Affinage

WNT3

Proto-oncogene Wnt-3 · UniProt P56703

Length
355 aa
Mass
39.6 kDa
Annotated
2026-06-11
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNT3 is a secreted, lipid-modified morphogen that drives canonical Wnt/β-catenin signaling to control axis formation, organizer induction, and tissue patterning across vertebrates (PMID:10431240, PMID:23085236). In the mouse embryo it is essential for primitive streak formation, mesoderm specification, and node formation; Wnt3-null epiblast proliferates but fails to gastrulate (PMID:10431240), with epiblast-derived WNT3 required to maintain gastrulation and to sustain its own and primitive-streak marker expression through β-catenin (PMID:23085236, PMID:18028899), while visceral-endoderm WNT3 sets the timing and position of streak formation (PMID:25907228). WNT3 also establishes and maintains the limb apical ectodermal ridge upstream of BMP signaling via ectodermal β-catenin (PMID:12569130), and a homozygous nonsense mutation (Q83X) causes human tetra-amelia, establishing WNT3 as required for the earliest stages of limb formation (PMID:14872406). Mechanistically, WNT3 engages Frizzled receptors (FZD7, Fzd1) together with the LRP5 co-receptor to stabilize β-catenin and activate TCF-dependent transcription (PMID:18313787, PMID:33236989, PMID:20039315). Its signaling competence depends on post-translational lipid modification: palmitoylation at a conserved serine (S212), and lipidation that targets WNT3 to cholesterol-dependent ordered membrane domains, is dispensable for secretion but essential for receptor engagement and pathway activation (PMID:27463143, PMID:31803740, PMID:34124053); N-glycosylation at Asn90/Asn301 further controls protein stability and FZD7 binding (PMID:38994173). Extracellular WNT3 spreads by HSPG-modulated diffusion and by cytoneme-based intercellular transport regulated by Flotillin-2 and Ror2 (PMID:33236989, PMID:36040316). Beyond canonical signaling, WNT3 acts through β-catenin-independent routes—RhoA/ROCK in myeloma adhesion and MAPK/ERK in cerebellar progenitors (PMID:17575106, PMID:24303070)—and regulates neural development, adult hippocampal neurogenesis, and intestinal Paneth-cell niche maintenance (PMID:21746862, PMID:26245956, PMID:36464209). Its expression is tightly controlled by transcriptional inputs and feedback, including Sp5-mediated repression, YAP-mediated enhancer silencing, Twist induction downstream of TGF-β/Smad3, and NEDD4L-mediated protein degradation (PMID:30659200, PMID:29269485, PMID:28337662, PMID:36597142).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established that WNT3 is genetically required for the founding event of the vertebrate body plan—primitive streak and mesoderm formation—resolving whether a single Wnt ligand is essential for gastrulation.

    Evidence Wnt3-null knockout mouse with marker analysis and histology

    PMID:10431240

    Open questions at the time
    • Does not identify the receptor/co-receptor mediating the gastrulation signal
    • Does not distinguish canonical vs non-canonical signaling in the epiblast
  2. 2003 High

    Placed ectodermal WNT3/β-catenin signaling upstream of BMP in apical ectodermal ridge establishment, defining its role in limb induction and dorsoventral polarity.

    Evidence Wnt3 KO plus conditional ectodermal β-catenin KO with epistasis to BMP

    PMID:12569130

    Open questions at the time
    • Receptor identity in the ectoderm not defined
    • Mechanism linking β-catenin to BMP induction unresolved
  3. 2004 High

    Demonstrated that WNT3 loss-of-function causes human tetra-amelia, translating the mouse limb phenotype into a Mendelian disease and confirming an essential role in human limb formation.

    Evidence Homozygosity mapping and sequencing of a nonsense Q83X mutation in a consanguineous family

    PMID:14872406

    Open questions at the time
    • Does not establish residual protein function of the truncation
    • No mechanistic readout in human tissue
  4. 2007 High

    Refined the source of the gastrulation signal by showing epiblast-intrinsic WNT3 activity, not posterior visceral endoderm, is required for primitive streak and mesoderm induction.

    Evidence Chimeric analysis and tissue-specific conditional Wnt3 KO with marker analysis

    PMID:18028899

    Open questions at the time
    • Does not address visceral endoderm contribution to timing
    • Downstream targets not enumerated
  5. 2007 Medium

    Revealed a β-catenin-independent WNT3 output by showing it drives myeloma cell adhesion and drug resistance through RhoA/ROCK.

    Evidence siRNA knockdown, Y27632 ROCK inhibitor, sFRP1 competition, Dkk1 negative control in adhesion assays

    PMID:17575106

    Open questions at the time
    • Receptor mediating RhoA activation not identified
    • Single lab, one cancer context
  6. 2008 Medium

    Provided direct biochemical evidence that WNT3 binds FZD7 to activate canonical β-catenin/TCF signaling, identifying a physical receptor partner.

    Evidence Co-immunoprecipitation, FZD7 siRNA, TCF reporter in HCC cells

    PMID:18313787

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Co-receptor requirement not tested here
  7. 2008 High

    Defined a genetic antagonist-agonist balance between Dkk1 and WNT3 governing head morphogenesis, establishing dose-sensitive regulation of WNT3 activity.

    Evidence Compound heterozygous mouse genetics and dose-dependent rescue

    PMID:18403408

    Open questions at the time
    • Molecular mechanism of Dkk1 antagonism of WNT3 not dissected here
  8. 2010 Medium

    Mapped WNT3 signaling determinants by chimeric and deletion analysis, showing the Fz cytoplasmic/PDZ tail, the CRD second cysteine loop, and LRP co-receptor are required for TCF activation and lineage decisions.

    Evidence Wnt3-Fz1 chimera, deletion mutagenesis, DKK-1 inhibition, osteoblast/adipocyte differentiation assays

    PMID:20039315

    Open questions at the time
    • Chimeric system may not reflect native ligand behavior
    • Single lab
  9. 2012 High

    Distinguished initiation from maintenance of gastrulation, showing epiblast WNT3 sustains the streak and autoregulates its own expression via β-catenin.

    Evidence Epiblast-specific conditional KO with primitive streak marker and pathway target analysis

    PMID:23085236

    Open questions at the time
    • Identity of the initiating signal independent of WNT3 not defined
  10. 2015 High

    Completed the spatial logic of streak formation by showing visceral-endoderm WNT3 controls streak timing and position, complementing the epiblast requirement.

    Evidence Visceral-endoderm-specific conditional Wnt3 KO with morphological/molecular analysis

    PMID:25907228

    Open questions at the time
    • Cross-tissue signaling mechanism between endoderm and epiblast not resolved
  11. 2016 High

    Established that lipid modification targets WNT3 to cholesterol-dependent membrane domains in vivo, linking Porcupine palmitoylation to membrane organization.

    Evidence SPIM-FCS in live zebrafish, Porcupine inhibitor C59, cholesterol depletion

    PMID:27463143

    Open questions at the time
    • Does not establish the signaling consequence of domain localization
  12. 2019 High

    Separated WNT3 secretion from signaling by showing serine palmitoylation is dispensable for secretion and Fz8 binding but essential for membrane-domain diffusion and β-catenin activation.

    Evidence Acylation-site mutagenesis with secretion, binding, diffusion, and reporter assays in zebrafish and mammalian cells

    PMID:31803740

    Open questions at the time
    • Precise structural basis of domain-dependent receptor engagement unresolved
  13. 2020 High

    Quantified WNT3 receptor engagement, showing Fzd1 binding requires the LRP5 co-receptor and that HSPGs shape its extracellular gradient.

    Evidence FCS/FCCS binding affinity, FRAP, LRP5 manipulation in zebrafish brain

    PMID:33236989

    Open questions at the time
    • Does not connect gradient parameters to specific developmental outputs
  14. 2021 High

    Resolved the dual-lipidation logic of WNT3, showing C80 or S212 lipidation suffices for secretion/membrane organization but S212 is specifically required for receptor interaction and signaling.

    Evidence C80A and S212A mutagenesis with secretion, membrane, receptor, and signaling readouts in zebrafish

    PMID:34124053

    Open questions at the time
    • The acyltransferase specificity for each site not defined in this study
  15. 2022 High

    Identified cytoneme-based transport as a route for WNT3 intercellular delivery, regulated by Flotillin-2 and Ror2 and conserved with Wnt8a.

    Evidence Live cytoneme imaging in gastric cancer cells, Flot2/Ror2 manipulation, zebrafish Wnt8a comparison

    PMID:36040316

    Open questions at the time
    • How cytoneme delivery integrates with diffusive spread in vivo not resolved
  16. 2024 Medium

    Showed N-glycosylation at Asn90/Asn301 controls WNT3 stability and FZD7 binding, adding a second post-translational layer to receptor competence.

    Evidence N-glycosylation site mutagenesis, stability assay, FZD7 co-localization, function assays in HCC cells

    PMID:38994173

    Open questions at the time
    • Single lab
    • Interplay with lipidation not tested
  17. 2023 Medium

    Established post-translational control of WNT3 abundance by showing NEDD4L ubiquitinates WNT3 for degradation, antagonized by the pro-renin receptor.

    Evidence Co-localization, (P)RR CRISPR knock-in mice, ubiquitination western blots in CRC

    PMID:36597142

    Open questions at the time
    • Direct ubiquitination of WNT3 by NEDD4L not reconstituted
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple transcriptional regulators (Sp5, YAP, Twist, HNF4α, ZFX), the lipidation/glycosylation modifications, and the diffusive vs cytoneme transport modes are integrated to produce context-specific canonical vs non-canonical WNT3 outputs remains unresolved.
  • No unified model linking PTM state to canonical vs RhoA/ERK output
  • Receptor-context determinants of pathway choice undefined
  • In vivo relevance of cancer-context regulators to development untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3
Partners
DKK1FLOT2FZD1FZD7LRP5NEDD4LROR2

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Wnt3 is required for primitive streak formation, mesoderm specification, and primary axis formation in mice; Wnt3-null embryos fail to form a primitive streak, mesoderm, or node, while the epiblast continues to proliferate in an undifferentiated state, demonstrating Wnt3's essential role in gastrulation. Knockout mouse (Wnt3-/- loss-of-function), in situ hybridization for expression pattern, histological analysis Nature genetics High 10431240
2003 Ectodermal Wnt3 signals through β-catenin to establish and maintain the apical ectodermal ridge (AER) during limb development; conditional removal of β-catenin in ventral ectoderm phenocopies Wnt3 loss, and Wnt/β-catenin signaling lies upstream of BMP signaling in AER establishment and dorsoventral polarity. Wnt3 knockout mouse, conditional β-catenin knockout in ectoderm, epistasis analysis with BMP pathway Genes & development High 12569130
2004 A homozygous nonsense mutation (Q83X) in WNT3 causes tetra-amelia (complete absence of all four limbs) with craniofacial and urogenital defects in humans, establishing WNT3 as required at the earliest stages of human limb formation. Homozygosity mapping, sequencing of WNT3 in affected family members, identification of loss-of-function mutation American journal of human genetics High 14872406
2008 Wnt3 physically interacts with the Frizzled-7 (FZD7) receptor as demonstrated by co-immunoprecipitation, and this interaction activates the canonical Wnt/β-catenin pathway (β-catenin accumulation, TCF transcriptional activity) in hepatocellular carcinoma cells; FZD7 siRNA knockdown abolishes Wnt3-driven pathway activation. Co-immunoprecipitation (Wnt3-FZD7 interaction), siRNA knockdown of FZD7, TCF transcriptional reporter assay, overexpression of Wnt3 in FOCUS HCC cells Journal of hepatology Medium 18313787
2008 Dkk1 antagonizes Wnt3 signaling during head morphogenesis; compound Dkk1/Wnt3 heterozygous embryos show head truncation and trunk malformation not seen in single heterozygotes, and reducing Wnt3 dose in Dkk1-/- embryos partially rescues head truncation, establishing a genetic antagonist-agonist relationship between Dkk1 and Wnt3. Compound heterozygous mouse genetics, genetic epistasis (double mutant rescue) Development (Cambridge, England) High 18403408
2007 Wnt3 drives cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells via a non-canonical Wnt/RhoA/ROCK signaling pathway (not canonical Dkk1-sensitive β-catenin); siRNA knockdown of Wnt3 reduces adhesion and reverses drug resistance, while Rho kinase inhibitor Y27632 and sFRP1 (Wnt receptor competitor) also abrogate the phenotype. siRNA knockdown of Wnt3, Rho kinase inhibitor (Y27632), sFRP1 competition assay, Dkk1 (canonical inhibitor) as negative control, co-culture adhesion assays Molecular cancer therapeutics Medium 17575106
2000 Wnt-3 regulates expression of cyclooxygenase-2 and periostin in mouse mammary epithelial cells through a β-catenin-independent pathway; overexpression of β-catenin or antisense knockdown of β-catenin had no effect on COX-2 or periostin expression, while Wnt-3 and GSK-3 inhibition regulated these genes. Retroviral Wnt-3 infection of mammary epithelial cells, gene expression profiling, β-catenin overexpression and antisense knockdown as controls, GSK-3 inhibition The Journal of biological chemistry Medium 10884377
2012 Wnt3 expression in the epiblast is required for maintenance (but not initiation) of gastrulation; conditional epiblast-specific Wnt3 knockout embryos initiate gastrulation but fail to sustain it, and Wnt3 regulates its own expression and that of primitive streak markers via canonical Wnt/β-catenin signaling. Conditional knockout (epiblast-specific Cre), in situ hybridization for primitive streak markers, β-catenin pathway target gene analysis Developmental biology High 23085236
2007 Wnt3 function in the epiblast (not the posterior visceral endoderm) is required for induction of the primitive streak and mesoderm, as shown by chimeric analyses and conditional removal of Wnt3 activity specifically in epiblast vs. visceral endoderm. Chimeric embryo analysis, conditional Wnt3 knockout in epiblast vs. visceral endoderm, molecular marker analysis Developmental biology High 18028899
2015 Wnt3 in the posterior visceral endoderm (extra-embryonic tissue) is required for timely formation of the primitive streak; absence of Wnt3 in the visceral endoderm causes delayed primitive streak formation and reveals that interplay between anterior and posterior visceral endoderm restricts primitive streak position. Conditional knockout of Wnt3 specifically in visceral endoderm, embryo morphological and molecular analysis Developmental biology High 25907228
2013 WNT3 suppresses cerebellar granule cell progenitor (GCP) proliferation and medulloblastoma growth through a non-canonical pathway activating MAPK/ERK1/2 and ERK5 (not β-catenin); MEK inhibitor reverses WNT3's anti-proliferative effect, and WNT3 downregulates SHH/Atoh1 pro-proliferative target genes. In vitro GCP proliferation assays, mouse medulloblastoma models, MEK inhibitor treatment, target gene expression analysis PloS one Medium 24303070
2012 WNT3 overexpression activates canonical Wnt/β-catenin signaling (increased nuclear β-catenin, TCF activity), transactivates EGFR expression, and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells; siRNA knockdown of Wnt3 restores cytoplasmic β-catenin, decreases EGFR, and reduces invasiveness. Stable Wnt3 transfection, siRNA knockdown, Western blot for β-catenin nuclear localization, EGFR expression analysis, invasion assays Molecular cancer research : MCR Medium 23071104
2011 Hippocampal astrocytes secrete Wnt3 as a paracrine factor to promote neural stem cell differentiation; reduction in Wnt3-secreting astrocytes and Wnt3 protein levels during aging impairs adult neurogenesis; exercise rescues impaired neurogenesis by increasing de novo Wnt3 expression. Wnt3 protein quantification in aging brain, correlation with neurogenesis markers, exercise intervention in aged animals FASEB journal Medium 21746862
2016 Wnt3 knockdown in the ventral hippocampus leads to impaired Wnt/β-catenin signaling, neurogenesis deficits, and depression-like behaviors; overexpression of Wnt3 reverses chronic restraint stress-induced depression-like behaviors; Wnt3 activates CREB, and there is a CREB-dependent positive feedback between Wnt2 and Wnt3. Hippocampal Wnt3 knockdown by stereotaxic viral injection, Wnt3 overexpression, behavioral assays for depression, neurogenesis analysis, CREB pathway analysis Translational psychiatry Medium 27622936
2017 YAP binds to the WNT3 gene enhancer and prevents its induction by Activin/SMAD signaling in proliferating hESCs; CRISPR/CAS9 knockout of YAP enables Activin to induce Wnt3 expression, which stabilizes β-catenin and synergizes with Activin-induced SMADs to activate cardiac mesoderm genes; YAP impairs SMAD recruitment and P-TEFb-associated RNAPII CTD-Ser7 phosphorylation at the WNT3 gene. ChIP-seq, CRISPR/CAS9 knockout of YAP in hESCs, Wnt3 expression analysis, β-catenin stabilization measurement, cardiomyocyte differentiation assay Genes & development High 29269485
2013 WNT3 expression level in hESCs predicts definitive endoderm (DE) differentiation potential; WNT3 knockdown inhibits and overexpression promotes DE differentiation in a WNT3 level-dependent manner. WNT3 knockdown and overexpression in hESCs, DE differentiation assays, correlation of mRNA levels with differentiation efficiency Stem cell reports Medium 24052941
2015 WNT3 protein is expressed specifically in the trophectoderm of human blastocysts and, together with membrane-associated β-catenin, promotes trophoblast progenitor development; WNT3 addition to culture medium promotes EOMES expression specific for trophoblast development, and these effects are not mediated via canonical TCF1 target genes. WNT3 protein localization by immunostaining of human blastocysts, β-catenin gain/loss-of-function with pharmacological agents, EOMES and CDX2 expression readouts Molecular human reproduction Medium 26108805
2015 Thalamic WNT3 secretion regulates the ribosomal protein composition (ribosome signature) in the developing neocortex; thalamic WNT3 promotes change in ribosomal protein L7 levels in polysomes and regulates translation of Foxp2 (promoting FOXP2 expression) and Apc (inhibiting APC expression), thereby driving neuronal differentiation and suppressing oligodendrocyte maturation. Polysome profiling, ribosomal protein analysis, WNT3 source identification (thalamic axons), RNA sequencing of polysome-associated mRNAs, in vivo manipulation The Journal of neuroscience Medium 26245956
2016 In zebrafish, Wnt3 is associated with cholesterol-dependent membrane domains (lipid rafts) at the plasma membrane in vivo; this association is dependent on palmitoylation by Porcupine (chemical inhibition of Porcupine reduces Wnt3 membrane domain association), and reduction of membrane cholesterol also decreases Wnt3 domain association. SPIM-FCS (single plane illumination microscopy-fluorescence correlation spectroscopy) in live transgenic zebrafish, FCS diffusion law analysis, Porcupine inhibitor (C59) treatment, cholesterol depletion Biophysical journal High 27463143
2019 Palmitoylation of Wnt3 at a conserved serine residue is dispensable for secretion and Fz8 binding but is essential for Wnt3's proper binding and diffusion in ordered (cholesterol-dependent) membrane domains; non-palmitoylated Wnt3 cannot activate Wnt/β-catenin signaling in zebrafish embryos or mammalian cells. Site-directed mutagenesis of Wnt3 acylation site, secretion assays, Fz8 binding assays, membrane domain diffusion measurements, Wnt/β-catenin reporter assay in zebrafish embryos and mammalian cells Frontiers in cell and developmental biology High 31803740
2021 Zebrafish Wnt3 is lipidated at both conserved cysteine (C80) and serine (S212) residues; lipid modification at either C80 or S212 is sufficient for secretion and membrane organization, but lipid modification at S212 is specifically required for receptor interaction and signaling activity. Site-directed mutagenesis of C80A and S212A in zebrafish Wnt3, secretion assays, membrane organization analysis, receptor interaction assays, signaling activity measurement Frontiers in cell and developmental biology High 34124053
2020 Wnt3 distributes extracellularly in the zebrafish brain via a diffusive mechanism modified by tissue morphology and interactions with heparan sulfate proteoglycans (HSPGs); binding to its receptor Frizzled1 (Fzd1) requires the co-receptor LRP5 (determined by fluorescence cross-correlation spectroscopy); HSPG interaction modulates Wnt3 gradient formation. Fluorescence correlation spectroscopy (FCS), fluorescence cross-correlation spectroscopy (FCCS) for Fzd1 binding affinity, fluorescence recovery after photobleaching (FRAP), LRP5 manipulation eLife High 33236989
2022 Gastric cancer cells transport Wnt3 intercellularly via cytonemes to promote proliferation and cell survival; the scaffolding protein Flotillin-2 (Flot2), together with the co-receptor Ror2, modulates the number and length of Wnt3 cytonemes; Flotillin-mediated cytoneme transport of Wnt8a also occurs in zebrafish embryogenesis, suggesting a conserved mechanism. Live imaging of cytonemes in gastric cancer cells, Flot2 and Ror2 manipulation, zebrafish embryo Wnt8a cytoneme analysis, cell proliferation/survival assays eLife High 36040316
2010 Wnt3 promotes neurite outgrowth in spinal cord neural precursor-derived neurons through β-catenin- and TCF4-dependent transcription; Wnt3 also transiently enhances SCNP proliferation and increases neurogenesis through β-catenin signaling (distinct from Wnt3a which causes sustained proliferation increase). Wnt3 treatment of spinal cord neural precursors, β-catenin signaling readouts, TCF4-dependent transcription assays, GSK-3β inhibitor comparison Journal of neuroscience research Medium 20722074
2013 Temozolomide methylates the promoter of the WNT3 gene in blood-brain barrier endothelial cells, reducing Wnt3 synthesis and disrupting the Wnt3/GSK3/β-catenin signaling, which reduces β-catenin binding to the MDR1 (ABCB1/Pgp) gene promoter and decreases P-glycoprotein expression. Promoter methylation analysis, Wnt3 expression measurement after temozolomide treatment, β-catenin ChIP on MDR1 promoter, Pgp expression and functional assays Cellular and molecular life sciences Medium 23771630
2017 TGF-β induces Wnt3 upregulation during EMT in HER2-overexpressing breast cancer cells via a Smad3-dependent mechanism; Twist transcription factor occupies the Wnt3 promoter (confirmed by ChIP) and is required for TGF-β-induced Wnt3 induction; Twist shRNA knockdown reduces Wnt3 expression. ChIP assay for Twist at Wnt3 promoter, Smad3 pathway inhibition, shRNA knockdown of Twist, secreted Wnt3 ELISA Breast cancer research and treatment Medium 28337662
2012 Wnt3 and Wnt3a are both required for induction of the mid-diencephalic organizer (MDO) in zebrafish; loss of Wnt3/Wnt3a prevents MDO induction by increasing apoptosis in the organizer primordium via Tp53-mediated apoptosis; canonical Wnt pathway activation rescues MDO formation in Wnt3/Wnt3a compound morphants. Morpholino knockdown of Wnt3 and Wnt3a in zebrafish, pharmacological Wnt pathway activation, apoptosis assays, Tp53 pathway analysis Neural development Medium 22475147
2009 In Hydra, apoptosis among interstitial cells at the head-regenerating site is both necessary and sufficient to induce Wnt3 production and head regeneration; Wnt3 from epithelial cells triggers head regeneration via morphallaxis; apoptosis-driven Wnt3 induction can cause ectopic head regeneration. Wnt3 expression analysis at regenerating tips, apoptosis induction/inhibition experiments, ectopic apoptosis induction, Hydra depleted of interstitial stem cells Developmental cell High 19686688
2011 In Hydra, a Wnt/β-catenin autoregulatory element and a repressor element combinatorially control HyWnt3 transcription to restrict expression to the head organizer; the autoregulatory element mediates direct β-catenin signaling input to activate HyWnt3, while the repressor element restricts its activity spatially. cis-regulatory element analysis, reporter gene assays for autoregulatory vs. repressor elements in Hydra Proceedings of the National Academy of Sciences of the United States of America Medium 21576458
2019 In Hydra, Sp5 acts as a transcriptional repressor of Wnt3 and is positively regulated by Wnt/β-catenin signaling, forming a negative feedback loop; Sp5 knockdown causes a multiheaded phenotype; both Hydra and zebrafish Sp5 repress Wnt3 promoter activity in reporter assays. Sp5 knockdown in Hydra (RNAi), Wnt3 promoter-reporter assays, zebrafish Sp5 assays, β-catenin/TCF interaction analysis Nature communications High 30659200
2018 Wnt3 inhibits axon regeneration in adult dorsal root ganglion (DRG) neurons by repressing mRNA translation of the transcription factor Gata4 via binding to the Gata4 3'UTR; downregulation of Gata4 reverses the phenotype of Wnt3 knockdown, establishing Wnt3-Gata4 as a regulatory axis for axon growth. Wnt3 overexpression and knockdown in adult DRG neurons, in vitro and in vivo axon regeneration assays, 3'UTR binding assay, Gata4 knockdown rescue experiment Biochemical and biophysical research communications Medium 29567480
2010 Wnt3 chimera with Frizzled-1 (Wnt3-Fz1) constitutively activates TCF-luciferase reporter; deletion of the Fz cytoplasmic tail or PDZ-binding region abolishes signaling; deletion of 29 amino acids in the 2nd cysteine loop of the CRD domain eliminates TCF activation; LRP (co-receptor) is required as DKK-1 blocks signaling; Wnt3-Fz1 promotes osteoblast and inhibits adipocyte differentiation. Wnt3-Fz1 chimera construction, deletion mutagenesis, TCF-luciferase reporter assay, DKK-1 inhibition, alkaline phosphatase and adipogenesis assays Journal of cellular biochemistry Medium 20039315
2023 The pro-renin receptor ((P)RR) promotes Wnt3 protein accumulation by inhibiting NEDD4L-mediated ubiquitination of Wnt3, thereby preventing Wnt3 protein degradation and activating Wnt/β-catenin signaling in colorectal cancer. Co-localization analysis of Wnt3 and NEDD4L by immunofluorescence, (P)RR knock-in mice (CRISPR/Cas9), western blotting for ubiquitination, immunohistochemistry in CRC specimens Cell communication and signaling : CCS Medium 36597142
2022 HNF4α transcriptionally regulates Wnt3 expression in intestinal epithelial cells and thereby controls Paneth cell fate and intestinal stem cell niche maintenance; deletion of Hnf4a in jejunal enteroids causes loss of Wnt3 expression and Paneth cell differentiation defects, which are rescued by Wnt3a supplementation or co-culture with mesenchymal cells. Hnf4a conditional knockout in jejunal enteroids, transcriptomic analysis, Wnt3a supplementation rescue, mesenchymal cell co-culture rescue Cellular and molecular gastroenterology and hepatology High 36464209
2024 Wnt3 has two N-glycosylation sites (Asn90 and Asn301); mutation of Asn301 alone reduces Wnt3 protein stability; simultaneous mutation of both sites decreases Wnt3-FZD7 binding and reduces Wnt/β-catenin pathway activation; single and double N-glycosylation site mutations impair HCC cell proliferation, migration, and invasion. Site-directed mutagenesis of N-glycosylation sites, actinomycin D stability assay, laser confocal microscopy for Wnt3-FZD7 co-localization, western blot for pathway proteins, cell function assays World journal of gastrointestinal oncology Medium 38994173
2017 Defective Wnt3 expression in post-pubertal Sertoli cells (curtailed by shRNA in transgenic mice) causes subfertility and oligozoospermia, with diminished expression of Connexin43 (a gap-junctional molecule essential for germ cell development), establishing Wnt3 as an FSH- and testosterone-regulated Sertoli cell paracrine factor required for spermatogenesis. Transgenic mouse with Sertoli cell-specific Wnt3 shRNA knockdown, fertility and sperm count analysis, Connexin43 expression measurement, microarray of infant vs. pubertal Sertoli cells Cell and tissue research Medium 29064078
2021 Wnt3 is transported along motor axons in vivo in a vesicular-like pattern and reaches the neuromuscular junction (NMJ) area; NSC-34 cells overexpressing Wnt3 induce acetylcholine receptor clustering on co-cultured myotubes, supporting a presynaptic Wnt3 role in postsynaptic differentiation at nascent NMJs. In ovo electroporation for Wnt3-EGFP in chick motor neurons, live axonal transport imaging, NSC-34 cell transfection, AChR clustering assay on co-cultured myotubes Biomolecules Medium 34944540
2023 ZFX transcriptionally regulates WNT3 expression in CML stem/progenitor cells; ZFX silencing decreases WNT3/β-catenin signaling (including c-MYC and CCND1); WNT3 overexpression partially rescues ZFX silencing-induced growth inhibition and imatinib hypersensitivity, establishing a ZFX/WNT3/β-catenin axis in CML. ChIP and luciferase reporter assay for ZFX at WNT3 promoter, shRNA/CRISPR dCas9 knockdown of ZFX, WNT3 overexpression rescue, microarray analysis Cellular & molecular biology letters Medium 37864206
2015 WNT3 knockdown in zebrafish causes cloaca malformations including disorganization of cloaca epithelium and expansion of cloaca lumen; overexpression of a WNT3 p.Cys91Arg patient variant (de novo mutation found in bladder exstrophy) does not cause embryonic lethality seen with wild-type WNT3 overexpression, suggesting the variant has altered function. Zebrafish wnt3 morpholino knockdown, RNA overexpression of wild-type vs. mutant Wnt3 (p.Cys91Arg), cloaca morphology analysis Human molecular genetics Medium 26105184

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Requirement for Wnt3 in vertebrate axis formation. Nature genetics 722 10431240
1993 Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. The Journal of neuroscience : the official journal of the Society for Neuroscience 523 7687285
2009 Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Developmental cell 329 19686688
2005 Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3. Developmental biology 237 16289026
2003 Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes & development 236 12569130
2012 Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Molecular cancer research : MCR 227 23071104
2004 Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. American journal of human genetics 208 14872406
1990 Wnt-3, a gene activated by proviral insertion in mouse mammary tumors, is homologous to int-1/Wnt-1 and is normally expressed in mouse embryos and adult brain. Proceedings of the National Academy of Sciences of the United States of America 187 2162045
2008 Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. Journal of hepatology 153 18313787
2011 Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 135 21746862
2019 CircRNA_100367 regulated the radiation sensitivity of esophageal squamous cell carcinomas through miR-217/Wnt3 pathway. Aging 127 31851619
2001 Molecular cloning and characterization of human WNT3. International journal of oncology 113 11604997
2011 Autoregulatory and repressive inputs localize Hydra Wnt3 to the head organizer. Proceedings of the National Academy of Sciences of the United States of America 93 21576458
2000 Regulation of cyclooxygenase-2 and periostin by Wnt-3 in mouse mammary epithelial cells. The Journal of biological chemistry 90 10884377
2008 Dkk1 and Wnt3 interact to control head morphogenesis in the mouse. Development (Cambridge, England) 89 18403408
2002 Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45. International journal of oncology 88 11788904
2007 Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. Molecular cancer therapeutics 79 17575106
2019 An evolutionarily-conserved Wnt3/β-catenin/Sp5 feedback loop restricts head organizer activity in Hydra. Nature communications 73 30659200
1992 Regional expression of the Wnt-3 gene in the developing mouse forebrain in relationship to diencephalic neuromeres. Mechanisms of development 69 1363370
2013 WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PloS one 63 24303070
2017 YAP repression of the WNT3 gene controls hESC differentiation along the cardiac mesoderm lineage. Genes & development 62 29269485
2016 The antidepressant roles of Wnt2 and Wnt3 in stress-induced depression-like behaviors. Translational psychiatry 62 27622936
2012 Wnt3 function in the epiblast is required for the maintenance but not the initiation of gastrulation in mice. Developmental biology 59 23085236
1994 Maintenance of Wnt-3 expression in Purkinje cells of the mouse cerebellum depends on interactions with granule cells. Development (Cambridge, England) 59 8026336
2007 Wnt3 signaling in the epiblast is required for proper orientation of the anteroposterior axis. Developmental biology 58 18028899
2022 Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model. Pharmaceuticals (Basel, Switzerland) 56 36015156
2010 Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling. Journal of neuroscience research 48 20722074
2013 Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling. Cellular and molecular life sciences : CMLS 46 23771630
2015 WNT3 and membrane-associated β-catenin regulate trophectoderm lineage differentiation in human blastocysts. Molecular human reproduction 45 26108805
2013 WNT3 is a biomarker capable of predicting the definitive endoderm differentiation potential of hESCs. Stem cell reports 45 24052941
2020 Circ_CHFR expedites cell growth, migration and inflammation in ox-LDL-treated human vascular smooth muscle cells via the miR-214-3p/Wnt3/β-catenin pathway. European review for medical and pharmacological sciences 44 32271446
2002 WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). International journal of molecular medicine 42 12011973
1997 Isolation of two novel WNT genes, WNT14 and WNT15, one of which (WNT15) is closely linked to WNT3 on human chromosome 17q21. Genomics 42 9441749
2015 Thalamic WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature and mRNA Translation to Specify Neocortical Cell Subtypes. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 26245956
2017 A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells. Breast cancer research and treatment 40 28337662
2003 Over- and ectopic expression of Wnt3 causes progressive loss of ameloblasts in postnatal mouse incisor teeth. Connective tissue research 40 12952185
2015 Extra-embryonic Wnt3 regulates the establishment of the primitive streak in mice. Developmental biology 39 25907228
2017 miR-1247-5p functions as a tumor suppressor in human hepatocellular carcinoma by targeting Wnt3. Oncology reports 38 28586038
2014 Mesenchymal-transitioned cancer cells instigate the invasion of epithelial cancer cells through secretion of WNT3 and WNT5B. Cancer science 37 24344732
2009 MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer letters 37 19815336
2016 The Secreted Signaling Protein Wnt3 Is Associated with Membrane Domains In Vivo: A SPIM-FCS Study. Biophysical journal 36 27463143
2012 Wnt3 and Wnt3a are required for induction of the mid-diencephalic organizer in the caudal forebrain. Neural development 36 22475147
2018 Mir-29b promotes human aortic valve interstitial cell calcification via inhibiting TGF-β3 through activation of wnt3/β-catenin/Smad3 signaling. Journal of cellular biochemistry 35 29227539
2007 Proliferation of neural stem cells correlates with Wnt-3 protein in hypoxic-ischemic neonate rats after hyperbaric oxygen therapy. Neuroreport 33 17921881
2019 Downregulation of Wnt3 Suppresses Colorectal Cancer Development Through Inhibiting Cell Proliferation and Migration. Frontiers in pharmacology 31 31632267
2017 MiR 376c inhibits osteoblastogenesis by targeting Wnt3 and ARF-GEF-1 -facilitated augmentation of beta-catenin transactivation. Journal of cellular biochemistry 31 29125885
2025 Inhibition of neutrophil extracellular traps alleviates blood-brain barrier disruption and cognitive dysfunction via Wnt3/β-catenin/TCF4 signaling in sepsis-associated encephalopathy. Journal of neuroinflammation 29 40102948
2016 Downregulation of human Wnt3 in gastric cancer suppresses cell proliferation and induces apoptosis. OncoTargets and therapy 29 27390525
2009 Zebrafish wnt3 is expressed in developing neural tissue. Developmental dynamics : an official publication of the American Association of Anatomists 29 19452545
2012 Functional consequences of WNT3/Frizzled7-mediated signaling in non-transformed hepatic cells. Oncogenesis 28 23552403
2018 TROAP regulates prostate cancer progression via the WNT3/survivin signalling pathways. Oncology reports 27 30431120
2015 Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell reports 26 25640183
2015 WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish. Human molecular genetics 26 26105184
2005 Comparative genomics on Wnt3-Wnt9b gene cluster. International journal of molecular medicine 26 15754041
2023 Anti-Alzheimer Activity of Combinations of Cocoa with Vinpocetine or Other Nutraceuticals in Rat Model: Modulation of Wnt3/β-Catenin/GSK-3β/Nrf2/HO-1 and PERK/CHOP/Bcl-2 Pathways. Pharmaceutics 24 37631278
1993 Molecular cloning and chromosomal localization to 17q21 of the human WNT3 gene. Genomics 24 8244403
2019 HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways. Cell transplantation 23 31694396
2017 Defective Wnt3 expression by testicular Sertoli cells compromise male fertility. Cell and tissue research 22 29064078
2004 Sonic hedgehog patterning in chick neural plate is antagonized by a Wnt3-like signal. Developmental dynamics : an official publication of the American Association of Anatomists 22 14991707
2016 Diabetes Impairs Wnt3 Protein-induced Neurogenesis in Olfactory Bulbs via Glutamate Transporter 1 Inhibition. The Journal of biological chemistry 21 27226528
2024 Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway. Journal of advanced research 20 38432393
2020 Wnt3 distribution in the zebrafish brain is determined by expression, diffusion and multiple molecular interactions. eLife 20 33236989
2018 The effects of letrozole and clomiphene citrate on ligands expression of Wnt3, Wnt7a, and Wnt8b in proliferative endometrium of women with Polycystic ovarian syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 19 29510649
2019 Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/β-catenin signalling. Artificial cells, nanomedicine, and biotechnology 18 31155960
2019 Overexpression of BMP‑7 reverses TGF‑β1‑induced epithelial‑mesenchymal transition by attenuating the Wnt3/β‑catenin and TGF-β1/Smad2/3 signaling pathways in HK‑2 cells. Molecular medicine reports 18 31974602
2016 Tanshinone I Enhances Neurogenesis in the Mouse Hippocampal Dentate Gyrus via Increasing Wnt-3, Phosphorylated Glycogen Synthase Kinase-3β and β-Catenin Immunoreactivities. Neurochemical research 18 27053301
2015 Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population. Genetics and molecular research : GMR 18 26505415
2019 More Favorable Palmitic Acid Over Palmitoleic Acid Modification of Wnt3 Ensures Its Localization and Activity in Plasma Membrane Domains. Frontiers in cell and developmental biology 17 31803740
2022 HNF4α Acts as Upstream Functional Regulator of Intestinal Wnt3 and Paneth Cell Fate. Cellular and molecular gastroenterology and hepatology 14 36464209
2016 Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations. Journal of enzyme inhibition and medicinal chemistry 14 27766889
2002 Molecular cloning and characterization of mouse Wnt14b, clustered with mouse Wnt3 in mouse chromosome 11. International journal of molecular medicine 14 11786923
2023 Single-cell RNA sequencing of intestinal crypts reveals vital events in damage repair and the double-edged sword effect of the Wnt3/β-catenin pathway in irradiated mice. Redox biology 13 37918127
2022 The scaffolding protein flot2 promotes cytoneme-based transport of wnt3 in gastric cancer. eLife 13 36040316
2018 Wnt3 and Gata4 regulate axon regeneration in adult mouse DRG neurons. Biochemical and biophysical research communications 12 29567480
2004 Wnt3 modulates the characteristics and cobblestone area-supporting activity of human stromal cells. Experimental hematology 12 15588944
2024 WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway. BMC cancer 11 38711026
2021 Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue. Frontiers in cell and developmental biology 11 34124053
2018 Wnt3 knockdown sensitizes human non-small cell type lung cancer (NSCLC) cells to cisplatin via regulating the cell proliferation and apoptosis. European review for medical and pharmacological sciences 11 29565490
2016 Altered Expression of PRKX, WNT3 and WNT16 in Human Nodular Basal Cell Carcinoma. Anticancer research 11 27630294
2022 The aOECs Facilitate the Neuronal Differentiation of Neural Stem Cells in the Inflammatory Microenvironment Through Up-Regulation of Bioactive Factors and Activation of Wnt3/β-Catenin Pathway. Molecular neurobiology 10 36371572
2020 Identification of candidate lncRNAs and circRNAs regulating WNT3/β-catenin signaling in essential hypertension. Aging 10 32392180
2020 MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells. Stem cells (Dayton, Ohio) 10 32997855
2022 Yiqi Jianpi Huayu Jiedu Decoction Inhibits Metastasis of Colon Adenocarcinoma by Reversing Hsa-miR-374a-3p/Wnt3/β-Catenin-Mediated Epithelial-Mesenchymal Transition and Cellular Plasticity. Frontiers in oncology 9 35837105
2021 WNT3 hypomethylation counteracts low activity of the Wnt signaling pathway in the placenta of preeclampsia. Cellular and molecular life sciences : CMLS 9 34608506
2023 (Pro)renin receptor promotes colorectal cancer progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota. Cell communication and signaling : CCS 8 36597142
2020 LncWNT3-IT affects the proliferation of Sertoli cells by regulating the expression of the WNT3 gene in goat testis. Reproduction in domestic animals = Zuchthygiene 7 32501574
2018 Association of the WNT3 polymorphisms and non-syndromic cleft lip with or without cleft palate: evidence from a meta-analysis. Bioscience reports 7 30355643
2010 Wnt3-frizzled 1 chimera as a model to study canonical Wnt signaling. Journal of cellular biochemistry 7 20039315
2023 A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells. Cellular & molecular biology letters 6 37864206
2021 Expression of Wnt3, β-catenin and MMP-7 in gastric cancer and precancerous lesions and their correlations with Helicobacter pylori infection. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 6 34275925
2010 Wnt-3 and Wnt-3a play different region-specific roles in neural crest development in avians. Cell biology international 6 19947940
2022 LINC01023 Promotes the Hepatoblastoma Tumorigenesis via miR-378a-5p/WNT3 Axis. Molecular and cellular biochemistry 5 36576714
2020 Wingless ligands and beta-catenin expression in the rat endometrium: The role of Wnt3 and Wnt7a/beta-catenin pathway at the embryo-uterine interface. Molecular reproduction and development 5 32949181
2012 Amphetamine stimulates Wnt3 increases in rat nucleus accumbens. Neuroreport 5 22922600
2024 N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway. World journal of gastrointestinal oncology 4 38994173
2023 Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell-derived Wnt3. Clinical science (London, England : 1979) 4 36503938
2007 [Changes of Wnt-3 protein during the proliferation of endogenous neural stem cells in neonatal rats with hypoxic-ischemic brain damage after hyperbaric oxygen therapy]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 4 17582265
2025 Organizer formation, organizer maintenance and epithelial cell plasticity in Hydra: Role of the Wnt3/β-catenin/TCF/Sp5/Zic4 gene network. Cells & development 3 39929422
2025 Impaired WNT3/IGF-1 Signaling in Dorsal Dentate Gyrus Contributes to Chronic Pain-Related Cognitive Impairment. CNS neuroscience & therapeutics 2 41414737
2021 Transport and Secretion of the Wnt3 Ligand by Motor Neuron-like Cells and Developing Motor Neurons. Biomolecules 2 34944540

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