Affinage

NODAL

Nodal homolog · UniProt Q96S42

Length
347 aa
Mass
39.6 kDa
Annotated
2026-04-29
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NODAL is a TGF-β superfamily ligand that functions as a morphogen to pattern embryonic mesendoderm, establish left-right asymmetry, and regulate cell fate specification during gastrulation. Proteolytic maturation of the Nodal precursor by Furin/PACE4 convertases generates the active ligand, which signals as a homodimer or as a more potent Nodal·GDF1 heterodimer through type II receptors (ActRIIA/B) and the type I receptor ALK4 (or ALK7), requiring the GPI-anchored EGF-CFC co-receptor Cripto/Cryptic — whose O-fucosylation, ALK4 binding via the CFC domain, and endosomal sorting function are each essential for pathway activation (PMID:11389842, PMID:12052855, PMID:18772886, PMID:24798330). Activated receptors phosphorylate Smad2/3, which cooperate with the transcription factors FoxH1 and Eomesodermin to specify distinct tissue fates (notochord vs. endoderm/mesoderm), while signal output is shaped by autoregulatory positive-feedback enhancers, extracellular antagonists (Lefty, Cerberus, ISM1), co-receptor-mediated restriction of ligand diffusion range, miRNA-dependent dampening of agonist and antagonist mRNAs, transcriptional co-repressors (Tgif1/2), Rap2-directed receptor trafficking, and TET-mediated epigenetic derepression of Lefty inhibitor loci (PMID:21637786, PMID:27101364, PMID:34036935, PMID:17761850, PMID:20040491, PMID:27760115, PMID:18606140).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing the core receptor complex: the question of how Nodal engages its receptors was answered by showing that the EGF-CFC co-receptor Cripto binds ALK4 via its CFC domain and is required for Nodal to access the ALK4/ActRIIB complex and activate Smad2, while Arkadia was identified as an essential nuclear potentiator of Nodal's mesendoderm-inducing activity.

    Evidence Co-immunoprecipitation, receptor-binding assays, Smad2 phosphorylation in cell culture (Cripto–ALK4); Xenopus gain-of-function and Arkadia-mutant mouse analysis (Arkadia)

    PMID:11298453 PMID:11389842 PMID:11909953

    Open questions at the time
    • Crystal structure of Nodal–Cripto–ALK4 ternary complex not determined
    • Mechanism by which Arkadia potentiates Smad-dependent transcription not fully resolved
  2. 2002 High

    Two prerequisites for ligand activity were defined: Cripto requires O-linked fucosylation to bind and present Nodal, and the Nodal precursor must be cleaved by Furin/PACE4 convertases in the extraembryonic ectoderm to generate signaling-competent mature ligand.

    Evidence Glycosylation mutant analysis with luciferase reporters (O-fucosylation); Spc1/Spc4 double-mutant embryo explants with recombinant mature vs. precursor Nodal rescue (processing)

    PMID:12052855 PMID:12447384

    Open questions at the time
    • Whether other glycosyltransferases besides POFUT1 modify EGF-CFC proteins in vivo
    • Quantitative contribution of each convertase in different tissues
  3. 2003 High

    Upstream transcriptional inputs and autoregulatory feedback were mapped: Notch signaling directly activates Nodal transcription at the node through RBP-J binding sites in a node-specific enhancer, while FoxH1 mediates Nodal autoregulation and left-sided expression in the lateral plate mesoderm; membrane-bound TMEFF1 was identified as a selective extracellular Nodal antagonist.

    Evidence RBP-J binding-site mutagenesis in transgenic mice and Dll1/Notch mutants (Notch→Nodal); conditional Foxh1 knockout with ectopic Nodal electroporation (FoxH1); Xenopus domain-deletion analysis (TMEFF1)

    PMID:12618130 PMID:12642485 PMID:12730124

    Open questions at the time
    • Whether Notch regulates Nodal at sites other than the node
    • Whether TMEFF1 acts by sequestering Nodal or blocking receptor access
  4. 2004 High

    Signaling through the alternative type I receptor ALK7 was shown to mediate Nodal's anti-proliferative and pro-apoptotic effects in trophoblast, and the Nicalin–Nomo transmembrane complex was identified as a novel intracellular antagonist of the pathway.

    Evidence Constitutively active and kinase-dead ALK7 with Smad2/3 mutants in trophoblast cells (ALK7); zebrafish morpholino knockdown and epistasis with Lefty (Nicalin–Nomo)

    PMID:15150278 PMID:15257293

    Open questions at the time
    • Whether ALK7-mediated apoptosis occurs in other Nodal-responsive tissues
    • Molecular mechanism by which Nicalin–Nomo antagonizes receptor signaling
  5. 2005 High

    Autoregulatory enhancer architecture was dissected: two Nodal-responsive enhancers (ASE and LSE) in the Nodal locus drive left-sided expression, with LSE requiring a conserved FoxH1-binding site and the co-receptor Cryptic, establishing a molecular basis for positive feedback.

    Evidence Transgenic enhancer mutagenesis in wild-type, Cryptic-mutant, and iv/inv-mutant mouse embryos

    PMID:15736223

    Open questions at the time
    • Chromatin accessibility dynamics at these enhancers during symmetry breaking
    • Whether additional transcription factors besides FoxH1 occupy these enhancers
  6. 2006 High

    GDF1 was established as a functional synergistic partner of Nodal signaling through ALK4, explaining why Gdf1 loss phenocopies partial Nodal deficiency in anterior development.

    Evidence Gdf1−/−;Nodal+/− compound mutant analysis and ALK4/ALK7 receptor reconstitution in mouse

    PMID:16564040

    Open questions at the time
    • Whether GDF1 and Nodal heterodimerize in vivo in this context (biochemically shown later)
  7. 2007 High

    Post-transcriptional tuning of the Nodal pathway by microRNAs was revealed: miR-430 simultaneously dampens both Nodal agonist (squint) and antagonist (lefty) mRNAs to balance signaling, while ventrally enriched miR-15/16 restrict organizer size by targeting the type II receptor Acvr2a, linking Wnt and Nodal crosstalk.

    Evidence Target protector morpholinos and miR-430 mutant zebrafish (miR-430); miRNA overexpression and morpholino knockdown in Xenopus (miR-15/16)

    PMID:17728715 PMID:17761850

    Open questions at the time
    • Whether miR-430 acts on Nodal pathway components in other vertebrates
    • Quantitative contribution of miRNA dampening vs. extracellular antagonism
  8. 2008 High

    The subcellular trafficking logic of Nodal signaling was elucidated: Cripto recruits Furin/PACE4 and guides uncleaved Nodal through detergent-resistant membranes to early endosomes, where specific Cripto residues (F78, G71) retain processed Nodal at the limiting membrane for receptor engagement; separately, Rap2 GTPase directs receptor recycling and delays ligand-dependent receptor turnover.

    Evidence Co-IP, density fractionation, electron microscopy, and Cripto point-mutant endosomal sorting assays (Cripto trafficking); Rap2 gain/loss-of-function with receptor trafficking assays in Xenopus (Rap2)

    PMID:18606140 PMID:18772886 PMID:19001664

    Open questions at the time
    • Whether Rap2 regulation is conserved in mammalian Nodal signaling
    • Identity of the endosomal sorting machinery that recognizes Cripto
  9. 2010 High

    Tgif1/Tgif2 were established as essential transcriptional co-repressors limiting Nodal signaling output: double-knockout embryos fail to gastrulate due to hyperactive Nodal, and reducing Nodal dose partially rescues these defects.

    Evidence Conditional Tgif1/Tgif2 double knockout with Nodal heterozygosity epistasis in mouse

    PMID:20040491

    Open questions at the time
    • Whether Tgif1/2 directly bind Nodal-responsive enhancers genome-wide
    • Relative contribution of each Tgif paralog
  10. 2011 High

    Nodal was shown to operate through two parallel transcriptional effector branches — FoxH1 (notochord) and Eomesodermin (endoderm, paraxial/intermediate mesoderm, blood) — whose combined loss phenocopies complete Nodal deficiency, resolving how a single morphogen specifies diverse fates.

    Evidence Novel zebrafish FoxH1 mutant (midway) with Eomesodermin morpholino double inhibition and Nodal overexpression epistasis

    PMID:21637786

    Open questions at the time
    • Whether additional transcription factors mediate Nodal responses in other tissues
    • How FoxH1 and Eomesodermin partition target gene access
  11. 2013 High

    Maternal translational control of Nodal mRNA by Ybx1 was identified, and downstream, the Nodal antagonist Cerberus-1 was shown to derepress SWI/SNF-mediated chromatin remodeling at cardiac loci, revealing how Nodal extinction enables cardiogenesis.

    Evidence Maternal-effect ybx1 mutant zebrafish with RNA-binding assays (Ybx1); siRNA to Cerberus-1/Baf60c/Brg1 with DNaseI sensitivity at Nkx2.5 enhancer in ES cells (Cerberus–SWI/SNF)

    PMID:24040511 PMID:24186978

    Open questions at the time
    • Whether Ybx1-mediated translational control occurs in mammalian embryos
    • Whether Cerberus-mediated SWI/SNF induction applies to in vivo cardiac specification
  12. 2014 High

    Biochemical characterization of Nodal·GDF1 heterodimers showed they signal far more potently than Nodal homodimers and are required for non-autonomous signaling via the co-receptor Cryptic, resolving the basis for GDF1's synergistic activity.

    Evidence Co-purification of Nodal·GDF1 heterodimer with propeptide complex, Acvr signaling reporter assays, human ES cell differentiation

    PMID:24798330

    Open questions at the time
    • Structural basis for heterodimer-enhanced potency
    • In vivo stoichiometry of homo- vs. heterodimers
  13. 2016 High

    A convergence of biophysical and genetic studies defined how the Nodal morphogen gradient is shaped: the EGF-CFC co-receptor restricts Nodal diffusion range by capturing ligand at target cells (transforming gradient into a travelling wave in its absence); Nodal clearance by degradation and Lefty/Acvr2b binding sets gradient range; extended Nodal signaling duration selects prechordal plate over endoderm fate; and TET-mediated demethylation of Lefty loci provides an epigenetic brake on Nodal output.

    Evidence Oep mutant/overexpression with computational modeling in live zebrafish (co-receptor); FCS/FCCS in live zebrafish (biophysics); optogenetic Nodal receptor in zebrafish (duration); triple-Tet knockout with Nodal heterozygosity and bisulfite sequencing in mouse (epigenetic)

    PMID:27101364 PMID:27396324 PMID:27760115 PMID:34036935

    Open questions at the time
    • Whether co-receptor-mediated capture operates identically in mammalian embryos
    • How Nodal duration is interpreted at the chromatin level
    • Which specific TET paralog is rate-limiting at Lefty loci
  14. 2016 High

    Additional modulators were identified: Aplnr acts as a non-cell-autonomous rheostat for Nodal output in zebrafish cardiogenesis, and ZIC2 physically interacts with SMAD2/3 to regulate FOXA2 transcription downstream of Nodal, with holoprosencephaly-associated ZIC2 variants being deficient in this activity.

    Evidence aplnr double mutant with Nodal rescue and agonist treatment in zebrafish (Aplnr); co-IP and reporter assays with HPE-variant ZIC2 in cells and Xenopus (ZIC2)

    PMID:27077952 PMID:27466203

    Open questions at the time
    • Mechanism by which Aplnr modulates Nodal non-cell-autonomously
    • Whether ZIC2–SMAD interaction is direct or bridged
  15. 2019 High

    ISM1 was identified as a selective extracellular Nodal antagonist that blocks Nodal–ALK4 interaction through its AMOP domain without affecting other TGF-β family ligands, expanding the repertoire of pathway-specific inhibitors.

    Evidence Recombinant protein signaling assays, AMOP domain-deletion co-IP, ectopic expression in chick embryos

    PMID:31171630

    Open questions at the time
    • In vivo requirement for ISM1 in Nodal-dependent patterning
    • Whether ISM1 also inhibits Nodal·GDF1 heterodimers

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of the Nodal–Cripto–ALK4 signaling complex, the quantitative interplay between multiple layers of Nodal regulation (transcriptional feedback, miRNA dampening, receptor trafficking, extracellular antagonism) in determining morphogen gradient precision, and how Nodal signal duration is decoded at the chromatin and transcription factor level to select among alternative cell fates.
  • No atomic-resolution structure of any Nodal-containing signaling complex
  • Quantitative integration of multiple regulatory tiers not modeled in a unified framework
  • Chromatin-level interpretation of Nodal signaling duration remains uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 4 GO:0005768 endosome 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 5
Partners
ACVR1BACVR2BFOXH1GDF1ISM1SMAD2SMAD3TDGF1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Cripto (EGF-CFC factor) interacts with the type I receptor ALK4 via its conserved CFC motif; this interaction is necessary for Nodal binding to the ALK4/ActRIIB receptor complex and for Smad2 activation by Nodal. Nodal can also inhibit BMP signaling in a Cripto-independent manner through heterodimerization with BMPs at the level of dimeric ligand production. Co-immunoprecipitation, receptor-binding assays, Smad2 phosphorylation assays, dominant-negative receptor experiments in cell culture Molecular cell High 11389842
2002 Cripto functions both as a coreceptor (cell surface) and as a secreted coligand for Nodal; binding of Cripto to Nodal and its ability to mediate Nodal signaling requires O-linked fucosylation at a conserved site within EGF-CFC proteins. Luciferase reporter assay, cell coculture assays, glycosylation mutant analysis Molecular and cellular biology High 12052855
2002 The proprotein convertases Spc1/Furin and Spc4/PACE4, expressed in adjacent extraembryonic ectoderm, are required for proteolytic maturation of the Nodal precursor; recombinant mature Nodal, but not uncleaved precursor, efficiently induces Cripto expression, demonstrating that extracellular proteolytic processing is required for Nodal signaling activity. Embryo explant assays, Spc1/Spc4 double-mutant analysis, recombinant mature vs. precursor Nodal rescue experiments Nature cell biology High 12447384
2002 Cripto-1 binds to ALK4 on the cell surface (co-immunoprecipitation confirmed), and phosphorylates Smad2 in epithelial cells only in the presence of both Nodal and ALK4; Cripto-1 can also activate MAP kinase and AKT pathways independently of Nodal and ALK4. Phage display library screening, co-immunoprecipitation, FACS, Smad2 phosphorylation assays Molecular and cellular biology High 11909953
2004 Nodal inhibits proliferation and induces apoptosis in human trophoblast cells by signaling through the type I receptor ALK7 and Smad2/3; this effect involves upregulation of p27 and downregulation of Cdk2 and cyclin D1, leading to G1 cell cycle arrest. Overexpression of Nodal, constitutively active ALK7, kinase-deficient ALK7, dominant-negative Smad2/3; Hoechst staining, flow cytometry, caspase-3 western blotting, BrdU assays The Journal of biological chemistry High 15150278
2008 Cripto recruits the proprotein convertases Furin and PACE4 to the cell surface, localizing Nodal precursor processing there; Cripto and uncleaved Nodal associate during secretion, and export to the cell surface occurs before entering the TGN/endosomal system; Cripto guides Nodal precursor in detergent-resistant membranes to endocytic microdomains, coupling Nodal processing and endocytosis. Co-immunoprecipitation, density fractionation, antibody uptake experiments, brefeldin A treatment, GFP-Flotillin co-localization, electron microscopy The EMBO journal High 18772886
2008 Cripto localizes Nodal at the limiting membrane of early endosomes via residues phenylalanine 78 and glycine 71 in its EGF-like motif; the CFC domain residues mediating ALK4 binding are required to prevent sequestration of Nodal in the endosomal lumen. The EGF-like motif of Cripto is not essential for Nodal binding per se, but is required for endosomal sorting. Site-directed mutagenesis of Cripto, immunofluorescence, subcellular fractionation, endosome co-localization assays Science signaling High 19001664
2004 Nicalin and Nomo form a transmembrane protein complex that antagonizes Nodal (and Activin) signaling; ectopic expression causes cyclopia in zebrafish, and downregulation of Nomo increases anterior axial mesendoderm, phenocopying elevated Nodal signaling; inhibition of Nodal signaling by Lefty was rescued by reducing Nomo levels. Gain-of-function expression in zebrafish, morpholino knockdown, cell-based Nodal/Activin reporter assay, epistasis with Lefty The EMBO journal High 15257293
2001 Arkadia, a nuclear protein, specifically potentiates the mesendoderm-inducing activity of Nodal-related ligands; its activity is blocked by extracellular inhibition of Nodal signaling, and Arkadia mutant mice lack a node and node-derived mesendoderm, placing Arkadia as an essential modulator within the Nodal signaling cascade. Xenopus gain-of-function assays, co-expression experiments, Arkadia mutant mouse phenotype analysis, extracellular Nodal antagonist rescue Nature High 11298453
2003 Nodal signaling initiates asymmetric Nodal expression in the left lateral plate mesoderm (LPM) via the transcription factor Foxh1; Foxh1 mutant mice lacking Nodal in LPM fail to express Nodal, Lefty2, and Pitx2 on the left. Ectopic Nodal introduction into right LPM induces Nodal expression in wild-type but not Foxh1-mutant embryos, and also induces Lefty1 at the midline floor plate. Conditional Foxh1 knockout, LPM transplantation, electroporation of Nodal vector, in situ hybridization Development (Cambridge, England) High 12642485
2003 Notch signaling (via Dll1 ligand and RBP-J transcriptional mediator) directly regulates Nodal gene expression at the node through RBP-J binding sites in the node-specific Nodal enhancer; mutation of these sites destroys node-specific enhancer activity in transgenic mice, placing Notch upstream of Nodal in left-right asymmetry determination. Dll1 mutant and Notch1/2 double mutant analysis, enhancer reporter transgenic mice, RBP-J binding site mutagenesis Genes & development High 12730124
2014 Nodal forms heterodimers with GDF1; these Nodal·GDF1 heterodimers copurify with cleaved propeptides as a low molecular weight complex that stimulates Activin receptor (Acvr) signaling far more potently than Nodal alone. GDF1 suppresses an unexpected dependence of Nodal on serum proteins and is critically required for non-autonomous signaling in cells expressing the co-receptor Cryptic. Co-immunoprecipitation, biochemical purification, Acvr signaling reporter assays, soluble receptor inhibition assays, human ES cell differentiation The Journal of biological chemistry High 24798330
2016 The EGF-CFC co-receptor Oep (zebrafish ortholog of Cripto/Cryptic) restricts the diffusive spread of Nodal ligands by setting the rate of capture by target cells; in the absence of Oep, Nodal activity spreads uniformly throughout the embryo, and depletion of Oep transforms the Nodal signaling gradient into a travelling wave. Increasing Oep levels sensitizes cells to Nodal ligands. In vivo Nodal signaling reporter assays, Oep mutant and overexpression analysis, computational modeling, live zebrafish embryo imaging eLife High 34036935
2016 TET-mediated oxidation of 5-methylcytosine promotes demethylation of Lefty1/Lefty2 gene loci (encoding Nodal inhibitors), thereby restraining Nodal signaling; loss of all three Tet genes elevates DNA methylation at Lefty loci, reduces Lefty expression, and causes hyperactive Nodal signaling and gastrulation failure. Reducing Nodal dose in Tet-mutant background partially restores patterning. Triple Tet knockout mice, epistasis with Nodal heterozygosity, Dnmt3a/3b double knockout rescue, bisulfite sequencing, Tet dioxygenase catalytic point mutant Nature High 27760115
2016 Extended duration of Nodal signaling promotes prechordal plate specification and suppresses endoderm differentiation; this is mediated by extended Nodal signaling inducing the transcriptional repressor goosecoid (gsc) in prechordal plate progenitors, which in turn prevents Nodal from upregulating the endoderm differentiation gene sox17. Photoactivatable (optogenetic) Nodal receptor in zebrafish embryos, light-controlled signaling duration manipulation, in situ hybridization Cell reports High 27396324
2016 Fluorescence correlation spectroscopy in live zebrafish revealed that Nodal ligand clearance via degradation shapes the Nodal morphogen gradient; diffusivity, extracellular interactions with Acvr2b and Lefty, and selective ligand destruction collectively determine the Nodal gradient range. The binding affinity of Nodal ligands to Acvr2b and to the Nodal inhibitor Lefty was directly measured in vivo. Fluorescence cross-correlation spectroscopy, fluorescence correlation spectroscopy in live zebrafish, computational simulation of gradient formation eLife High 27101364
2010 Tgif1 and Tgif2 transcriptional co-repressors limit the transcriptional response to Nodal signaling during gastrulation; embryos lacking both Tgifs fail to gastrulate, and genetic reduction of Nodal dose in Tgif-null embryos partially rescues gastrulation defects and left-right asymmetry defects. Double Tgif1/Tgif2 knockout mice, conditional epiblast deletion, Nodal heterozygosity epistasis Development (Cambridge, England) High 20040491
2019 ISM1 (Isthmin1) is an extracellular antagonist of Nodal signaling that specifically inhibits Nodal-induced phosphorylation of SMAD2 without affecting TGF-β1, Activin-A, or BMP4 signaling; mechanistically, ISM1 interacts with Nodal ligand and the type I receptor ACVR1B (ALK4) through its AMOP domain, competitively disrupting the NODAL-ACVR1B interaction. In vitro signaling assays with recombinant proteins, co-immunoprecipitation, domain deletion analysis (AMOP domain mutants), ectopic expression in chick embryos, Smad2 phosphorylation western blotting The Journal of cell biology High 31171630
2003 Tomoregulin-1 (TMEFF1) inhibits Nodal (but not Activin) signaling in Xenopus; both its follistatin modules and EGF motif contribute to Nodal inhibition, but membrane localization of TMEFF1 is essential for its function—a soluble form is insufficient. TMEFF1 inhibits BMP2 through a distinct mechanism requiring its cytoplasmic tail. Xenopus gain-of-function assays, deletion mutant analysis, membrane-anchored vs. soluble TMEFF1 comparison, Nodal/BMP reporter assays Developmental biology High 12618130
2006 GDF-1 synergizes with Nodal through ALK4 (but not ALK7) to control anterior axis development; receptor reconstitution experiments showed GDF-1 signals via ALK4 and ALK7, but compound mutant analysis placed ALK4 as the relevant receptor mediating synergistic GDF-1/Nodal effects in the anterior primitive streak. Genetic compound mutant analysis (Gdf1-/-;Nodal+/-), receptor reconstitution experiments, ALK4/ALK7 epistasis analysis Developmental biology High 16564040
2008 Rap2 (Ras GTPase family member) positively regulates Activin/Nodal signaling by directing internalized receptors into a recycling pathway (preventing degradation) in the absence of ligand; upon ligand activation, Rap2 delays receptor turnover. Rap2 also antagonizes Smad7. Asymmetric Rap2 expression along the dorsoventral axis of Xenopus embryos contributes to asymmetric Smad2 activation. Loss-of-function and gain-of-function in Xenopus embryos, receptor trafficking assays, Smad2 phosphorylation assays, Smad7 epistasis Developmental cell High 18606140
2013 FGF9 from somatic cells induces testicular germ cells to upregulate Cripto, which triggers Nodal signaling in male germ cells during a critical developmental window; loss of Nodal signaling leads to premature differentiation and reduced pluripotency marker expression, while human testicular tumors show proportional upregulation of NODAL and CRIPTO. Conditional Nodal/Cripto mutant mice, EG cell colony formation assay in vitro, FGF9 treatment experiments, immunohistochemistry Development (Cambridge, England) Medium 23034635
2013 In multipotent cardiac progenitors, transient Nodal inhibition by the dual Nodal/BMP antagonist Cerberus-1 induces Brahma-associated factor 60c (Baf60c), the cardiomyogenic variant of the SWI/SNF chromatin remodeling complex; siRNA to Cerberus-1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented chromatin opening at the Nkx2.5 cardiac enhancer. Overexpression of Baf60c fully rescued these deficits, placing Baf60c downstream of Nodal inhibition. ES cell differentiation assay, siRNA knockdown, chromatin accessibility assay (DNaseI sensitivity), Baf60c overexpression rescue Genes & development High 24186978
2016 ZIC2 physically interacts with SMAD2 and SMAD3 (the transcriptional mediators of NODAL signaling); together, ZIC2 and SMAD3 regulate FOXA2 transcription. HPE-associated variant forms of ZIC2 are deficient in influencing SMAD-dependent transcription, placing ZIC2 as a downstream effector in the NODAL signal transduction pathway. Co-immunoprecipitation, reporter assays in cultured cells, Xenopus expression experiments, HPE variant ZIC2 functional analysis Human molecular genetics Medium 27466203
2011 Nodal signals through two parallel transcriptional effector arms: FoxH1-dependent (required for notochord specification) and Eomesodermin-dependent (required for endoderm, paraxial mesoderm, intermediate mesoderm, and blood specification); inhibition of Eomesodermin in FoxH1-null embryos phenocopies complete loss of Nodal signaling, demonstrating combinatorial transcription factor use in determining pathway output. Novel zebrafish FoxH1 (midway) mutant characterization, gel shift assays, Nodal overexpression epistasis, Eomesodermin morpholino knockdown in midway mutants PLoS genetics High 21637786
2007 miR-430 dampens and balances Nodal agonist (squint) and antagonist (lefty) mRNA levels post-transcriptionally; specific protection of squint mRNA from miR-430 enhanced Nodal signaling, protection of lefty mRNA reduced it, and simultaneous protection of both or absence of miR-430 caused imbalance and net reduction in Nodal signaling. Target protector morpholinos, zebrafish in vivo assays, miR-430 mutant analysis Science (New York, N.Y.) High 17761850
2007 In Xenopus, miR-15 and miR-16 restrict organizer size by targeting the Nodal type II receptor Acvr2a; miR-15 and miR-16 are ventrally enriched because they are negatively regulated by the dorsal Wnt/β-catenin pathway, linking Wnt and Nodal pathway crosstalk through microRNA regulation. Xenopus gain/loss-of-function assays, miRNA overexpression, morpholino knockdown, dorsal/ventral embryo half analysis Nature High 17728715
2013 Maternal Y box-binding protein 1 (Ybx1) binds the 3' UTR of squint (sqt/nodal) mRNA and prevents its premature translation; maternal-effect ybx1 mutations cause deregulated Nodal signaling and gastrulation failure, and Nodal-coated beads phenocopy ybx1 mutant defects. Proteomic screen for sqt RNA 3' UTR binding proteins, maternal-effect mutant zebrafish, RNA-protein binding assays, Nodal bead implantation eLife High 24040511
2016 In zebrafish, both stochastic processes and Nodal signaling (mediated by Lefty1) select prospective distal visceral endoderm (DVE) cells; Lefty1 expression in prospective DVE depends on Nodal signaling, and the cell that experiences the highest Nodal signaling begins Lefty1 expression. Deletion of Lefty1 alone or with Lefty2 increased DVE cell numbers, while ablation of prospective DVE cells triggered Lefty1 expression in remaining cells via Nodal. Lefty1/2 mutant mouse analysis, single-cell Nodal signaling readout, cell ablation experiments Nature communications Medium 29138408
2016 The Apelin receptor (Aplnr) modulates Nodal/TGFβ signaling in zebrafish: loss of Aplnr reduces Nodal target gene expression and delays cardiogenic transcription factor (mespaa/ab) expression; activation of Aplnr by a non-peptide agonist increases Nodal target expression. Aplnr acts as a specific rheostat for Nodal output in a non-cell-autonomous manner, and elevating Nodal rescues cardiac differentiation defects from Aplnr loss. aplnr morpholino knockdown, double aplnra/b mutant, non-peptide agonist treatment, Nodal overexpression rescue, Nodal point-source assay eLife High 27077952
2005 Two Nodal-responsive enhancers (ASE in intron 1 and LSE upstream) control asymmetric Nodal expression in the left lateral plate mesoderm; LSE activity requires a conserved FoxH1-binding sequence and depends on the Nodal co-receptor Cryptic, indicating Nodal autoregulatory positive feedback through both enhancers. Transgenic mouse enhancer analysis, FoxH1 binding site mutagenesis, Cryptic mutant embryo analysis, iv and inv mutant analysis Developmental dynamics High 15736223

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. The American journal of clinical nutrition 1019 21289221
1996 Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 481 8610012
2007 Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science (New York, N.Y.) 425 17761850
2007 Nodal signaling: developmental roles and regulation. Development (Cambridge, England) 413 17287255
1995 Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development (Cambridge, England) 375 8582278
2004 KCNQ2 is a nodal K+ channel. The Journal of neuroscience : the official journal of the Society for Neuroscience 352 14762142
2001 Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Molecular cell 317 11389842
2018 Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature 227 29795348
2001 Nodal signaling in early vertebrate embryos: themes and variations. Developmental cell 208 11709181
2003 Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes & development 198 12730124
2006 The sarcomeric Z-disc: a nodal point in signalling and disease. Journal of molecular medicine (Berlin, Germany) 185 16416311
2002 Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Molecular and cellular biology 175 12052855
2002 Extraembryonic proteases regulate Nodal signalling during gastrulation. Nature cell biology 175 12447384
2016 TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling. Nature 167 27760115
1993 Atrioventricular nodal reentry. Clinical, electrophysiological, and therapeutic considerations. Circulation 164 8319342
2004 Polycystins and mechanosensation in renal and nodal cilia. BioEssays : news and reviews in molecular, cellular and developmental biology 158 15273987
2007 MicroRNA control of Nodal signalling. Nature 157 17728715
2015 Activin/Nodal signalling in stem cells. Development (Cambridge, England) 142 25670788
2016 The genetics of nodal marginal zone lymphoma. Blood 134 27335277
2002 Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Molecular and cellular biology 123 11909953
2004 Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. The Journal of biological chemistry 97 15150278
1998 Nodal metastases: predictive factors. Otolaryngologic clinics of North America 97 9687325
2016 Optogenetic Control of Nodal Signaling Reveals a Temporal Pattern of Nodal Signaling Regulating Cell Fate Specification during Gastrulation. Cell reports 96 27396324
2012 Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development (Cambridge, England) 88 23034635
2003 Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development (Cambridge, England) 86 12642485
2006 Synergistic interaction between Gdf1 and Nodal during anterior axis development. Developmental biology 80 16564040
2002 Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development. Development (Cambridge, England) 79 12070082
2006 Protein clusters associated with carcinogenesis, histological differentiation and nodal metastasis in esophageal cancer. Proteomics 74 17133371
2009 Development and cancer: at the crossroads of Nodal and Notch signaling. Cancer research 73 19738053
2004 Characterization of subforms of AV nodal reentrant tachycardia. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 71 15172656
2008 Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation. The EMBO journal 69 18772886
2007 European trends in preoperative and intraoperative nodal staging: ESTS guidelines. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 68 17409811
2016 Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal. Cardiovascular research 67 26762270
2013 Nodal signalling in embryogenesis and tumourigenesis. The international journal of biochemistry & cell biology 65 23291354
2001 Arkadia enhances nodal-related signalling to induce mesendoderm. Nature 64 11298453
2019 RICK/RIP2 is a NOD2-independent nodal point of gut inflammation. International immunology 62 31132297
1993 "AV nodal" reentry: Part I: "AV nodal" reentry revisited. Journal of cardiovascular electrophysiology 60 8269322
2017 Nomograms for preoperative prediction of axillary nodal status in breast cancer. The British journal of surgery 57 28718896
2016 Optimizing therapy for nodal marginal zone lymphoma. Blood 57 26989202
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