Affinage

NDP

Norrin · UniProt Q00604

Length
133 aa
Mass
15.0 kDa
Annotated
2026-04-29
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Norrin, encoded by the NDP gene, is a secreted cystine-knot homodimeric growth factor that functions as a high-affinity, Frizzled-4 (FZD4)-specific ligand to activate canonical Wnt/β-catenin signaling, thereby controlling vascular development, blood–retina barrier and blood–brain barrier formation and maintenance, and neuroprotection. Norrin binds the FZD4 cysteine-rich domain via an extended β-sheet surface that overlaps the Wnt-binding site, recruits LRP5/6 co-receptors through a separate binding patch, and is selectively amplified by the co-receptor TSPAN12, which promotes FZD4 multimerization and enhances ligand selectivity (PMID:15035989, PMID:24186977, PMID:26158506, PMID:19837033). Signaling occurs predominantly in vascular endothelial cells, where it drives retinal and CNS angiogenesis, induces Sox17 and claudin-5, and maintains barrier integrity; in Müller glia, Norrin-stimulated β-catenin signaling induces neuroprotective growth factors (FGF2, BDNF, LIF, CNTF) that protect retinal neurons from excitotoxic damage (PMID:19837032, PMID:20427659, PMID:32086377). Loss-of-function mutations in NDP cause Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR), characterized by failed retinal vascularization, blindness, and in some cases hearing loss (PMID:8252044, PMID:15035989).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 Medium

    Establishing that NDP mutations cause not only Norrie disease but also X-linked FEVR unified two retinal vascular disorders under a single gene, framing NDP as central to retinal vascular development.

    Evidence Cosegregation of an NDP missense mutation (Leu124Phe) with FEVR in a four-generation family

    PMID:8252044

    Open questions at the time
    • Molecular function of Norrin protein was unknown
    • No receptor or signaling pathway identified
  2. 1997 High

    Biochemical characterization revealed Norrin as a secreted, disulfide-linked oligomer associated with extracellular matrix, establishing its identity as a diffusible signaling molecule and showing that disease mutations reduce ECM incorporation.

    Evidence Pulse-labeling, SDS-PAGE under reducing/non-reducing conditions, and Cys95 mutagenesis in COS-7 cells

    PMID:9407136

    Open questions at the time
    • Receptor identity unknown
    • Signaling pathway not identified
    • Physiological oligomeric state in vivo uncertain
  3. 2004 High

    Identification of FZD4 as Norrin's specific receptor and demonstration that Norrin activates canonical Wnt/β-catenin signaling in an LRP-dependent manner provided the first mechanistic explanation for retinal vascular phenotypes in Norrie disease, FEVR, and related disorders.

    Evidence Binding assays showing specificity for FZD4 over other Frizzleds, Wnt reporter assays, and mouse genetic models

    PMID:15035989

    Open questions at the time
    • Structural basis of Norrin–FZD4 interaction not resolved
    • Co-receptor requirements beyond LRP not explored
    • Endothelial cell-type specificity of signaling not yet demonstrated
  4. 2005 High

    Transgenic rescue of Ndp-knockout retinal vasculature by ectopic Norrin confirmed that Norrin directly drives capillary endothelial cell proliferation, and discovery of uterine vascular defects in female knockouts broadened Norrin's vascular role beyond the retina.

    Evidence Lens-specific Norrin transgene rescue in Ndp-KO mice; BrdU endothelial proliferation assays; histological analysis of Ndp-KO uteri

    PMID:15716406 PMID:16035034

    Open questions at the time
    • Downstream endothelial signaling targets uncharacterized
    • Uterine phenotype not confirmed by conditional approaches
  5. 2006 High

    Systematic mutagenesis mapped the Norrin–FZD4 CRD interface, showing Norrin and Wnt8 compete for overlapping FZD4 CRD epitopes and that heparin enhances binding ~10-fold, establishing Norrin as a Wnt-mimetic ligand.

    Evidence Site-directed mutagenesis of Norrin and FZD4 CRD, binding assays across 15 Frizzled/sFRP CRDs

    PMID:17158104

    Open questions at the time
    • No atomic-resolution structure available
    • Role of heparan sulfate proteoglycans in vivo not tested
  6. 2009 High

    Endothelial cell-specific conditional knockouts established that Norrin/FZD4/LRP5 signaling acts cell-autonomously in endothelial cells to control retinal and cerebellar vascular growth and BBB integrity, with Sox17 identified as a key downstream transcription factor; simultaneously, TSPAN12 was identified as a selective co-receptor that amplifies Norrin (but not Wnt) signaling by promoting FZD4 multimerization.

    Evidence Endothelial-specific Fz4 conditional KO mice; Tspan12 KO mice phenocopying Ndp/Fz4/Lrp5 mutants; reciprocal co-IP; Wnt reporter assays

    PMID:19837032 PMID:19837033

    Open questions at the time
    • TSPAN12's precise molecular mechanism of FZD4 multimerization unknown
    • Sox17 downstream targets in endothelium not delineated
  7. 2010 High

    Norrin's functional repertoire was expanded to include neuroprotection via Müller glia-mediated induction of growth factors (FGF2, BDNF, LIF, CNTF), and proangiogenic effects through angiopoietin-2 induction, both β-catenin-dependent, while FEVR-associated FZD4 CRD mutations were shown to abolish Norrin binding.

    Evidence Intravitreal Norrin injection in NMDA damage model; DKK-1 and anti-Ang-2 blocking; FZD4 CRD mutant binding and reporter assays in HEK293 and Xenopus

    PMID:20053900 PMID:20427659 PMID:21177847

    Open questions at the time
    • Whether neuroprotection occurs in vivo independently of vascular effects not fully resolved
    • Relative contributions of Ang-2 vs. other downstream effectors to angiogenesis unclear
  8. 2012 High

    Norrin signaling was shown to maintain blood–retina and blood–brain barriers in adults, not just during development, and a vascular quality-control mechanism was revealed whereby wild-type endothelial cells instruct but then eliminate Fz4-deficient neighbors.

    Evidence Conditional gain/loss-of-function Norrin/Fz4 mouse models, genetic mosaics, in vivo imaging; Ndp-KO morphometric and mitogenesis analysis

    PMID:22394677 PMID:23217714

    Open questions at the time
    • Molecular basis of endothelial quality-control elimination unknown
    • Adult barrier maintenance pathway details incomplete
  9. 2013 High

    Crystal structure of the Norrin homodimer revealed a novel cystine-knot dimer interface required for FZD4 activation and separate binding sites for FZD4 CRD and LRP5/6, providing the first atomic framework for ternary complex formation; a separate study reported Norrin can also engage LGR4 and antagonize BMPs, suggesting pathway complexity beyond FZD4.

    Evidence X-ray crystallography with mutagenesis and functional assays; binding and reporter assays for LGR4 interaction

    PMID:23444378 PMID:24186977

    Open questions at the time
    • LGR4 interaction not independently confirmed
    • BMP antagonism physiological significance unclear
    • No structure of ternary complex with LRP5/6
  10. 2015 High

    Co-crystal structures of Norrin–FZD4 CRD with and without GAG analogues demonstrated that Norrin mimics Wnt recognition of Frizzled and that a heparan sulfate binding site spanning the interface enhances signaling, providing a structural explanation for heparin's potentiating effect.

    Evidence X-ray crystallography, SAXS, biophysical binding assays, cellular signaling assays

    PMID:26158506

    Open questions at the time
    • No structure of full-length FZD4 in complex with Norrin
    • In vivo role of specific HS modifications not tested
  11. 2017 High

    TSPAN12's direct physical interaction with both FZD4 and Norrin was mapped to its extracellular loops, and Norrin was shown to trigger FZD4 ubiquitination and ESCRT-dependent internalization into the endo-lysosomal pathway, a step required for productive β-catenin signaling and CNS angiogenesis.

    Evidence Co-IP and mutagenesis of TSPAN12 loops; dominant-negative VPS4 EQ in vitro and in vivo mouse models; ubiquitination assays

    PMID:28658627 PMID:28675177

    Open questions at the time
    • E3 ubiquitin ligase responsible for FZD4 ubiquitination not identified
    • Stoichiometry of the Norrin–FZD4–TSPAN12 complex not determined
  12. 2018 High

    The FZD4 linker domain between CRD and transmembrane region was found to contribute ~10-fold binding affinity for Norrin and undergo conformational changes propagated to ICL3, providing the first evidence for how extracellular Norrin binding triggers intracellular signaling through receptor conformational dynamics; combinatorial genetic studies showed Norrin and Wnt7a/7b have partially redundant roles in BBB maintenance.

    Evidence HDX-MS of FZD4 with/without Norrin; FZD4 linker/ICL3 mutagenesis; double/triple conditional KO mice for Norrin and Wnt7a

    PMID:30104375 PMID:30478038

    Open questions at the time
    • Full receptor activation mechanism (G-protein vs. Dishevelled coupling) not resolved structurally
    • Threshold for Wnt/Norrin redundancy in human BBB unknown
  13. 2019 Medium

    Norrin's roles were extended to non-vascular contexts: cortical layer V astroglia-derived Norrin regulates neuronal dendritic spines, and dermal papilla-secreted Norrin promotes hair follicle growth via β-catenin signaling in keratinocytes.

    Evidence Transgenic reporter mice with dendritic spine analysis in Norrie disease model; EV-mediated Norrin delivery with siRNA knockdown and hair follicle growth assays

    PMID:30936556 PMID:31237401

    Open questions at the time
    • FZD4 dependence of dendritic spine phenotype not confirmed
    • Hair follicle findings from single lab, not independently replicated
    • Receptor identity in keratinocytes not established
  14. 2020 High

    Norrin restores blood–retinal barrier after VEGF-induced permeability by enriching claudin-5 at tight junctions in a β-catenin-dependent manner, with VEGF paradoxically enhancing Norrin responsiveness by increasing surface TSPAN12 via MEK/ERK signaling; separately, context-dependent Norrin signaling was shown in glioblastoma stem cells where Norrin can alternatively activate Notch independently of Wnt.

    Evidence Intravitreal injection in diabetic rats, TEER and permeability assays, siRNA; patient-derived GBM stem cells with ASCL1-dependent pathway switching

    PMID:32086377 PMID:32182224

    Open questions at the time
    • VEGF–TSPAN12–Norrin crosstalk not validated in human retinal endothelium
    • Norrin–Notch mechanism in GSCs not structurally characterized
    • Relevance of non-canonical Norrin signaling to normal physiology unknown
  15. 2021 High

    Discovery that CTNNA1 mutations cause FEVR through overactivation of Norrin/β-catenin signaling demonstrated that both insufficient and excessive pathway activation disrupt retinal vascularization, establishing a signaling-amplitude threshold model.

    Evidence Exome sequencing; endothelial-specific Ctnna1 KO and gain-of-function Ctnnb1 mice; VE-cadherin and F-actin analysis

    PMID:33497368

    Open questions at the time
    • Precise β-catenin activity thresholds for normal vs. pathological outcomes not quantified
    • Whether other FEVR genes also operate via gain-of-function not tested
  16. 2024 High

    Glutamatergic neuronal activity was shown to regulate retinal Norrin/β-catenin signaling in endothelial cells, linking sensory circuit activity to deep plexus angiogenesis and barrier maturation, and providing a neurovascular coupling mechanism for Norrin pathway regulation.

    Evidence Vglut1-KO and Gnat1-KO mouse models with scRNA-seq and pharmacological rescue of endothelial β-catenin signaling

    PMID:38599212

    Open questions at the time
    • Identity of the intermediate signal(s) between neurons and Norrin-producing cells unknown
    • Whether this neurovascular coupling extends to brain vasculature untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the cryo-EM or crystal structure of the full quaternary Norrin–FZD4–LRP5/6–TSPAN12 signaling complex, the identity of the E3 ligase mediating FZD4 ubiquitination, independent validation of Norrin–LGR4 and BMP-antagonist activities, the molecular intermediates by which neuronal activity regulates Norrin expression, and the in vivo significance of Norrin signaling outside the vasculature (dendrites, hair follicles, glioma).
  • No structure of the full signaling complex
  • E3 ubiquitin ligase for FZD4 unknown
  • LGR4 interaction and BMP antagonism await independent replication
  • Neurovascular coupling intermediates unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1500931 Cell-Cell communication 3
Partners
DVLFZD4LGR4LRP5LRP6TSPAN12
Complex memberships
Norrin–FZD4–LRP5/6–TSPAN12 receptor complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Norrin (NDP gene product) functions as a high-affinity ligand for Frizzled-4 (Fz4) receptor, binding specifically to Fz4 and not other Frizzled family members, and activates the classical Wnt/β-catenin pathway in an Fz4- and LRP-dependent manner to control vascular development in the retina and inner ear. Binding assays, Wnt pathway reporter assays, disease-associated variant functional analysis, mouse genetic models Cell High 15035989
2009 Norrin/Fz4/Lrp5 signaling acts specifically in endothelial cells to control retinal vascular growth; loss of Fz4 in endothelial cells causes defective vascular growth and disrupts the blood-brain barrier in the cerebellum; Sox17 is a downstream transcription factor upregulated by this signaling pathway that induces the angiogenic program. Conditional mouse knockouts (endothelial cell-specific), cell culture models, genetic epistasis Cell High 19837032
2009 TSPAN12 (tetraspanin-12) is a co-receptor component of the Norrin/Frizzled-4 signaling complex; TSPAN12 associates with the Norrin receptor complex, selectively amplifies Norrin/β-catenin (but not Wnt/β-catenin) signaling, and promotes FZD4 multimerization to achieve physiological signaling levels. Co-immunoprecipitation, siRNA knockdown, overexpression, reporter assays, mouse genetics (Tspan12 knockout phenocopying Norrin/Fz4/Lrp5 mutants) Cell High 19837033
2012 Norrin/Frizzled4 signaling maintains blood-retina barrier and blood-brain barrier function in adult animals in a cell-autonomous manner; precocious Norrin production leads to premature retinal vascular invasion; wild-type endothelial cells can non-cell-autonomously instruct neighboring Fz4-/- ECs to form architecturally normal vasculature, but Fz4-/- ECs are subsequently eliminated by a quality control program. Genetically engineered mice with conditional gain/loss of Norrin/Fz4 signaling, genetic mosaics, in vivo imaging Cell High 23217714
2013 Crystal structure of Norrin reveals a unique homodimer with each monomer adopting a cystine-knot fold; the novel dimer interface is required for Fz4 activation; Norrin contains separate binding sites for Fz4 CRD and for Lrp5/Lrp6, inducing formation of a ternary Norrin-Fz4-Lrp5/6 signaling complex. X-ray crystallography, mutational analysis, binding assays, functional reporter assays Genes & development High 24186977
2015 Crystal structures of Norrin in complex with the Fz4 cysteine-rich domain (Fz4CRD), with and without GAG analogues, reveal that Norrin mimics Wnt for Frizzled recognition; Fz4 and putative Lrp5/6 binding sites map to distinct patches on Norrin; a GAG (heparan sulfate) binding site spans the Norrin-Fz4CRD interface and enhances signaling. X-ray crystallography, SAXS, biophysical binding assays, cellular signaling assays, mutagenesis eLife High 26158506
2006 Norrin binds specifically to the Fz4 CRD and not to the 14 other mammalian Frizzled or sFRP CRDs; Norrin and Xenopus Wnt8 recognize overlapping regions of the Fz4 CRD; Norrin function requires three conserved disulfide bonds; a contiguous group of amino acids in the extended β-sheet domain of Norrin is responsible for CRD binding; heparin enhances Norrin-CRD binding ~10-fold. Binding assays with panels of CRDs, site-directed mutagenesis of Norrin and Fz4 CRD The Journal of biological chemistry High 17158104
1997 Norrin is secreted and forms disulfide-linked oligomers (up to ~20 monomers) that associate with the extracellular matrix; covalently cross-linked dimers are key structural components; Cys95 is required for oligomer formation beyond dimers; disease-associated mutations (V60E, R121Q) reduce the amount of Norrin in the extracellular matrix. Pulse-labeling with [35S]cysteine, SDS-PAGE under reducing/non-reducing conditions, site-directed mutagenesis, cross-linking, COS-7 transfection The Journal of biological chemistry High 9407136
2017 TSPAN12 is an essential component of the NDP/Norrin receptor complex, interacting with FZD4 and NDP via its extracellular loops; TSPAN12 acts as a co-receptor that enhances FZD4 ligand selectivity for NDP; FEVR-linked TSPAN12 mutations prevent its incorporation into the receptor complex; TSPAN12 can rescue defects of FZD4 M105V mutation in vitro and in Xenopus embryos. Co-immunoprecipitation, mutagenesis, reporter assays, Xenopus functional assays Cell reports High 28658627
2017 NDP/Norrin is a potent trigger of FZD4 ubiquitination and induces internalization of the NDP receptor complex into the endo-lysosomal compartment via the MVB/ESCRT pathway; inhibition of ESCRT-mediated transport (dominant-negative VPS4 EQ) strongly impairs NDP/FZD4 β-catenin signaling in vitro and causes CNS angiogenesis and blood-CNS barrier defects in mice. Dominant-negative ESCRT construct (VPS4 EQ), ubiquitination assays, in vitro signaling, in vivo mouse models Nature communications High 28675177
2018 The flexible linker domain connecting the FZD4 CRD to the transmembrane domain directly contributes ~10-fold higher binding affinity to Norrin and is required for Norrin signaling specificity; Norrin binding induces conformational changes in the FZD4 linker domain and intracellular loop 3 (ICL3) as shown by hydrogen/deuterium exchange MS; ICL3 mutations (L430A, L433A) and C-terminal tail truncation reduce β-catenin signaling. Biophysical binding assays, hydrogen/deuterium exchange mass spectrometry, mutagenesis, cell-based reporter assays Proceedings of the National Academy of Sciences of the United States of America High 30104375
2018 Norrin and Wnt7a/Wnt7b signaling systems show threshold and partial redundancy effects in maintaining the blood-brain and blood-retina barrier; combined loss of Wnt7a and Norrin (or Fz4) causes far more severe BBB defects than individual losses; glia are the source of Wnt7a in the cerebellum; Tspan12 is less potent than Norrin in BBB maintenance, consistent with it amplifying the Norrin signal amplitude. Mouse genetic loss-of-function analysis (double/triple conditional KO), in vivo BBB assays Proceedings of the National Academy of Sciences of the United States of America High 30478038
2010 Norrin activates Wnt/β-catenin signaling in Müller glia, which induces neuroprotective growth factors (FGF2, BDNF, LIF, CNTF, EDN2); this neuroprotective pathway protects retinal ganglion cells from NMDA-mediated excitotoxic damage; DKK-1 (Wnt/β-catenin inhibitor) blocks both the Norrin-induced Wnt activation and the neuroprotective effects. Intravitreal injection of Norrin in mouse NMDA damage model, Müller cell culture, DKK-1 blocking, conditioned medium experiments The Journal of neuroscience High 20427659
2013 Norrin functions as a ligand for LGR4 (but not LGR5/6); norrin can activate Wnt signaling via both FZD4 and LGR4 receptors; norrin also acts as a BMP antagonist; different Norrie disease mutations can be categorized by selective defects for signaling through FZD4, LGR4/5/6, or BMP pathway. Binding studies, Wnt reporter assays in mammalian cells, mutagenesis Journal of cell science Medium 23444378
2005 Ectopic norrin expression from a lens-specific promoter in Norrie disease (Ndp knockout) mice restores normal retinal vascular network formation and neuronal function; lens-derived norrin induces proliferation of microvascular endothelial cells in co-culture, demonstrating that norrin directly induces growth of ocular capillaries. Transgenic mouse rescue experiment, retinal vascular morphology, BrdU proliferation assay, in vitro co-culture The Journal of neuroscience High 15716406
2005 Loss of Norrin signaling in female Ndp homozygous knockout mice causes defects in uterine vascular development and decidualization leading to near-complete infertility, revealing a role for Norrin in female reproductive tissue vascular development. Ndp knockout mouse model, histological and in situ hybridization analysis, RT-PCR Genesis Medium 16035034
2010 Norrin promotes proliferation, viability, migration, and tube formation in microvascular endothelial cells; these effects are blocked by DKK-1 (Wnt/β-catenin inhibitor); Norrin induces angiopoietin-2 (Ang-2) expression, and inhibitory antibodies against Ang-2 suppress Norrin's proliferative effects. In vitro endothelial cell assays, transgenic mouse OIR models, DKK-1 inhibition, anti-Ang-2 antibody The Journal of neuroscience High 20053900
2010 The cysteine-rich domain (CRD) of FZD4 is essential for Norrin binding and β-catenin signaling activation; FEVR-associated FZD4 CRD mutations (C45Y, Y58C, C204R) abolish Norrin binding and fail to transduce Wnt/β-catenin signaling in HEK293 cells and in Xenopus embryos. Cell-surface and overlay binding assays, luciferase reporter assays, Xenopus embryo injection, HEK293 transfection The Journal of biological chemistry High 21177847
2020 Norrin restores blood-retinal barrier properties after VEGF-induced permeability in a β-catenin-dependent manner; VEGF promotes Norrin responsiveness by increasing TSPAN12 at cell membranes via a MEK/ERK-dependent mechanism; Norrin requires both β-catenin signaling and VEGF co-stimulation to enrich claudin-5 at tight junctions. In vivo intravitreal injection in diabetic rats, in vitro transendothelial electrical resistance, FITC-albumin permeability, Western blotting, siRNA knockdown The Journal of biological chemistry High 32086377
2016 The FZD4 C-terminus distal to the KTXXXW motif (minimum three residues) is essential for Dishevelled (DVL) recruitment and Norrin-stimulated Lef/Tcf-dependent transcriptional activation. FZD4 truncation/mutation analysis, DVL recruitment assays, reporter assays Journal of molecular signaling Medium 27096005
2019 Norrin expressed by a molecularly defined subpopulation of cortical layer V astroglia regulates neuronal dendrites and synaptic spines; loss of astrocytic Norrin (as in Norrie disease) contributes to cortical dendritic spine loss. Transgenic reporter mice, transcriptomic/histological characterization, in vivo dendritic spine analysis in Norrie disease model Nature neuroscience Medium 30936556
2012 Norrin stimulates endothelial cell proliferation in the superficial retinal vascular plexus; loss of Norrin (Ndp knockout) causes reduced endothelial cell proliferation rates, decreased mitogenic activity, altered PDGF-β/PDGFRβ expression, and elevated mural cell coverage. Mouse KO model, morphometric analysis, BrdU proliferation assay, in vitro mitogenesis assay, marker expression analysis Human molecular genetics Medium 22394677
2019 Dermal papilla cells stimulated by extracellular vesicles from activated dermal fibroblasts secrete Norrin, which activates β-catenin signaling in follicular keratinocytes in a non-cell-autonomous manner to promote hair follicle growth; FZD4 delivered via DF-EVs potentiates Norrin effects. EV isolation, transcriptomic analysis, NDP siRNA knockdown, β-catenin reporter assays, ex vivo hair follicle growth assay Stem cells Medium 31237401
2024 Glutamatergic neuronal activity regulates deep plexus retinal angiogenesis and blood-retinal barrier maturation by modulating endothelial Norrin/β-catenin signaling; Norrin expression and endothelial Norrin/β-catenin signaling are downregulated in Vglut1-/- retinas (reduced glutamate release) and upregulated in Gnat1-/- retinas (excessive glutamate); pharmacological activation of endothelial Norrin/β-catenin rescues angiogenesis defects in Vglut1-/- retinas. In vivo mouse genetic models (Vglut1-/-, Gnat1-/-), scRNA-seq, pharmacological rescue, functional validation Neuron High 38599212
1993 A missense mutation in the NDP gene (Leu124Phe) causes X-linked familial exudative vitreoretinopathy (XLFEVR), demonstrating that phenotypes of both XLFEVR and Norrie disease result from mutations in the same gene. Molecular genetic analysis, cosegregation in a 4-generation family Nature genetics Medium 8252044
2021 CTNNA1 (α-catenin) mutations cause FEVR by overactivating Norrin/β-catenin signaling through impaired cadherin-catenin complex protein interactions, demonstrating that precise regulation of β-catenin activation level (not just loss-of-function) is critical for retinal vascular development. Exome sequencing, CTNNA1 endothelial-specific KO mice, gain-of-function Ctnnb1 mice, isolated EC experiments, F-actin and VE-cadherin distribution assays The Journal of clinical investigation High 33497368
2020 Norrin mediates opposing tumor-suppressive and -promoting effects in glioblastoma stem cells depending on ASCL1 expression level; in ASCL1lo GSCs, Norrin signals through FZD4 to inhibit growth; in ASCL1hi GSCs, Norrin promotes Notch signaling independently of WNT to promote tumor progression. Patient-derived GBM stem cell culture, loss-of-function and forced ASCL1 expression, signaling pathway analysis The Journal of clinical investigation Medium 32182224

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 722 15035989
2009 Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 375 19837032
2012 Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 324 23217714
2009 TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell 323 19837033
1993 A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nature genetics 283 8252044
2002 NDP kinase 2 interacts with two oxidative stress-activated MAPKs to regulate cellular redox state and enhances multiple stress tolerance in transgenic plants. Proceedings of the National Academy of Sciences of the United States of America 273 12506203
2010 The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends in molecular medicine 147 20688566
2018 Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. Proceedings of the National Academy of Sciences of the United States of America 128 30478038
2010 Norrin mediates neuroprotective effects on retinal ganglion cells via activation of the Wnt/beta-catenin signaling pathway and the induction of neuroprotective growth factors in Muller cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 20427659
2015 Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. eLife 105 26158506
2013 Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex. Genes & development 102 24186977
2003 Multiple biochemical activities of NM23/NDP kinase in gene regulation. Journal of bioenergetics and biomembranes 96 12848339
2006 Mutational analysis of Norrin-Frizzled4 recognition. The Journal of biological chemistry 94 17158104
2014 Norrin protected blood-brain barrier via frizzled-4/β-catenin pathway after subarachnoid hemorrhage in rats. Stroke 81 25550365
2017 TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling. Cell reports 77 28658627
1996 Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. Proceedings of the National Academy of Sciences of the United States of America 75 8692914
2005 Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 15716406
1998 NM23-NDP kinase. The international journal of biochemistry & cell biology 73 9924799
2010 Norrin promotes vascular regrowth after oxygen-induced retinal vessel loss and suppresses retinopathy in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 20053900
2021 Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide. Cell research 70 34561620
2001 Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. Journal of medicinal chemistry 70 11405661
1995 A human NDP-kinase B specifically binds single-stranded poly-pyrimidine sequences. Nucleic acids research 70 7479028
2012 Norrin: molecular and functional properties of an angiogenic and neuroprotective growth factor. Progress in retinal and eye research 68 22387751
2019 Molecularly defined cortical astroglia subpopulation modulates neurons via secretion of Norrin. Nature neuroscience 64 30936556
2013 Multi-functional norrin is a ligand for the LGR4 receptor. Journal of cell science 64 23444378
1995 A new function of Nm23/NDP kinase as a differentiation inhibitory factor, which does not require it's kinase activity. FEBS letters 64 7737424
2021 Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/β-catenin signaling. The Journal of clinical investigation 63 33497368
2006 Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clinical & experimental ophthalmology 63 16970763
1999 A novel human nucleoside diphosphate (NDP) kinase, Nm23-H6, localizes in mitochondria and affects cytokinesis. Journal of cellular biochemistry 63 10618642
2019 Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution. Proceedings of the National Academy of Sciences of the United States of America 60 30988181
2017 Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 58 28494495
1997 Norrie disease protein (norrin) forms disulfide-linked oligomers associated with the extracellular matrix. The Journal of biological chemistry 55 9407136
2012 Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage. Neurobiology of disease 54 23009755
2021 A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy. EMBO molecular medicine 53 34105895
2007 Synthesis and evaluation of bivalent NDP-alpha-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). Bioconjugate chemistry 53 17591746
2003 Knockout mice as model systems for studying nm23/NDP kinase gene functions. Application to the nm23-M1 gene. Journal of bioenergetics and biomembranes 53 12848338
1996 The enzymatic activity of Drosophila AWD/NDP kinase is necessary but not sufficient for its biological function. Developmental biology 49 8806830
2000 Inhibition by protein kinase C of the K(NDP) subtype of vascular smooth muscle ATP-sensitive potassium channel. Circulation research 48 10903994
2003 Nm23/NDP kinases in human male germ cells: role in spermiogenesis and sperm motility? Experimental cell research 45 14499630
1999 Inhibitory activity of nm23-H1 on invasion and colonization of human prostate carcinoma cells is not mediated by its NDP kinase activity. Cancer letters 45 10530775
2018 Biophysical and functional characterization of Norrin signaling through Frizzled4. Proceedings of the National Academy of Sciences of the United States of America 42 30104375
2019 Familial Exudative Vitreoretinopathy-Related Disease-Causing Genes and Norrin/β-Catenin Signal Pathway: Structure, Function, and Mutation Spectrums. Journal of ophthalmology 40 31827910
1999 A novel NDP-6-deoxyhexosyl-4-ulose reductase in the pathway for the synthesis of thymidine diphosphate-D-fucose. The Journal of biological chemistry 39 10358040
2020 Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability. The Journal of biological chemistry 38 32086377
2019 Extracellular Vesicles from Activated Dermal Fibroblasts Stimulate Hair Follicle Growth Through Dermal Papilla-Secreted Norrin. Stem cells (Dayton, Ohio) 38 31237401
2015 NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors. Molecular and cellular neurosciences 38 26003413
2008 The relationship between dNTP pool levels and mutagenesis in an Escherichia coli NDP kinase mutant. Proceedings of the National Academy of Sciences of the United States of America 38 18621712
2019 Müller Cell-Localized G-Protein-Coupled Receptor 81 (Hydroxycarboxylic Acid Receptor 1) Regulates Inner Retinal Vasculature via Norrin/Wnt Pathways. The American journal of pathology 37 31220454
2005 Fetal loss in homozygous mutant Norrie disease mice: a new role of Norrin in reproduction. Genesis (New York, N.Y. : 2000) 37 16035034
2017 Norrin-induced Frizzled4 endocytosis and endo-lysosomal trafficking control retinal angiogenesis and barrier function. Nature communications 36 28675177
2012 Norrin stimulates cell proliferation in the superficial retinal vascular plexus and is pivotal for the recruitment of mural cells. Human molecular genetics 36 22394677
2017 Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 34 29181528
2010 An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy. The Journal of biological chemistry 33 21177847
2004 Nm23-M2/NDP kinase B induces endogenous c-myc and nm23-M1/NDP kinase A overexpression in BAF3 cells. Both NDP kinases protect the cells from oxidative stress-induced death. Experimental cell research 32 15530864
2003 NDP gene mutations in 14 French families with Norrie disease. Human mutation 32 14635119
2014 The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling. Investigative ophthalmology & visual science 31 25414188
2007 Moderate reduction of Norrin signaling activity associated with the causative missense mutations identified in patients with familial exudative vitreoretinopathy. Human genetics 31 17955262
2011 Nucleotide pyrophosphatase employs a P-loop-like motif to enhance catalytic power and NDP/NTP discrimination. Proceedings of the National Academy of Sciences of the United States of America 29 21831832
2017 FZD4 Marks Lateral Plate Mesoderm and Signals with NORRIN to Increase Cardiomyocyte Induction from Pluripotent Stem Cell-Derived Cardiac Progenitors. Stem cell reports 28 29249665
2016 Structure of NDP-forming Acetyl-CoA synthetase ACD1 reveals a large rearrangement for phosphoryl transfer. Proceedings of the National Academy of Sciences of the United States of America 28 26787904
2012 Protective action of NDP-MSH in experimental subarachnoid hemorrhage. Experimental neurology 27 22230666
2009 Double knockout Nme1/Nme2 mouse model suggests a critical role for NDP kinases in erythroid development. Molecular and cellular biochemistry 26 19381783
2013 Retinal vascular rescue of oxygen-induced retinopathy in mice by norrin. Investigative ophthalmology & visual science 25 23188723
2003 Receptor activation regulates cortical, but not vesicular localization of NDP kinase. Journal of cell science 24 12829743
2024 Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling. Neuron 23 38599212
2020 Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and Wnt. The Journal of clinical investigation 22 32182224
2017 Characterization of a Novel Nicotine Degradation Gene Cluster ndp in Sphingomonas melonis TY and Its Evolutionary Analysis. Frontiers in microbiology 22 28337179
2014 A novel signaling pathway regulates colon cancer angiogenesis through Norrin. Scientific reports 22 25005225
2009 A novel NDP mutation in an infant with unilateral persistent fetal vasculature and retinal vasculopathy. Ophthalmic genetics 22 19373682
2003 Physiological and pathological relevance of extracellular NM23/NDP kinases. Journal of bioenergetics and biomembranes 22 12848346
2010 Interactions of the melanocortin-4 receptor with the peptide agonist NDP-MSH. Journal of molecular biology 21 20600126
2006 Nm23/NDP kinases in hepatocellular carcinoma. Journal of bioenergetics and biomembranes 21 16944304
2004 Wnt signaling: Ig-norrin the dogma. Current biology : CB 21 15182694
2003 Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets. Molecular pharmacology 21 12606760
2021 Structure-function relationships in NDP-sugar active SDR enzymes: Fingerprints for functional annotation and enzyme engineering. Biotechnology advances 20 33571638
2007 Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy. American journal of medical genetics. Part A 20 17431911
1996 Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin. Ophthalmology 20 9003348
2017 Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia. Experimental eye research 19 28823941
2016 Mutation spectrum of the Norrie disease pseudoglioma (NDP) gene in Indian patients with FEVR. Molecular vision 19 27217716
2014 Protective effects of the melanocortin analog NDP-α-MSH in rats undergoing cardiac arrest. European journal of pharmacology 19 25446929
2007 Regulation of norrin receptor frizzled-4 by Wnt2 in colon-derived cells. BMC cell biology 19 17386109
1996 The Enzymatic Activity of Drosophila AWD/NDP Kinase Is Necessary but Not Sufficient for Its Biological Function. Developmental biology 19 8812147
2023 A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response. iScience 18 37559903
2020 Ethacrynic acid, a loop diuretic, suppresses epithelial-mesenchymal transition of A549 lung cancer cells via blocking of NDP-induced WNT signaling. Biochemical pharmacology 18 33189676
2015 Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1. Experimental eye research 18 26706283
2009 Norrin attenuates protease-mediated death of transformed retinal ganglion cells. Molecular vision 18 19137075
2009 The peptide NDP-MSH induces phenotype changes in the heart that resemble ischemic preconditioning. Peptides 18 19799952
2004 Norrin and frizzled; a new vein for the eye. Developmental cell 18 15068782
2003 ErbB2 and the antimetastatic nm23/NDP kinase in regulating serum induced breast cancer invasion. International journal of molecular medicine 18 12792823
2012 Melanocortin-1 receptor-mediated signalling pathways activated by NDP-MSH and HBD3 ligands. Pigment cell & melanoma research 17 22364200
1997 The in vitro DNA binding properties of NDP kinase are related to its oligomeric state. FEBS letters 16 9414094
2022 Spectrum of Mutations in NDP Resulting in Ocular Disease; a Systematic Review. Frontiers in genetics 15 35651932
2015 NDP-α-MSH attenuates heart and liver responses to myocardial reperfusion via the vagus nerve and JAK/ERK/STAT signaling. European journal of pharmacology 15 26477637
2008 Vascular changes in the cerebellum of Norrin /Ndph knockout mice correlate with high expression of Norrin and Frizzled-4. The European journal of neuroscience 15 18547247
2020 Role of NDP- and FZD4-Related Novel Mutations Identified in Patients with FEVR in Norrin/β-Catenin Signaling Pathway. BioMed research international 14 32420371
2016 Frizzled-4 C-terminus Distal to KTXXXW Motif is Essential for Normal Dishevelled Recruitment and Norrin-stimulated Activation of Lef/Tcf-dependent Transcriptional Activation. Journal of molecular signaling 14 27096005
2015 Homogeneous fluorescence anisotropy-based assay for characterization of ligand binding dynamics to GPCRs in budded baculoviruses: the case of Cy3B-NDP-α-MSH binding to MC4 receptors. Methods in molecular biology (Clifton, N.J.) 14 25563175
2012 Screening for NDP mutations in 44 unrelated patients with familial exudative vitreoretinopathy or Norrie disease. Current eye research 14 22563645
2010 NDP kinase 7 is a conserved microtubule-binding protein preferentially expressed in ciliated cells. Cell structure and function 14 20215702
2002 Stability of Natrialba magadii NDP kinase: comparisons with other halophilic proteins. Extremophiles : life under extreme conditions 14 12013434