catenin to repress activin βB (Inhbb) (PMID:16700629, PMID:17728319, PMID:20454446, PMID:23095882). WNT4 also mediates hormone-driven morphogenesis downstream of progesterone in mammary side-branching and estrogen in endometrial decidualization and lobular carcinoma proliferation, and controls Müllerian duct elongation, pancreatic β-cell calcium signaling, and neuromuscular junction formation via the MuSK receptor (PMID:10733525, PMID:23142810, PMID:26721931, PMID:36271049, PMID:22253844). Its transcription is governed by an extensive regulatory network including PAX2, WT1/SOX11, TEAD1/BRD4, and Nr4a1 as activators and E2F1, ER, and MM-1/Egr-1 as context-specific repressors or controllers (PMID:16368682, PMID:22465478, PMID:27650553, PMID:33441379, PMID:38374140, PMID:18281035, PMID:38429926). Notably, WNT4 secretion is PORCN-independent and its activity is predominantly cell-autonomous rather than paracrine (PMID:31740580).

Mechanistic history

Synthesis pass · year-by-year structured walk · 51 steps
  1. 1998 High

    Established WNT4 as the molecular trigger of mesenchymal-to-epithelial transition in kidney development, answering whether a single Wnt could initiate tubulogenesis.

    Evidence Ex vivo rescue of Wnt4-null metanephric mesenchyme with Wnt4-expressing cells, with cofactor and Wnt-comparison controls

    PMID:9753677

    Open questions at the time
    • Receptor mediating the tubulogenic signal not identified
    • Downstream transcriptional program left undefined
    • Canonical vs non-canonical mode not distinguished at this stage
  2. 1998 High

    Identified sFRP-2 as a direct WNT4-binding partner and downstream target, providing the first biochemical interaction for WNT4 in the kidney.

    Evidence Co-immunoprecipitation of WNT4 with sFRP-2 CRD plus expression analysis in Wnt4-null kidneys

    PMID:9853965

    Open questions at the time
    • Functional consequence of sFRP-2 binding (agonism vs antagonism) not resolved
    • Signaling receptor still unknown
  3. 2000 High

    Placed WNT4 downstream of progesterone receptor signaling in the mammary gland, linking a developmental Wnt to hormonal control of branching.

    Evidence Transplantation of Wnt4-null mammary epithelium, progesterone induction, and PR-knockout comparison

    PMID:10733525

    Open questions at the time
    • Signaling pathway downstream of WNT4 in mammary cells not defined here
    • Cell-autonomous vs paracrine target not resolved
  4. 2001 Medium

    Connected WNT4 dosage to sex reversal via DAX1 upregulation, providing a mechanism for dosage-sensitive XY female reversal.

    Evidence Overexpression with DAX1 reporter in testicular cell lines, linked to human 1p duplication

    PMID:11283799

    Open questions at the time
    • Overexpression in cell lines may not reflect endogenous regulation
    • Direct vs indirect DAX1 induction not established
  5. 2002 Medium

    Demonstrated WNT4 activates canonical β-catenin signaling in a pathological context (renal fibrosis), extending WNT4 beyond normal development.

    Evidence Renal injury models, in vitro β-catenin stabilization, and subrenal capsule implantation of Wnt4-expressing fibroblasts

    PMID:11832423

    Open questions at the time
    • Receptor not identified
    • Single-lab in vivo model
  6. 2002 Medium

    Defined WNT4 as required for adrenal zona glomerulosa formation and adrenal/gonadal cell sorting through control of steroidogenic enzyme expression.

    Evidence Wnt4-knockout phenotyping with aldosterone measurement and Cyp gene expression

    PMID:12399432

    Open questions at the time
    • Signaling pathway not dissected
    • Direct vs indirect enzyme regulation unresolved
  7. 2002 High

    Confirmed evolutionary conservation of WNT4's tubulogenic role in the Xenopus pronephros, separating tubule from duct development.

    Evidence Xenopus morpholino knockdown and gain-of-function mRNA injection with pronephric markers

    PMID:12142017

    Open questions at the time
    • Receptor and downstream effectors in pronephros not defined
  8. 2003 High

    Showed WNT4 represses migration of steroidogenic and endothelial cells into the XX gonad rather than blocking their differentiation, refining its anti-male role.

    Evidence Wnt4 null and XY transgenic misexpression mice with cell migration and vascular readouts

    PMID:12835383

    Open questions at the time
    • Molecular mechanism of migration repression unknown
    • Signaling pathway not identified
  9. 2005 High

    Identified a non-canonical WNT4 requirement in Xenopus eye development through induction of the Pol II elongation factor component EAF2, broadening WNT4 outputs.

    Evidence Xenopus gain/loss-of-function with β-catenin-independence confirmed and EAF2 rescue epistasis

    PMID:15775981

    Open questions at the time
    • Receptor mediating non-canonical eye signal unknown
    • Mechanism linking WNT4 to EAF2 induction undefined
  10. 2005 High

    Established PAX2 as a direct transcriptional activator of WNT4 during nephrogenesis, beginning the map of WNT4's upstream regulators.

    Evidence EMSA, promoter-reporter co-transfection, overexpression, and Pax2 heterozygous mouse kidney analysis

    PMID:16368682

    Open questions at the time
    • Other co-regulators of the WNT4 promoter not yet mapped
  11. 2006 High

    Defined the mutual antagonism between WNT4 and FGF9/SOX9 as the central switch of mammalian sex determination.

    Evidence Single and double Fgf9/Wnt4 knockouts with Sox9/Fgf9 expression analysis in XX gonads

    PMID:16700629

    Open questions at the time
    • Direct molecular mechanism of Fgf9 repression by WNT4 not resolved
  12. 2006 Medium

    Showed context-dependent, cAMP-modulated WNT4 control of human adrenocortical steroidogenesis.

    Evidence Adenoviral WNT4 delivery to human adrenocortical cells with steroid and enzyme mRNA readouts

    PMID:16981135

    Open questions at the time
    • Single-lab gain-of-function
    • Signaling pathway not dissected
  13. 2004 Medium

    Showed WNT4 can activate canonical β-catenin/TCF signaling in kidney epithelial cells while binding Frizzled-6, yet Frizzled-6 does not transduce that canonical signal.

    Evidence TCF/LEF reporter assays in MDCK cells with dominant-negative constructs and WNT4–Frizzled-6 CRD co-IP

    PMID:15265686

    Open questions at the time
    • The canonical-signal-transducing Frizzled left unidentified
    • Functional meaning of Frizzled-6 binding unclear here
  14. 2007 High

    Defined a β-catenin-independent WNT4 pathway activating p38 MAPK via Axin to drive osteogenic differentiation and bone formation.

    Evidence p38 activation and β-catenin-stabilization assays with Axin dependence and in vivo craniofacial bone defect model

    PMID:17720811

    Open questions at the time
    • Receptor for the p38/Axin branch not identified
  15. 2007 High

    Showed WNT4 and FOXL2 act as independent anti-testis factors maintaining female sex determination.

    Evidence Wnt4/Foxl2 double knockout causing complete XX female-to-male sex reversal plus Foxl2 transgenics

    PMID:17728319

    Open questions at the time
    • Molecular interaction (if any) between WNT4 and FOXL2 pathways not defined
  16. 2007 High

    Established WNT4 as a repulsive synaptic target-specificity cue acting via Frizzled-2, Derailed-2 and Dishevelled in Drosophila.

    Evidence Reciprocal gain- and loss-of-function in Drosophila muscle with synaptic morphology readouts

    PMID:17764943

    Open questions at the time
    • Conservation of this receptor module in vertebrate synapses untested
  17. 2008 Medium

    Revealed a non-canonical mechanism whereby WNT4 redirects β-catenin to the membrane, switching it from transcription to adhesion and inhibiting TCF activity.

    Evidence Subcellular fractionation/immunofluorescence of β-catenin, TCF/LEF reporter, and stability western blots

    PMID:17976036

    Open questions at the time
    • Single lab
    • Receptor and molecular switch mechanism not defined
  18. 2008 High

    Showed WNT4 expands hematopoietic progenitors and thymopoiesis non-cell-autonomously through β-catenin-independent signaling.

    Evidence Wnt4 gain- and loss-of-function mice with flow cytometry of LSK/thymocyte populations

    PMID:18617424

    Open questions at the time
    • Receptor and effector kinase not yet identified at this stage
  19. 2008 Medium

    Implicated WNT4 as a positive non-canonical regulator of adipogenesis.

    Evidence siRNA knockdown during 3T3-L1 differentiation with TAG accumulation and gene expression

    PMID:18708054

    Open questions at the time
    • Single method/single lab
    • Pathway and receptor not defined
  20. 2008 Medium

    Identified MM-1 and Egr-1 as repressive transcriptional regulators of the WNT4 promoter.

    Evidence ChIP, EMSA, promoter-deletion reporters, and MM-1 knockdown

    PMID:18281035

    Open questions at the time
    • Physiological context of MM-1/Egr-1 repression not established
  21. 2009 Medium

    Defined a Notch→hrt1→Wnt-4 pathway patterning the pronephric medio-lateral axis, positioning Notch upstream of WNT4 in renal morphogenesis.

    Evidence Xenopus Notch gain/loss-of-function and hrt1 morpholino with pronephric markers

    PMID:19793883

    Open questions at the time
    • Single-lab epistasis
    • Directness of hrt1 control over Wnt4 not biochemically shown
  22. 2010 High

    Established that WNT4/β-catenin maintains fetal female germ cell survival by repressing activin βB (Inhbb).

    Evidence Conditional β-catenin activation in Wnt4-KO somatic cells and Wnt4/Inhbb double knockout with germ cell counts

    PMID:20454446

    Open questions at the time
    • Mechanism of Inhbb repression by β-catenin not defined
  23. 2010 High

    Showed WNT4 controls female meiosis entry through regulation of E-cadherin/β-catenin, Stra8, and the RA-degrading enzyme Cyp26b1, acting redundantly with Wnt5a.

    Evidence Wnt4 and Wnt4/Wnt5a double knockouts with immunofluorescence, RT-PCR, and ex vivo rescue

    PMID:20106871

    Open questions at the time
    • Direct transcriptional targets among meiotic genes not pinned down
  24. 2010 High

    Demonstrated granulosa-cell WNT4/CTNNB1 signaling is required for antral follicle development and steroidogenic gene regulation.

    Evidence Conditional Wnt4 knockout, follicle counting, RT-PCR, and overexpression with microarray

    PMID:20371632

    Open questions at the time
    • Receptor in granulosa cells not identified
  25. 2010 High

    Identified Frizzled-1 as the receptor for canonical WNT4-driven vascular smooth muscle cell proliferation.

    Evidence siRNA, recombinant WNT4, Frizzled-1 knockdown epistasis, and Wnt4 heterozygous carotid ligation model

    PMID:21193738

    Open questions at the time
    • Whether Frizzled-1 mediates WNT4 canonical signaling in other tissues untested
  26. 2011 High

    Positioned Notch in a pathway parallel to WNT4/WNT9b for nephron MET and established that only nephron stem cells are competent to respond.

    Evidence Ectopic Notch activation in Wnt4/Wnt9b double-null kidney explants with lineage and fate analysis

    PMID:21852398

    Open questions at the time
    • Molecular convergence point of Notch and Wnt pathways unresolved
  27. 2011 High

    Pinpointed the non-canonical WNT4 hematopoietic mechanism as Frizzled-6–Rac1–JNK2 signaling.

    Evidence Rac1/JNK activation assays, Frizzled-6 identification, Jnk2-KO and Wnt4-heterozygous mice, competitive reconstitution

    PMID:21541287

    Open questions at the time
    • Co-receptor requirement for the Frizzled-6 branch not defined
  28. 2011 High

    Showed WNT4 maintains thymic cellularity through a thymic epithelial cell–dependent mechanism, including in adults.

    Evidence Conventional and conditional Wnt4-null mice with flow cytometry of TEC and thymocyte subsets

    PMID:21937690

    Open questions at the time
    • Signaling pathway in TECs not dissected
  29. 2011 Medium

    Linked canonical WNT4/β-catenin signaling to myogenic differentiation via negative regulation of myostatin.

    Evidence Wnt4 overexpression/siRNA in C2C12 and satellite cells with myostatin-knockout epistasis

    PMID:21248078

    Open questions at the time
    • Single lab
    • Receptor not identified
  30. 2012 High

    Identified MuSK as a WNT4 receptor at the neuromuscular junction required for AChR prepatterning.

    Evidence Wnt4-null NMJ morphology, AChR cluster counting, WNT4–MuSK ectodomain co-IP, and MuSK phosphorylation assay

    PMID:22253844

    Open questions at the time
    • Downstream signaling from MuSK activation by WNT4 not detailed
  31. 2012 High

    Placed WNT4 downstream of BMP2 and upstream of β-catenin/FOXO1 in human endometrial decidualization.

    Evidence siRNA, adenoviral overexpression, DKK1 and β-catenin siRNA, and gene profiling in HESCs

    PMID:23142810

    Open questions at the time
    • Receptor mediating endometrial WNT4 signaling unidentified
  32. 2012 High

    Established that WNT4 and RSPO1 jointly drive proliferation of the early undifferentiated gonadal coelomic epithelium in both sexes.

    Evidence Wnt4/Rspo1 double knockout with BrdU proliferation and Sertoli cell/tubule morphology

    PMID:23095882

    Open questions at the time
    • Molecular cooperation between WNT4 and RSPO1 not biochemically defined
  33. 2013 Medium

    Showed WNT4 drives myofibroblast differentiation in vitro but is dispensable in vivo for renal fibrosis, revealing functional redundancy among Wnt ligands.

    Evidence Conditional Wnt4 knockout (negative in vivo), constitutive β-catenin activation, and pericyte differentiation assays

    PMID:23766539

    Open questions at the time
    • Identity of compensating Wnt ligands unknown
    • Single lab
  34. 2013 High

    Defined an instructive, redundant role for Drosophila Wnt4 (with Wingless) in planar cell polarity via modulation of Frizzled–Van Gogh interactions.

    Evidence Drosophila wing loss-of-function with PCP axis and Fz-Vang interaction assays

    PMID:23912125

    Open questions at the time
    • Vertebrate relevance of this PCP role untested
  35. 2013 High

    Showed WNT4 controls follicular cell polarity, basement membrane integrity, connexin-43, and directly upregulates Amh during folliculogenesis.

    Evidence Conditional Wnt4 KO, Wnt4 knock-in reporter, immunofluorescence panel, and Amh reporter in granulosa cells

    PMID:24371124

    Open questions at the time
    • Mechanism linking WNT4 to basement-membrane and junctional control unresolved
  36. 2013 Medium

    Mapped Frizzled and LRP co-receptor selectivity, showing WNT4 activates β-catenin only with specific FZD fusions and differential LRP5/LRP6 dependence.

    Evidence WNT/FZD fusion-construct TCF/LEF reporter assays with LRP5/LRP6 overexpression in HEK293

    PMID:24269653

    Open questions at the time
    • Fusion-construct system may not reflect native receptor pairing
    • Endogenous FZD partners not confirmed
  37. 2014 High

    Defined a β-catenin-independent WNT4 mechanism that inhibits NF-κB by targeting TAK1 to suppress osteoclastogenesis and protect against bone loss.

    Evidence Wnt4 transgenic mice in ovariectomy/TNF/aging bone-loss models with TAK1/NF-κB analysis and recombinant WNT4 treatment

    PMID:25108526

    Open questions at the time
    • Receptor delivering the anti-NF-κB signal not identified
  38. 2015 Medium

    Showed exosome-delivered WNT4 from MSCs activates β-catenin to promote skin cell proliferation/migration and wound re-epithelialization.

    Evidence Exosome Wnt4 knockdown, β-catenin nuclear translocation, ICG-001 inhibitor, and rat burn model

    PMID:24964196

    Open questions at the time
    • Single lab
    • Receptor not identified
  39. 2015 Medium

    Extended exosomal WNT4/β-catenin signaling to endothelial proliferation and angiogenesis in wound healing.

    Evidence Exosome Wnt4 siRNA, β-catenin translocation, tube formation, and rat burn model with ICG-001

    PMID:25824139

    Open questions at the time
    • Single lab
    • Mechanism of exosomal WNT4 delivery to endothelium not detailed
  40. 2015 High

    Established WNT4 as the luminal-to-myoepithelial signal coordinating progesterone-driven and hormone-independent mammary stem cell function.

    Evidence Serial transplantation, Wnt4 reporter, conditional deletion, and PR/RANKL epistasis

    PMID:25603931

    Open questions at the time
    • Myoepithelial receptor for luminal WNT4 not identified
  41. 2015 High

    Defined WNT4 as required for directional cell migration and elongation of the Müllerian duct.

    Evidence Wnt4 fate mapping, function-blocking antibody, hypomorphic allele, and NIH3T3 migration assay

    PMID:26721931

    Open questions at the time
    • Signaling pathway driving directional migration unresolved
  42. 2016 High

    Showed ER directly controls WNT4 in invasive lobular carcinoma and that WNT4 mediates estrogen-induced proliferation by suppressing CDKN1A/p21.

    Evidence ChIP for ER at the WNT4 locus, siRNA, CDKN1A epistasis, and endocrine-resistant ILC model

    PMID:27650553

    Open questions at the time
    • Receptor/pathway linking WNT4 to p21 suppression not defined
  43. 2019 Medium

    Showed WNT4 promotes neuronal differentiation of neural stem cells via β-catenin/MAPK-JNK activation and Notch suppression, with functional spinal cord repair.

    Evidence WNT4 overexpression in NSCs with pathway westerns, Notch ligand co-treatment, and rat SCI transplantation

    PMID:31914702

    Open questions at the time
    • Single lab
    • Receptor not identified
  44. 2019 High

    Established that WNT4 secretion is PORCN-independent and its activity is cell-autonomous rather than paracrine, distinguishing it from canonical Wnts.

    Evidence PORCN inhibitor, WLS knockdown, and paracrine vs cell-autonomous assays across multiple cell lines

    PMID:31740580

    Open questions at the time
    • Mechanism of PORCN-independent WNT4 maturation not defined
  45. 2019 High

    Showed muscle-fiber-derived WNT4 enforces satellite cell quiescence via RhoA-dependent YAP repression and biophysical niche control.

    Evidence Cell-specific inducible Wnt4 KO/OE, RhoA assays, YAP localization, and stiffness/FRAP measurements

    PMID:31495781

    Open questions at the time
    • Receptor delivering the RhoA signal in satellite cells unidentified
  46. 2019 Medium

    Showed WNT4 negatively regulates TGF-β1-induced fibroblast-to-myofibroblast transition by blocking Smad3 and ERK phosphorylation.

    Evidence Recombinant WNT4 and siRNA with collagen contraction and phospho-signaling westerns in scar fibroblasts

    PMID:31776823

    Open questions at the time
    • Single lab
    • Receptor and mechanism of Smad3/ERK inhibition undefined
  47. 2021 High

    Established E2F1 as a germ-cell repressor of WNT4 required to maintain spermatogenesis.

    Evidence E2f1-null and E2f1/Wnt4 double-null mice with germ cell counts and fertility testing

    PMID:33441379

    Open questions at the time
    • Directness of E2F1 binding at the Wnt4 locus not shown here
  48. 2021 Medium

    Showed WNT4 (with WNT2) promotes cardiac fibrosis through β-catenin/NF-κB signaling via Frizzled-2/Frizzled-4 and LRP6.

    Evidence Wnt2/Wnt4 siRNA in MI model with receptor/co-receptor analysis and patient ELISA

    PMID:34911029

    Open questions at the time
    • Single lab
    • Relative contributions of WNT2 vs WNT4 not separated
  49. 2022 High

    Defined WNT4 as a regulator of pancreatic β-cell calcium signaling, metabolism, and insulin secretion, marking mature versus proliferative β-cells.

    Evidence Adult β-cell-specific Wnt4 knockout with calcium imaging, ATP/ADP measurement, insulin secretion, and reporters

    PMID:36271049

    Open questions at the time
    • Receptor and signaling branch in β-cells not identified
  50. 2024 Medium

    Identified Nr4a1 as a transcriptional activator of WNT4 promoting BMSC osteogenesis and reversing TGF-β1 inhibition.

    Evidence ChIP at the Wnt4 promoter, Nr4a1 overexpression, osteogenic assays, and in vivo fracture models

    PMID:38429926

    Open questions at the time
    • Single lab
    • WNT4 receptor in BMSC osteogenesis undefined
  51. 2024 High

    Established a TEAD1–BRD4–WNT4 axis driving cardiac fibroblast-to-myofibroblast transition.

    Evidence ChIP-seq, co-IP/MS, luciferase, conditional TEAD1 KO, and Wnt4 siRNA epistasis with echocardiography

    PMID:38374140

    Open questions at the time
    • Downstream WNT4 receptor/effectors in cardiac fibroblasts not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor logic that selects among WNT4's many context-dependent outputs—canonical β-catenin, membrane β-catenin sequestration, p38/Axin, Rac1/JNK, RhoA, and TAK1/NF-κB inhibition—remains incompletely defined, as does the mechanism of its PORCN-independent secretion.
  • No unified model linking specific FZD/co-receptor pairings to specific downstream branches
  • Mechanism of PORCN-independent WNT4 maturation unknown
  • Determinants of cell-autonomous vs paracrine action across tissues unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 4
Localization
GO:0005576 extracellular region 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1474165 Reproduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3
Partners
FZD1FZD2FZD4FZD6LRP5LRP6MUSKSFRP2

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 WNT-4 is sufficient to trigger mesenchymal-to-epithelial transition (tubulogenesis) in isolated metanephric mesenchyme; its signaling depends on cell contact and sulphated glycosaminoglycans and is required only for triggering tubulogenesis, not for later morphogenetic events. Dorsal spinal cord signals likely act by inducing endogenous WNT-4 in the mesenchyme. Ex vivo rescue assay: isolated metanephric mesenchyme from Wnt-4 null mice treated with Wnt-4-expressing cells; comparison with Wnt-11 and dorsal spinal cord co-culture Development (Cambridge, England) High 9753677
1998 sFRP-2 is a direct downstream target of WNT-4 signaling in the developing metanephric kidney; sFRP-2 expression is absent in Wnt-4 null kidneys, and the cysteine-rich domain of sFRP-2 binds WNT-4 directly as shown by co-immunoprecipitation. Co-immunoprecipitation, in situ hybridization in Wnt-4 null versus wild-type kidneys, co-induction assay in isolated mesenchyme Developmental dynamics : an official publication of the American Association of Anatomists High 9853965
2000 WNT-4 acts downstream of progesterone receptor (PR) signaling in mammary epithelium: progesterone induces Wnt-4 expression in PR+ luminal cells, and Wnt-4 is required for ductal side-branching during early pregnancy. PR and Wnt-4 mRNAs colocalize in the luminal compartment. Wnt-4(-/-) mammary epithelium transplantation, progesterone treatment of mammary epithelial cells, PR knockout comparison Genes & development High 10733525
2001 WNT-4 upregulates DAX1 expression in Sertoli and Leydig cells; overexpression of WNT-4 leads to up-regulation of DAX1, which antagonizes SRY and results in XY female sex reversal, providing a mechanism for dosage-sensitive sex reversal. Cell transfection/overexpression of WNT-4 with DAX1 reporter and expression analysis in testicular cell lines; association with human 1p31-p35 duplication American journal of human genetics Medium 11283799
2002 WNT-4 induces stabilization of cytosolic β-catenin in cultured myofibroblasts, and WNT-4-producing fibroblasts placed under the renal capsule induce lesions with tubular epithelial destruction, demonstrating a functional role for WNT-4 in renal fibrosis through canonical β-catenin signaling. Wnt-4 expression in four murine renal injury models (in vivo); β-catenin stabilization assay in cultured myofibroblast cell line; subrenal capsule implantation of Wnt-4-expressing fibroblasts American journal of physiology. Renal physiology Medium 11832423
2002 Loss of WNT-4 in the adrenal gland reduces expression of Cyp11B2 and preadipocyte factor 1, resulting in significantly reduced aldosterone production. It also alters Cyp17 expression and allows ectopic Cyp21-positive cells in gonads, suggesting WNT-4 is required for zona glomerulosa formation and adrenal/gonadal cell sorting. Wnt-4 knockout mouse phenotypic analysis; aldosterone measurement; Cyp gene expression by in situ hybridization and RT-PCR Endocrinology Medium 12399432
2003 WNT4 represses mesonephric endothelial and steroidogenic cell migration into the XX gonad, preventing formation of a male-specific coelomic blood vessel and ectopic androgen production. Transgenic Wnt4 misexpression in the XY gonad affects vascular patterning but does not block Leydig cell differentiation, indicating WNT4 represses migration of steroidogenic adrenal precursors rather than their differentiation. Wnt4 null mouse analysis; Wnt4 transgenic misexpression in XY gonad; mesonephric cell migration assays Development (Cambridge, England) High 12835383
2004 WNT-4 activates canonical β-catenin/LEF/TCF signaling in kidney epithelial (MDCK) cells. WNT-4 forms a biochemical complex with the Frizzled-6 CRD, but Frizzled-6 does not appear to transduce WNT-4's canonical signal, implying another Frizzled receptor mediates β-catenin activation by WNT-4. TCF/LEF reporter assays in MDCK cells; dominant-negative β-catenin (β-Engrailed) and dnTCF-4 constructs; co-immunoprecipitation of WNT-4 with Frizzled-6 CRD Experimental cell research Medium 15265686
2005 PAX2 transcription factor activates WNT4 gene expression during nephrogenesis: PAX2 binds three novel recognition motifs in the WNT4 promoter (EMSA), activates WNT4 promoter 5-fold in co-transfection assays, increases endogenous WNT4 mRNA 7-fold, and heterozygous Pax2 mutant mice show 60% reduction in Wnt4 mRNA in condensing mesenchyme. Electromobility shift assay (EMSA), promoter-reporter co-transfection, PAX2-overexpression in JTC12 cells, Pax2 heterozygous mouse kidney analysis The Journal of biological chemistry High 16368682
2006 FGF9 and WNT4 act as opposing signals in mammalian sex determination: in the XY gonad, SRY initiates a feed-forward loop between Sox9 and Fgf9 that represses Wnt4 to establish the testis pathway. Loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry, demonstrating mutual antagonism. Gain- and loss-of-function mouse genetics; Fgf9 and Wnt4 single and double knockouts; Sox9/Fgf9 expression analysis in Wnt4 null XX gonads PLoS biology High 16700629
2007 Noncanonical WNT-4 signaling activates p38 MAPK (independently of β-catenin stabilization) via Axin, enhancing osteogenic differentiation of mesenchymal stem cells in vitro and promoting bone formation in craniofacial defect models in vivo. β-catenin stabilization assay (negative result for canonical), p38 MAPK activation assay, Axin-dependent signaling knockdown, in vivo craniofacial bone defect model with Wnt-4-engineered MSCs The Journal of biological chemistry High 17720811
2007 Simultaneous inactivation of Wnt4 and Foxl2 in XX mice leads to complete female-to-male sex reversal including testis tubule formation and spermatogonia, demonstrating that WNT4 and FOXL2 independently act as anti-testis factors maintaining all major aspects of female sex determination. Wnt4/Foxl2 double knockout mouse; histological and germ cell analysis; Foxl2 transgenic XY mice showing impaired testis tubule differentiation Human molecular genetics High 17728319
2007 WNT4 functions as a local repulsive cue determining synaptic target specificity in Drosophila: Wnt4 expressed in muscle M13 prevents synapse formation by M12-innervating motor neurons via Frizzled 2, Derailed-2, and Dishevelled. Loss of Wnt4 or its receptors/Dishevelled causes ectopic nerve endings on M13; ectopic expression of Wnt4 in M12 inhibits synapse formation. Single-cell microarray, loss-of-function (RNAi/mutation) and gain-of-function (ectopic expression) in Drosophila; synaptic morphology assays Current biology : CB High 17764943
2008 WNT4 redirects β-catenin to the cell membrane without affecting its stability, thereby inhibiting β-catenin/TCF transcriptional activity. This noncanonical mechanism acts as a switch between transcriptional and cell-adhesion functions of β-catenin. Subcellular fractionation/immunofluorescence of β-catenin localization; TCF/LEF reporter assays; β-catenin stability (western blot) Biology of the cell Medium 17976036
2008 WNT4 activates non-canonical (β-catenin-independent) signaling to expand multipotent hematopoietic progenitors and thymopoiesis. Wnt4 gain- and loss-of-function models show that Flt3+ bone marrow LSKs are key targets and that Wnt4's effects on hematopoietic cells are mainly non-cell-autonomous. Wnt4 transgenic and Wnt4(-/-) mouse models; flow cytometric analysis of LSK/thymocyte populations; β-catenin pathway reporter to confirm non-canonical signaling Immunity High 18617424
2008 WNT4 promotes adipogenesis in 3T3-L1 cells acting as a positive regulator through the non-canonical Wnt pathway; siRNA-mediated inhibition of Wnt4 prevented triacylglycerol accumulation and decreased expression of adipogenesis-related genes. siRNA knockdown during adipogenic differentiation; triacylglycerol accumulation assay; gene expression analysis FEBS letters Medium 18708054
2010 WNT4/β-catenin pathway maintains female germ cell survival in the fetal ovary by inhibiting activin βB (Inhbb): β-catenin acts downstream of WNT4 (activation of β-catenin in somatic cells of Wnt4-KO ovary rescues germ cell numbers), and removal of Inhbb in Wnt4-KO ovaries prevents germ cell degeneration. Conditional β-catenin activation in Wnt4-KO somatic cells; Wnt4/Inhbb double knockout; germ cell counting and apoptosis assays PloS one High 20454446
2010 WNT4 is required for normal antral follicle development and regulates steroidogenic gene expression (Star, Cyp11a1, Cyp19) via the WNT/CTNNB1 (β-catenin) signaling pathway in granulosa cells. Granulosa-cell-specific Wnt4 deletion reduces antral follicle numbers and serum progesterone. Conditional Wnt4 knockout (Amhr2-Cre); serial follicle counting; RT-PCR of steroidogenic genes in isolated granulosa cells; WNT4 and CTNNB1 overexpression with microarray FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 20371632
2010 WNT4 maintains germ cell cysts and female pattern of E-cadherin/β-catenin expression; in Wnt-4-deficient ovaries Stra8 is downregulated and Cyp26b1 is ectopically expressed, suggesting WNT4 controls female meiosis entry by regulating RA-degrading Cyp26b1. Combined Wnt-4/Wnt-5a deficiency completely inhibits meiosis. Wnt-4 and Wnt-4/Wnt-5a double knockout mouse; immunofluorescence for E-cadherin/β-catenin; RT-PCR for Stra8, Cyp26b1, Irx3; reintroduction of Wnt-4 signal to ex vivo ovary Human molecular genetics High 20106871
2010 WNT4 induces VSMC proliferation via the β-catenin signaling pathway through Frizzled 1; siRNA knockdown of Wnt4 (but not Wnt2) significantly reduces PDGF-BB-induced VSMC proliferation, and recombinant WNT4 increases proliferation ~2-fold. Wnt4(+/-) mice show significantly retarded intimal thickening after carotid ligation. siRNA knockdown; recombinant WNT4 treatment; Frizzled 1 knockdown epistasis; Wnt4(+/-) mouse carotid ligation model; western blot; immunohistochemistry Circulation research High 21193738
2011 Wnt4 activates canonical β-catenin signaling during myogenic differentiation in C2C12 cells and satellite cells and negatively regulates myostatin expression; myostatin knockout satellite cells are refractory to Wnt4-induced hypertrophy, and recombinant myostatin antagonizes Wnt4-induced differentiation. Wnt4 overexpression/siRNA in C2C12 and satellite cells; myostatin knockout; fusion index; western blot for β-catenin, myostatin pathway American journal of physiology. Cell physiology Medium 21248078
2011 Notch activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells, positioning Notch in a parallel pathway to WNT4. After MET, Notch directs cells to proximal tubule fate. Only nephron stem cells (not stromal mesenchyme) are competent to undergo MET in response to Wnt or Notch. Ectopic Notch activation in Wnt4/Wnt9b double null embryonic kidney explants; lineage-specific gene manipulation; nephron fate analysis Development (Cambridge, England) High 21852398
2011 Wnt4 expands hematopoietic progenitor cells through a non-canonical, β-catenin-independent pathway involving Frizzled 6 (receptor identification), Rac1 activation, and JNK kinase activity. JNK2-deficient HPCs phenocopy Wnt4 hemizygosity; competitive reconstitution improvement is Jnk2-dependent. Rac1 and JNK activation assays; β-catenin reporter (negative for canonical); Frizzled 6 identification; Jnk2-KO and Wnt4(+/-) mouse bone marrow analysis; competitive reconstitution PloS one High 21541287
2011 WNT4 controls thymic cellularity through a thymic epithelial cell (TEC)-dependent mechanism: Wnt4 deletion suppresses TEC numbers, alters the medullary-to-cortical TEC ratio, and causes disproportionate loss of cKit(hi) thymocyte precursors. Conditional null models show Wnt4 is also required for adult thymopoiesis. Conventional and conditional Wnt4 null mice; flow cytometric analysis of TEC subsets and thymocyte populations; TEC counting Blood High 21937690
2012 WNT4 acts downstream of BMP2 and signals via β-catenin (canonical WNT) to regulate human endometrial stromal cell decidualization; WNT4 knockdown blocks BMP2-induced decidualization, WNT4 overexpression advances it, and the effect requires nuclear β-catenin accumulation. FOXO1 is identified as a common downstream mediator of BMP2 and WNT4. siRNA knockdown; adenoviral overexpression; Dickkopf-1 inhibitor; β-catenin siRNA; immunofluorescence; gene expression profiling in HESCs Endocrinology High 23142810
2012 WNT4 and RSPO1 together are required for cell proliferation of coelomic epithelium in the early undifferentiated gonad (both sexes); simultaneous ablation impairs progenitor proliferation and results in hypoplastic testis with few seminiferous tubules in XY double mutants. Wnt4/Rspo1 double knockout mouse; BrdU proliferation assay; Sertoli cell counting and seminiferous tubule morphology Development (Cambridge, England) High 23095882
2012 WT1 and Sox11 synergistically regulate the Wnt4 promoter in embryonic kidney cells: WT1/Sox11 form an immunoprecipitable complex; dominant-negative WT1 mutants (P129L, F154S) inhibit Wnt4 expression and fail to interact with Sox11; morpholino knockdown of either wt1 or sox11 reduces Wnt4 expression in Xenopus pronephros. Promoter-reporter assay; co-immunoprecipitation; dominant-negative WT1 mutants; Xenopus morpholino knockdown with in situ hybridization Experimental cell research High 22465478
2013 Wnt4 drives myofibroblast differentiation of pericyte-like cells in vitro via β-catenin signaling; however, conditional deletion of Wnt4 in interstitial cells does not reduce myofibroblast number or gene expression during renal fibrosis in vivo, suggesting compensatory Wnt ligands. Constitutive activation of canonical Wnt/β-catenin in interstitial pericytes is sufficient to drive spontaneous myofibroblast differentiation. Conditional Wnt4 knockout in interstitial cells; constitutive β-catenin activation mouse model; myofibroblast marker analysis; in vitro pericyte differentiation assay Journal of the American Society of Nephrology : JASN Medium 23766539
2013 Wg (Wingless) and Drosophila Wnt4 provide instructive directional input for planar cell polarity (PCP) axis determination in the wing by modulating the intercellular Frizzled–Van Gogh (Vang) interaction. Loss-of-function shows they act redundantly in PCP; their graded distribution establishes polarity axes. Drosophila wing loss-of-function (Wg and dWnt4 mutants); PCP axis analysis; Fz-Vang interaction assays Nature cell biology High 23912125
2013 WNT4 regulates cell polarity, basement membrane integrity, connexin-43 expression, and AMH (antimüllerian hormone) gene expression during ovarian folliculogenesis; in vitro, WNT4 signaling directly upregulates Amh gene expression in KK1 granulosa cells. Amhr2-Cre and inducible Cre conditional Wnt4 knockout; Wnt4(mCherry) knock-in; immunofluorescence for N-cadherin, β-catenin, laminin, collagen IV, connexin 43; Amh reporter in KK1 cells FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 24371124
2013 WNT4 and WNT5a are identified as noncanonical Wnt ligands capable of activating β-catenin–dependent signaling only when fused to specific Frizzled receptors (FZD combinations), with selective dependence on LRP5 or LRP6 co-receptors differing from canonical WNT3a which broadly activates β-catenin via LRP6. WNT/FZD fusion construct reporter assay in HEK293 TCF/LEF reporter cells; LRP5/LRP6 overexpression; Gaussia luciferase reporter Cellular signalling Medium 24269653
2014 WNT4 inhibits NF-κB activation via noncanonical Wnt signaling (independently of β-catenin) by targeting TAK1 (Tak1) in macrophages and osteoclast precursors, thereby preventing osteoclast formation and bone resorption. Wnt4 transgenic mice are protected from ovariectomy-, TNF-, and aging-induced bone loss. Wnt4 transgenic mice (osteoblast-driven); ovariectomy and TNF-induced bone loss models; TAK1/NF-κB pathway analysis; β-catenin reporter (independence confirmed); recombinant Wnt4 in vivo treatment Nature medicine High 25108526
2015 Exosome-delivered WNT4 from human umbilical cord MSCs promotes β-catenin nuclear translocation in skin cells, enhancing proliferation and migration; knockdown of Wnt4 in exosomes abrogates β-catenin activation and impairs wound re-epithelialization in rat burn model in vivo. Wnt4-containing exosome characterization; siRNA knockdown of Wnt4 in exosomes; β-catenin nuclear translocation assay; rat skin burn model; β-catenin inhibitor ICG001 Stem cells (Dayton, Ohio) Medium 24964196
2015 Exosome-delivered WNT4 from hucMSCs induces β-catenin nuclear translocation in endothelial cells, promoting proliferation, tube formation, and angiogenesis; WNT4 knockdown in exosomes abrogates these effects and impairs wound healing angiogenesis in vivo. Wnt4 siRNA knockdown in exosomes; β-catenin nuclear translocation assay; tube formation assay; rat burn model; ICG-001 inhibitor Stem cells translational medicine Medium 25824139
2015 WNT4 coordinates directional cell migration and elongation of the Müllerian duct: Wnt4(EGFPCre) fate mapping shows MD tip cells are derived from Wnt4+ lineage; anti-Wnt4 function-blocking antibodies after MD initiation arrest elongation; WNT4 overexpression in NIH3T3 cells promotes wound-healing migration. Wnt4(EGFPCre) fate mapping; function-blocking antibody treatment ex vivo; Wnt4 hypomorphic mouse (Wnt4mCh/mCh); NIH3T3 cell migration assay Human molecular genetics High 26721931
2015 Progesterone and WNT4 control mammary stem cell function via luminal-myoepithelial crosstalk: canonical Wnt signaling in the myoepithelium requires both PR and Wnt4 (luminal source), whereas perinatal Wnt4 expression is hormone-independent and functionally important for mammary regeneration capacity. Serial mammary transplantation; fluorescent Wnt4 reporter; conditional Wnt4 deletion; PR knockout comparison; RANKL deletion epistasis The EMBO journal High 25603931
2016 In invasive lobular carcinoma (ILC) cells, ER directly controls WNT4 expression via an ER binding site at the WNT4 locus. WNT4 is required for estrogen-induced proliferation; WNT4 knockdown blocks estrogen-induced growth, and WNT4 signals through suppression of CDKN1A/p21. WNT4 siRNA knockdown; ChIP for ER at WNT4 locus; CDKN1A knockdown epistasis; proliferation assays in ILC cell lines; ILC-LTED endocrine-resistant model Breast cancer research : BCR High 27650553
2019 WNT4 from muscle fibers maintains satellite cell quiescence through RhoA activation: Wnt4-RhoA signaling constrains SC numbers, maintains mechanical strain, restricts niche movement, and represses YAP. YAP induction upon RhoA disruption is essential for SC activation; loss of fiber-derived Wnt4 accelerates activation, while overexpression deepens quiescence. Cell-specific inducible Wnt4 knockout and overexpression in mice; RhoA activity assays; YAP localization; cell stiffness/FRAP measurements; satellite cell activation assays Cell stem cell High 31495781
2019 WNT4 promotes differentiation of neural stem cells into neurons by activating β-catenin and MAPK/JNK pathways and suppressing Notch signaling via downregulation of NICD and prevention of NICD-RbpJ nuclear interaction. WNT4-modified NSC transplantation repairs injured spinal cord and recovers motor function in vivo. WNT4 overexpression in NSCs; pathway reporter/western blot for β-catenin, JNK, NICD; Notch ligand Jagged co-treatment; rat SCI transplantation model FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 31914702
2019 WNT4 secretion is independent of porcupine O-acyltransferase (PORCN) in all tested cell models, whereas WLS is required for Wnt secretion and paracrine signaling. WNT4 does not exhibit paracrine activity; instead it activates Wnt signaling cell-autonomously, independently of PORCN or Wnt secretion. PORCN inhibitor treatment; WLS knockdown; conditioned media paracrine assay; co-culture systems; WNT4/WNT3A overexpression in multiple cell lines The Journal of biological chemistry High 31740580
2019 WNT4 negatively regulates TGF-β1-induced fibroblast-to-myofibroblast transition by blocking phosphorylation of Smad3 and ERK (but not AKT or JNK) and inhibiting TGF-β1 autocrine signaling; WNT4 knockdown further increases α-SMA and collagen I. Recombinant WNT4 treatment; WNT4 siRNA knockdown; collagen lattice contraction assay; western blot for Smad3/ERK/AKT/JNK phosphorylation; hypertrophic scar-derived fibroblasts Cell and tissue research Medium 31776823
2021 E2F1 represses WNT4 in germ cells to maintain spermatogenesis: E2f1-null mice develop cryptorchidism and germ cell loss; double-null Wnt4/E2f1 mice are fertile, demonstrating that germ cell depletion in E2f1-null mice is dependent on elevated WNT4 levels. E2f1-null and E2f1/Wnt4 conditional double-null mouse models; germ cell counting; fertility testing Development (Cambridge, England) High 33441379
2021 WNT4 and WNT2 activate β-catenin/NF-κB signaling to promote cardiac fibrosis through cooperation of Frizzled-4/Frizzled-2 and LRP6 in fibroblasts. Knockdown of Wnt2 and Wnt4 attenuates myocardial remodeling after experimental MI. Wnt2/Wnt4 siRNA knockdown in MI mouse model; Fzd2, Fzd4, LRP6 co-receptor analysis; β-catenin/NF-κB pathway western blot; ELISA in patients EBioMedicine Medium 34911029
2022 WNT4 controls calcium signaling and metabolic pathways in pancreatic β-cells: WNT4 knockout in adult β-cells reduces calcium activation in response to glucose, lowers ATP/ADP ratios, and thereby reduces insulin secretion. Wnt4-positive β-cells are more mature while Wnt4-negative cells are more proliferative. Adult β-cell-specific Wnt4 knockout; calcium imaging; ATP/ADP ratio measurement; insulin secretion assay; Wnt4 reporter in zebrafish and mouse Nature communications High 36271049
2024 TEAD1 promotes cardiac fibroblast-to-myofibroblast transition via the BRD4/WNT4 signaling axis: TEAD1 binds the WNT4 promoter (ChIP-seq confirmed) and activates Wnt signaling; genetic Wnt4 knockdown inhibits TEAD1-overexpression-induced pro-transformation phenotype in CFs. TEAD1-BRD4 interaction was confirmed by co-IP/mass spectrometry. RNA-seq, ChIP-seq, co-IP/mass spectrometry, luciferase assay, conditional TEAD1 KO, Wnt4 siRNA epistasis, echocardiography Signal transduction and targeted therapy High 38374140
2012 WNT4 participates in vertebrate neuromuscular junction formation: Wnt4(-/-) mice show motor axon overgrowth past AChR clusters and a 30% reduction in prepatterned AChR clusters. WNT4 interacts with MuSK ectodomain and mediates MuSK activation, identifying MuSK as a WNT4 receptor at the NMJ. Wnt4(-/-) mouse NMJ morphology; AChR cluster counting; WNT4 overexpression in myotubes; co-immunoprecipitation of WNT4 with MuSK ectodomain; MuSK phosphorylation assay PloS one High 22253844
2008 MM-1 (c-Myc-binding protein) negatively regulates WNT4 transcription by binding the WNT4 promoter region (−286 to −229 from TSS) together with Egr-1; chromatin immunoprecipitation and gel mobility shift assays confirm MM-1 complex binding; MM-1 and Egr-1 mutually down-regulate WNT4 promoter activity. DNA microarray; promoter-reporter with deletion constructs; ChIP; EMSA; MM-1 knockdown Experimental cell research Medium 18281035
2005 In Xenopus, noncanonical (β-catenin-independent) WNT-4 signaling is required for eye development and induces expression of EAF2, a component of the ELL-mediated RNA Pol II elongation factor complex; EAF2 is expressed specifically in the eye and regulates the eye-specific transcription factor Rx. Xenopus gain- and loss-of-function (morpholino); β-catenin reporter (independence confirmed); EAF2 identification as target gene; EAF2 morpholino; neuralized animal cap assay for Rx regulation The EMBO journal High 15775981
2009 In Xenopus pronephros, Notch signaling patterns the medio-lateral axis by upregulating Wnt-4 expression via the Notch effector gene hrt1; Wnt-4 then patterns proximal pronephric compartments. This defines a Notch→hrt1→Wnt-4 pathway in renal morphogenesis. Xenopus Notch gain- and loss-of-function; hrt1 morpholino; wnt4 expression analysis; pronephric compartment markers Development (Cambridge, England) Medium 19793883
2002 In Xenopus, Wnt-4 is critically required for tubulogenesis in the pronephric kidney (as in the metanephros); morpholino-mediated knockdown causes complete absence of pronephric tubules while pronephric duct development is unaffected, demonstrating evolutionary conservation of Wnt-4's tubulogenic function. Xenopus morpholino antisense knockdown; gain-of-function mRNA injection; pronephric marker gene analysis Developmental biology High 12142017
2006 WNT4, delivered by adenovirus to human adrenocortical cells, increases steroidogenesis when added alone (increasing CYP17 and CYP21 mRNA), but decreases it in the presence of cAMP. WNT4 increases CYP11B2 (aldosterone synthase) mRNA, consistent with a role in zona glomerulosa function. Adenovirus-mediated WNT4 delivery to cultured human adrenocortical cells; aldosterone/cortisol measurement; steroidogenic enzyme mRNA by real-time PCR Hormone and metabolic research Medium 16981135
2024 Nr4a1 binds the WNT4 promoter to enhance its transcription, thereby activating the WNT4/β-catenin pathway and promoting BMSC osteogenesis; Nr4a1 overexpression reverses TGF-β1-mediated osteogenic inhibition in a WNT4-dependent manner. ChIP of Nr4a1 at Wnt4 promoter; Nr4a1 overexpression; WNT4 transcriptomic readout; BMSC osteogenic assays; Nr4a1 agonist in vivo fracture models Molecular therapy : the journal of the American Society of Gene Therapy Medium 38429926

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem cells (Dayton, Ohio) 638 24964196
2006 Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS biology 408 16700629
2015 Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem cells translational medicine 402 25824139
1998 Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Development (Cambridge, England) 393 9753677
2000 Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes & development 383 10733525
2003 Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development (Cambridge, England) 277 12835383
2007 Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Human molecular genetics 249 17728319
2001 Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. American journal of human genetics 222 11283799
2002 Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 187 12399432
2007 Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. The Journal of biological chemistry 182 17720811
2014 Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB. Nature medicine 177 25108526
2013 Wnt4/β-catenin signaling in medullary kidney myofibroblasts. Journal of the American Society of Nephrology : JASN 154 23766539
2002 A role for Wnt-4 in renal fibrosis. American journal of physiology. Renal physiology 144 11832423
2010 Wnt4/β-catenin signaling induces VSMC proliferation and is associated with intimal thickening. Circulation research 139 21193738
2013 Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in Drosophila. Nature cell biology 137 23912125
2010 WNT4 is required for normal ovarian follicle development and female fertility. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 132 20371632
2019 Wnt4 from the Niche Controls the Mechano-Properties and Quiescent State of Muscle Stem Cells. Cell stem cell 130 31495781
2003 Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. Journal of the American Society of Nephrology : JASN 128 12707392
2004 Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells. Experimental cell research 119 15265686
1995 Wnt4 affects morphogenesis when misexpressed in the zebrafish embryo. Mechanisms of development 114 8541205
2012 WNT4 acts downstream of BMP2 and functions via β-catenin signaling pathway to regulate human endometrial stromal cell differentiation. Endocrinology 109 23142810
1998 sFRP-2 is a target of the Wnt-4 signaling pathway in the developing metanephric kidney. Developmental dynamics : an official publication of the American Association of Anatomists 108 9853965
2003 Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer science 101 12841867
2015 Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk. The EMBO journal 98 25603931
1995 Wnt-4 expression induces a pregnancy-like growth pattern in reconstituted mammary glands in virgin mice. Developmental biology 94 7649383
2002 Wnt-1 and Wnt-4 regulate thymic cellularity. European journal of immunology 93 11920562
2007 Wnt4 is a local repulsive cue that determines synaptic target specificity. Current biology : CB 91 17764943
2006 Wnt4 action in gonadal development and sex determination. The international journal of biochemistry & cell biology 89 16905353
2012 WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. Development (Cambridge, England) 86 23095882
2008 Wnt4 and Wnt5a promote adipocyte differentiation. FEBS letters 86 18708054
2004 Matrilysin (MMP-7) expression in renal tubular damage: association with Wnt4. Kidney international 84 15149334
2005 Noncanonical Wnt-4 signaling and EAF2 are required for eye development in Xenopus laevis. The EMBO journal 83 15775981
2014 R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation. Reproduction (Cambridge, England) 79 25187620
2008 Wnt4 inhibits beta-catenin/TCF signalling by redirecting beta-catenin to the cell membrane. Biology of the cell 73 17976036
2012 Wnt4 participates in the formation of vertebrate neuromuscular junction. PloS one 72 22253844
2002 Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1. Oncogene 71 12082525
2002 Essential function of Wnt-4 for tubulogenesis in the Xenopus pronephric kidney. Developmental biology 68 12142017
2013 β-Catenin-dependent pathway activation by both promiscuous "canonical" WNT3a-, and specific "noncanonical" WNT4- and WNT5a-FZD receptor combinations with strong differences in LRP5 and LRP6 dependency. Cellular signalling 67 24269653
2011 Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development (Cambridge, England) 67 21852398
2010 Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Human molecular genetics 67 20106871
2021 Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review. Cell death discovery 62 34642299
2020 WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/β-catenin signalling pathway. Journal of experimental & clinical cancer research : CR 58 33222684
2016 WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines. Breast cancer research : BCR 57 27650553
2011 Wnt4 activates the canonical β-catenin pathway and regulates negatively myostatin: functional implication in myogenesis. American journal of physiology. Cell physiology 56 21248078
2010 Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence. PloS one 56 20502698
2005 PAX2 activates WNT4 expression during mammalian kidney development. The Journal of biological chemistry 56 16368682
2012 WNT4, RSPO1, and FOXL2 in sex development. Seminars in reproductive medicine 55 23044875
2019 EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure. EBioMedicine 54 31707150
2007 Involvement of Wnt4 signaling during myogenic proliferation and differentiation of skeletal muscle. Developmental dynamics : an official publication of the American Association of Anatomists 52 17879321
2021 Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction. EBioMedicine 51 34911029
2010 WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary. PloS one 50 20454446
2011 Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. PloS one 49 21541287
2015 Wnt4 is essential to normal mammalian lung development. Developmental biology 48 26321050
2015 Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract. Human molecular genetics 48 26721931
2008 The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through beta-catenin-independent signaling. Immunity 48 18617424
2013 Wnt4, a pleiotropic signal for controlling cell polarity, basement membrane integrity, and antimüllerian hormone expression during oocyte maturation in the female follicle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 47 24371124
2011 Distinct roles for Wnt-4 and Wnt-11 during retinoic acid-induced neuronal differentiation. Stem cells (Dayton, Ohio) 45 21280163
2011 Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors. Blood 43 21937690
2020 PRMT5/Wnt4 axis promotes lymph-node metastasis and proliferation of laryngeal carcinoma. Cell death & disease 42 33060569
2019 Wnt4 negatively regulates the TGF-β1-induced human dermal fibroblast-to-myofibroblast transition via targeting Smad3 and ERK. Cell and tissue research 41 31776823
2008 Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway. Endocrine pathology 40 19034702
2024 TEA domain transcription factor 1(TEAD1) induces cardiac fibroblasts cells remodeling through BRD4/Wnt4 pathway. Signal transduction and targeted therapy 39 38374140
2020 Introduction of Somatic Mutation in MED12 Induces Wnt4/β-Catenin and Disrupts Autophagy in Human Uterine Myometrial Cell. Reproductive sciences (Thousand Oaks, Calif.) 39 32046450
2011 Wnt-4 protects thymic epithelial cells against dexamethasone-induced senescence. Rejuvenation research 39 21453014
2008 WNT4 and sex development. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 39 18987495
2006 Wnt-4 expression is increased in fibroblasts after TGF-beta1 stimulation and during fetal and postnatal wound repair. Plastic and reconstructive surgery 39 16772932
2009 WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival. Molecular and cellular endocrinology 38 19962424
2013 Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis. Cell death and differentiation 37 23645207
2009 Mapping of the fate of cell lineages generated from cells that express the Wnt4 gene by time-lapse during kidney development. Differentiation; research in biological diversity 37 19740593
2003 Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 37 14689056
2019 Wnt4-modified NSC transplantation promotes functional recovery after spinal cord injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 31914702
2018 Icariin Ameliorate Thiram-Induced Tibial Dyschondroplasia via Regulation of WNT4 and VEGF Expression in Broiler Chickens. Frontiers in pharmacology 36 29527166
2015 Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Experimental cell research 36 25645944
2021 A circular RNA, circUSP36, accelerates endothelial cell dysfunction in atherosclerosis by adsorbing miR-637 to enhance WNT4 expression. Bioengineered 34 34519627
2011 Ovary-predominant wnt4 expression during gonadal differentiation is not conserved in the rainbow trout (Oncorhynchus mykiss). Molecular reproduction and development 34 22125114
2013 Regulation of Wnt4 in chronic obstructive pulmonary disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 23463699
2009 Generation of an allele to inactivate Wnt4 gene function conditionally in the mouse. Genesis (New York, N.Y. : 2000) 33 19830824
2015 Association of WNT4 polymorphisms with endometriosis in infertile patients. Journal of assisted reproduction and genetics 31 26139156
2007 Conditional expression of Wnt4 during chondrogenesis leads to dwarfism in mice. PloS one 31 17505543
2019 Wnt family member 4 (WNT4) and WNT3A activate cell-autonomous Wnt signaling independent of porcupine O-acyltransferase or Wnt secretion. The Journal of biological chemistry 30 31740580
2006 Adenovirus-delivered DKK3/WNT4 and steroidogenesis in primary cultures of adrenocortical cells. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 30 16981135
2016 Dysfunction of WNT4/WNT5A in deciduas: possible relevance to the pathogenesis of preeclampsia. Journal of hypertension 29 26848991
2019 Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 31216173
2018 Transcriptomic analysis of Portunus trituberculatus reveals a critical role for WNT4 and WNT signalling in limb regeneration. Gene 28 29524579
2011 Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic β-cell proliferation. American journal of physiology. Endocrinology and metabolism 28 21771967
2014 Identification and embryonic expression of Wnt2, Wnt4, Wnt5 and Wnt9 in the millipede Glomeris marginata (Myriapoda: Diplopoda). Gene expression patterns : GEP 26 24398121
2008 Negative regulation of the Wnt signal by MM-1 through inhibiting expression of the wnt4 gene. Experimental cell research 26 18281035
2006 Differential expression of WNT4 in testicular and ovarian development in a marsupial. BMC developmental biology 26 17014734
2016 WNT4 mediates the autocrine effects of growth hormone in mammary carcinoma cells. Endocrine-related cancer 25 27323961
2012 WT1 and Sox11 regulate synergistically the promoter of the Wnt4 gene that encodes a critical signal for nephrogenesis. Experimental cell research 25 22465478
2024 Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration. Molecular therapy : the journal of the American Society of Gene Therapy 24 38429926
2020 Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4. Cancers 24 33053661
2016 Anti-cancer drug 3,3'-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis. Oncotarget 23 26918831
2022 Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function. Nature communications 22 36271049
2016 Molecular cloning, characterization and expression analysis of Wnt4, Wnt5, Wnt6, Wnt7, Wnt10 and Wnt16 from Litopenaeus vannamei. Fish & shellfish immunology 22 27153750
2015 Wnt4 signaling is associated with the decrease of proliferation and increase of apoptosis during age-related thymic involution. Molecular medicine reports 22 26397044
2009 Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros. Development (Cambridge, England) 21 19793883
2021 E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling. Development (Cambridge, England) 19 33441379
2018 Wnt4 is significantly upregulated during the early phases of cisplatin-induced acute kidney injury. Scientific reports 19 30002385
2014 Association of CDKN2B-AS and WNT4 genetic polymorphisms in Korean patients with endometriosis. Fertility and sterility 19 25154675

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