Affinage

CDON

Cell adhesion molecule-related/down-regulated by oncogenes · UniProt Q4KMG0

Length
1287 aa
Mass
139.1 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDON is a multifunctional cell-surface co-receptor of the immunoglobulin/fibronectin type III superfamily that serves as a signaling hub in Hedgehog pathway reception, promyogenic/proneurogenic differentiation, Wnt pathway suppression, and dependence-receptor-mediated apoptosis. As an obligate Hedgehog co-receptor, CDON binds all three mammalian Hedgehog ligands via its third FNIII repeat in a calcium-dependent manner and cooperates with PTCH1, GAS1, and BOC to transduce Hedgehog signals essential for neural tube patterning, craniofacial development, and limb outgrowth, while in specific tissues it acts as a ligand-sequestering decoy receptor (PMID:16647304, PMID:18794898, PMID:21664576, PMID:25001599). In myoblasts and neural precursors, N-cadherin ligation of CDON assembles an intracellular scaffold—including JLP, Bnip-2, Abl, TAK1/ASK1, and APPL1—that activates Cdc42→p38 MAPK and Akt signaling to drive tissue-specific bHLH heterodimer formation and differentiation (PMID:17074887, PMID:18678706, PMID:20160094, PMID:20484574). CDON also suppresses canonical Wnt/β-catenin signaling by binding LRP6 through its Ig2 ectodomain, protecting against aberrant proliferation in the forebrain and osteogenic transdifferentiation in vascular smooth muscle (PMID:25406935, PMID:36609601). Loss-of-function mutations in CDON cause holoprosencephaly spectrum phenotypes in mice and humans, and CDON functions as a Hedgehog-dependent dependence receptor whose intracellular cleavage activates caspase-9-mediated apoptosis when ligand is absent (PMID:12620190, PMID:21802063, PMID:23940460).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Identification of CDO as a novel Ig/FNIII-containing cell-surface glycoprotein whose expression is downregulated by serum and oncogenic transformation established it as a candidate differentiation regulator.

    Evidence Molecular cloning, Northern/Western blotting in transformed vs. normal fibroblasts

    PMID:9214393

    Open questions at the time
    • No signaling pathway or ligand identified
    • Functional role inferred only from expression pattern
  2. 1998 High

    Demonstration that CDO positively regulates skeletal myogenesis and participates in a positive feedback loop with MyoD established CDO's first defined biological function.

    Evidence Overexpression and dominant-negative constructs in C2C12 myoblasts with differentiation and reporter assays

    PMID:9786951

    Open questions at the time
    • Intracellular signaling mechanism unknown
    • Extracellular ligand for promyogenic function not identified
  3. 2002 High

    Discovery that CDO and BOC form heteromeric complexes in cis and that BOC's promyogenic activity depends on CDO revealed CDO operates as part of a co-receptor system rather than in isolation.

    Evidence Reciprocal co-immunoprecipitation and dominant-negative rescue in myoblasts

    PMID:11782431

    Open questions at the time
    • Stoichiometry and structure of CDO-BOC complex unknown
    • Shared versus distinct signaling outputs not resolved
  4. 2003 High

    Cdon knockout mice displaying holoprosencephaly-like facial defects provided the first in vivo evidence that Cdon is required for midline patterning, linking it to a developmental disorder.

    Evidence Gene targeting/knockout mouse with morphological analysis

    PMID:12620190

    Open questions at the time
    • Which signaling pathway is disrupted in vivo not yet defined
    • Whether phenotype is Shh-dependent not directly tested
  5. 2004 High

    In vivo demonstration that Cdon loss delays skeletal muscle development and that Cdo activates myogenic bHLH factors via E-protein hyperphosphorylation resolved how Cdo links cell-surface events to transcriptional activation.

    Evidence Cdo KO mouse muscle phenotype, satellite cell differentiation assays, reporter and interaction studies

    PMID:15572127

    Open questions at the time
    • Kinase responsible for E-protein phosphorylation not identified
    • Direct versus indirect mechanism not resolved
  6. 2006 High

    Identification of CDO/BOC as direct Hedgehog-binding co-receptors that promote Shh signaling at the level of signal reception—and the parallel discovery that Cdo scaffolds JLP/p38 MAPK signaling in myoblasts—established CDO as a multifunctional co-receptor operating in two mechanistically distinct pathways.

    Evidence Binding assays and genetic epistasis in mouse neural tube (Hh pathway); co-IP plus kinase assays and KO rescue in myoblasts (p38 pathway); Drosophila Ihog epistasis

    PMID:16630821 PMID:16647303 PMID:16647304 PMID:17074887

    Open questions at the time
    • How CDO coordinates Hh versus p38 MAPK signaling at the same cell surface not resolved
    • Whether JLP recruitment is triggered by a specific extracellular ligand unknown
  7. 2008 High

    Crystal structure of ShhN–CDO(FNIII3) revealed a calcium-dependent binding interface distinct from Drosophila Ihog–Hh, and mapping of HPE/brachydactyly mutations to this site connected structural biology to human disease mechanism.

    Evidence X-ray crystallography with mutagenesis and biophysical binding assays

    PMID:18794898

    Open questions at the time
    • Structure of full-length CDO or CDO in complex with PTCH1 not determined
    • Calcium regulation in vivo not explored
  8. 2008 High

    Discovery that CDO scaffolds Bnip-2 to activate Cdc42, which feeds into the JLP/p38 cascade, completed the proximal signaling module linking CDO to MAPK activation during myogenesis.

    Evidence Co-IP, Cdc42 activity assays, and gain/loss-of-function in myoblasts

    PMID:18678706

    Open questions at the time
    • Whether Cdc42 activation also feeds into pathways other than p38 not tested
    • Structural basis of Bnip-2–CDO interaction unknown
  9. 2010 High

    Demonstration that N-cadherin—but not Shh—triggers CDO-dependent p38 MAPK activation, and that GAS1/CDO/BOC are collectively obligatory for Hh signaling in vivo, established that CDO's two major signaling functions are ligand-segregated and that the Hh co-receptor system is non-redundant at the organismal level.

    Evidence N-cadherin ligation vs. Shh treatment with co-IP in myoblasts; triple KO mouse with neural tube analysis

    PMID:20160094 PMID:20519495 PMID:21664576

    Open questions at the time
    • How CDO partitions between Hh and N-cadherin complexes at the membrane not defined
    • Structural basis of triple co-receptor cooperativity unknown
  10. 2010 High

    Identification of APPL1 as a CDO-interacting adaptor linking CDO to Akt activation during myogenesis added a second major intracellular signaling branch to the CDO scaffold.

    Evidence Co-IP, RNAi, constitutively active Akt rescue of Cdo-depleted myoblasts

    PMID:20484574

    Open questions at the time
    • Whether Akt and p38 branches are activated simultaneously or sequentially not resolved
    • Direct phosphorylation events downstream of CDO-APPL1-Akt not mapped
  11. 2011 High

    Functional analysis of human CDON HPE mutations showed they impair association with PTCH1 and GAS1 without reducing SHH binding, establishing that co-receptor complex assembly—not ligand capture—is the critical signaling step disrupted in disease.

    Evidence Cell-based SHH signaling assays, co-IP, and SHH binding assays with patient-derived missense mutations

    PMID:21802063

    Open questions at the time
    • Whether additional modifiers are needed for human HPE penetrance not resolved
    • Structural basis of CDO–PTCH1 interaction not determined
  12. 2012 High

    Identification of TAK1 and ASK1 as the MAP3Ks operating within the CDO/JLP scaffold completed the kinase cascade from CDO to p38 MAPK activation.

    Evidence Co-IP with domain mapping, RNAi, and rescue of p38 activation in Cdo−/− myoblasts by TAK1/ASK1 overexpression

    PMID:22337877

    Open questions at the time
    • Whether TAK1 and ASK1 act redundantly or sequentially not resolved
    • Direct kinase–substrate relationships within the scaffold not demonstrated by in vitro kinase assays
  13. 2013 High

    Discovery that CDON functions as a Hedgehog-dependent dependence receptor—triggering caspase-9 activation via intracellular proteolytic cleavage in the absence of SHH—revealed a pro-apoptotic function independent of its co-receptor role.

    Evidence Caspase activity and proteolytic cleavage assays, in vivo tumor model, cell death assays with ligand manipulation

    PMID:23940460

    Open questions at the time
    • Identity of the protease cleaving CDO not determined
    • Physiological tissues where dependence-receptor apoptosis is the dominant function not fully mapped
  14. 2014 High

    Demonstration that CDON suppresses canonical Wnt/β-catenin signaling by binding LRP6 through its Ig2 domain established a third major signaling axis for CDON, mechanistically distinct from both Hh co-reception and p38 scaffolding.

    Evidence Domain-mapping co-IP, Wnt reporter assays, increased Wnt signaling in Cdo−/− forebrain

    PMID:25406935

    Open questions at the time
    • Whether CDO–LRP6 interaction is constitutive or regulated not known
    • Structural basis of Ig2–LDLR interaction not determined
  15. 2014 High

    Context-dependent role of Cdon as a negative Hedgehog regulator (decoy receptor) in optic vesicle neuroepithelium demonstrated that Cdon can trap Hh ligand basolaterally to limit signaling, independent of Patched.

    Evidence In vivo imaging and gain/loss-of-function in zebrafish and chick optic vesicle

    PMID:25001599

    Open questions at the time
    • Molecular basis of tissue-specific switch from positive co-receptor to decoy receptor not resolved
    • Whether post-translational modification or co-factor availability drives the switch unknown
  16. 2020 High

    Conditional satellite cell-specific Cdon ablation revealed that CDON regulates surface localization of FGFR1/FGFR4 and integrin β1 activation, broadening its role to growth factor receptor trafficking in adult muscle stem cells.

    Evidence Inducible satellite cell-specific Cdon KO mouse, co-IP, surface localization assays, muscle regeneration analysis

    PMID:32103583

    Open questions at the time
    • Mechanism by which CDO controls FGFR surface localization not defined
    • Whether CDO-FGFR interaction is direct or scaffolded not resolved
  17. 2020 High

    Discovery that Cdon mutation synergizes with fetal alcohol exposure to inhibit Nodal signaling during gastrulation expanded the pathway repertoire of CDON beyond Hh, Wnt, and p38 into TGF-β superfamily signaling.

    Evidence Cdo KO mouse with timed ethanol exposure, Nodal reporter assays, genetic rescue

    PMID:32876567

    Open questions at the time
    • Whether CDON directly binds Nodal pathway components or acts indirectly not determined
    • Mechanism of ethanol–CDON synergy at the molecular level not resolved
  18. 2023 High

    Tissue-specific CDON functions in vascular calcification (via Wnt/Runx2 suppression in VSMCs) and motor neuron maintenance (via ErbB4/FGFR/Akt signaling) demonstrated that CDON's multifunctional co-receptor activities extend to adult tissue homeostasis and degeneration.

    Evidence VSMC-specific and motor neuron-specific Cdon KO mice with pathway analysis and domain-mapping rescue

    PMID:36609601 PMID:37559423

    Open questions at the time
    • Therapeutic potential of recombinant Ig2 domain in calcification not validated in large animal models
    • Whether motor neuron degeneration is Hh-dependent, Wnt-dependent, or independent not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular logic governing tissue-specific switching of CDON between positive Hh co-receptor, Hh decoy receptor, Wnt suppressor, p38/Akt scaffold, and dependence receptor remains undefined; no integrated structural model of full-length CDON in any multi-receptor complex exists.
  • Full-length CDO structure not solved
  • How post-translational modifications or membrane organization partition CDO among its distinct functions is unknown
  • Whether CDO's dependence-receptor and Wnt-suppressor functions are relevant in adult human tissues not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 7 R-HSA-1500931 Cell-Cell communication 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ABL1APPL1BNIP2BOCGAS1JLPLRP6PTCH1
Complex memberships
CDO-APPL1-Akt signaling complexCDO-BOC-GAS1 Hedgehog co-receptor complexCDO-JLP-p38 MAPK scaffold complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CDO is a novel cell surface glycoprotein of the Ig superfamily containing five Ig-like repeats, three fibronectin type III-like repeats in its extracellular region, and a 256-amino acid intracellular region; its mRNA is rapidly down-regulated by serum stimulation and constitutively down-regulated in oncogene-transformed cells, while CDO protein levels are regulated post-transcriptionally by cell-substratum adhesion. Molecular cloning, Northern blot, Western blot, cell fractionation The Journal of cell biology Medium 9214393
1998 CDO positively regulates skeletal myogenesis: overexpression in C2C12 cells accelerates differentiation, secreted soluble CDO ectodomain inhibits differentiation, and CDO participates in a positive feedback loop with MyoD whereby CDO induces MyoD expression and MyoD induces CDO transcription. Overexpression and dominant-negative constructs in C2C12 myoblasts, reporter assays, mRNA expression analysis The Journal of cell biology High 9786951
2002 CDO and BOC form complexes in cis via association of both their ectodomains and intracellular domains; BOC's promyogenic activity depends on CDO, as a dominant-negative CDO inhibits soluble BOC-induced differentiation. Co-immunoprecipitation, soluble fusion protein assays, dominant-negative constructs in myoblasts The EMBO journal High 11782431
2003 Mice homozygous for targeted mutations of Cdon display hallmark facial defects of holoprosencephaly microforms, establishing a role for Cdon in midline facial patterning in vivo. Gene targeting/knockout mouse, histological and morphological analysis Current biology : CB High 12620190
2004 CDO promotes myogenic differentiation in vivo; mice lacking CDO display delayed skeletal muscle development and their satellite cells differentiate defectively in vitro. CDO activates myogenic bHLH factors via enhanced heterodimer formation, likely by inducing hyperphosphorylation of E proteins. CDO knockout mouse, in vitro satellite cell differentiation assays, reporter assays, protein interaction studies Developmental cell High 15572127
2006 Cdo and Boc bind Sonic Hedgehog (Shh) through a high-affinity interaction with a specific fibronectin type III repeat; ectopic expression of Cdo or Boc results in Shh-dependent, cell-autonomous promotion of ventral cell fates, and loss of Cdo results in Shh dosage-dependent reduction of the floor plate, establishing Cdo as a positive component of the Shh signaling pathway. Binding assays (pulldown), in vivo ectopic expression in mouse neural tube, genetic loss-of-function Developmental cell High 16647304
2006 Cdo functions at multiple points in the Shh pathway: it positively regulates Shh signaling at signal reception and via a parallel mechanism required at the level of Gli transcription factors; Cdo-deficient mice display holoprosencephaly with reduced Shh target gene expression in the developing forebrain. Cdo knockout mouse, in vitro Shh signaling assays, epistasis analysis Developmental cell High 16647303
2006 The Drosophila CDO/BOC ortholog Ihog binds Hh protein via its first fibronectin type III domain; epistasis analysis places Ihog action at or upstream of Patched; other family members including mammalian CDO and BOC also interact with Hh ligands via a specific FNIII domain. RNAi screen, in vitro binding assays, epistasis analysis in Drosophila Cell High 16630821
2006 Cdo intracellular region interacts with JLP, a scaffold protein for the p38alpha/beta MAPK pathway; Cdo, JLP, and p38alpha/beta form complexes in differentiating myoblasts; Cdo and JLP cooperate to enhance active p38alpha/beta levels; Cdo-/- primary myoblasts are deficient in p38alpha/beta activity, and expression of activated MKK6 rescues differentiation of Cdo-/- cells. Co-immunoprecipitation, kinase activity assays, primary myoblasts from Cdo-/- mice, rescue by activated MKK6 The Journal of cell biology High 17074887
2006 Mice lacking CDO display cortical thinning and hydrocephalus; CDO promotes neuronal differentiation by enhancing neurogenin1/E47 heterodimer formation in reporter assays; CDO levels increase during neuronal precursor differentiation, and modulation of CDO by overexpression or RNAi enhances or diminishes differentiation. Cdo KO mouse, neural progenitor cultures, co-transfection reporter assays, RNAi Molecular and cellular biology High 16648472
2007 Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development; removal of both Gas1 and Cdo results in a Shh dose-dependent loss of cell identities more severe than either single mutant, establishing genetic epistasis. Gas1 and Cdo single and double knockout mice, neural tube analysis, genetic epistasis Genes & development High 17504941
2008 X-ray crystal structure of ShhN bound to the third FNIII repeat of CDO reveals that the ShhN–CDO interaction requires calcium binding at a previously undetected site on ShhN; this interaction is completely unlike the HhN–Ihog interaction and the calcium-binding site is a hotspot for interactions with CDO, Ptc, Hip, and Gas1; HPE- and brachydactyly-causing mutations map to this calcium-binding site. X-ray crystallography, biochemical and biophysical binding assays, mutagenesis Nature High 18794898
2008 Cdo interacts with Bnip-2 (a Cdc42 GAP regulator); Cdo brings together Bnip-2 and JLP through mutual interaction; the Cdo-Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38alpha/beta activity and myoblast differentiation. Co-immunoprecipitation, gain- and loss-of-function experiments in myoblasts, Cdc42 activity assays The Journal of cell biology High 18678706
2009 Cdo promotes neuronal differentiation via activation of Cdc42 and p38MAPK using the same scaffold proteins (JLP and Bnip-2) as in myogenesis; Cdo also promotes heterodimerization of neurogenin1 and E47, suggesting a conserved intracellular mechanism for tissue-specific bHLH factor regulation. Overexpression, RNAi, kinase activity assays in neural precursor cells and P19 cells FASEB journal Medium 19244314
2009 Cdo binds Abl tyrosine kinase via a proline-rich motif in Cdo through Abl's SH3 domain; Cdo is important for full Abl kinase activity; Abl associates with both Cdo and JLP during myoblast differentiation and is necessary for full p38 MAPK activation during myogenic differentiation. Co-immunoprecipitation, domain mapping, kinase assays, knockdown/rescue experiments in myoblasts Molecular and cellular biology High 19470755
2010 N-cadherin ligation activates p38alpha/beta MAPK in myoblasts in a Cdo-, Bnip-2-, and JLP-dependent manner, while Shh binding to Cdo does not activate p38alpha/beta and does not recruit JLP or Bnip-2; this demonstrates that Cdo serves as a multifunctional co-receptor with mechanistically distinct roles in different signaling pathways. N-cadherin ligation assays, co-immunoprecipitation, p38 kinase activity assays, myoblast differentiation Proceedings of the National Academy of Sciences of the United States of America High 20160094
2010 GAS1, CDO, and BOC play overlapping and collectively essential roles in Hedgehog-mediated ventral neural patterning; triple genetic loss-of-function reveals an obligatory requirement for these co-receptors in HH pathway activity in multiple tissues. Single, double, and triple knockout mice, neural tube patterning analysis Developmental cell High 21664576
2010 All three mammalian Hedgehog proteins (Sonic, Indian, Desert Hh) bind CDO and BOC in the same manner via the same non-orthologous FNIII domains; X-ray crystal structures of Shh, Ihh, and Dhh bound to CDO and BOC confirm conserved binding mode; CDO–Hh interactions are weakened at low pH. X-ray crystallography, biochemical binding assays with all three mammalian Hh proteins The Journal of biological chemistry High 20519495
2010 Cdo interacts with APPL1 (an Akt-binding protein); both Cdo and APPL1 are required for efficient Akt activation during myoblast differentiation; overexpression of constitutively active Akt rescues defective differentiation of Cdo-depleted cells, placing Cdo upstream of Akt. Co-immunoprecipitation, RNAi, Akt activity assays, rescue with constitutively active Akt Molecular biology of the cell High 20484574
2010 Boc acts as a silent HPE modifier gene; Cdo;Boc double mutants display lobar HPE with defects in Shh target gene expression in the developing forebrain, while either single mutant on the same background does not, demonstrating that Cdo and Boc have partially redundant roles in Shh signaling in the mammalian forebrain. Single and double knockout mice, Shh target gene expression analysis in developing forebrain Disease models & mechanisms High 21183473
2011 CDON missense mutations identified in human HPE patients impair CDON's ability to support SHH-dependent gene expression but do not reduce SHH binding; instead, the mutant CDON proteins fail to efficiently associate with PTCH1 and GAS1, demonstrating that CDON must interact with other Hedgehog receptor components for signaling. Cell-based SHH signaling assays, co-immunoprecipitation, SHH binding assays American journal of human genetics High 21802063
2011 Integrin/FAK signaling is required for Cdo expression in myoblasts; overexpression of FAK rescues Cdo and MyoD expression as well as myotube formation on integrin-independent substrates; Cdo mediates Integrin/FAK-dependent activation of Cdc42 and p38MAPK signaling. Culture on integrin-independent substrates, FAK overexpression, Western blotting, differentiation assays Cellular signalling Medium 21397010
2011 Gas1 and Cdo are coexpressed in muscle cells and form a complex in differentiating myoblasts; Gas1 depletion causes defects in p38MAPK activation; Gas1 overexpression in Cdo-depleted myoblasts restores p38MAPK activity and differentiation ability. Co-immunoprecipitation, RNAi, p38 kinase assays, differentiation rescue experiments Cellular signalling Medium 21820049
2012 Netrin-2/Cdo signaling induces Stim1 phosphorylation at serine 575 via ERK1/2, promoting NFATc3 activation and myoblast differentiation; Cdo and Stim1 form a complex in differentiating myoblasts; alanine substitution of Stim1 S575 fails to rescue differentiation of Stim1-depleted cells. Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis, rescue experiments Molecular biology of the cell High 22298426
2012 TAK1 and ASK1 both interact with the cytoplasmic tail of Cdo and with the scaffold protein JLP; depletion of TAK1 or ASK1 decreases p38MAPK activation and myoblast differentiation; overexpression of TAK1 or ASK1 in Cdo-/- myoblasts restores p38MAPK activation and differentiation, identifying them as MAP3Ks in Cdo-mediated p38MAPK activation. Co-immunoprecipitation, RNAi knockdown, kinase assays, rescue in Cdo-/- cells The Journal of biological chemistry High 22337877
2012 Cx43 physically interacts with Cdo to form dynamic complexes during myoblast differentiation, as shown by co-localization and FRET/FLIM analysis. FRET/FLIM imaging, co-immunoprecipitation, co-localization Journal of biophotonics Medium 22930637
2013 CDON behaves as a SHH dependence receptor: in the absence of SHH, CDON actively triggers apoptosis via a proteolytic cleavage in its intracellular domain, allowing recruitment and activation of caspase-9; SHH binding to CDON inhibits this pro-apoptotic activity. Caspase activity assays, proteolytic cleavage assays, tumor growth in vivo, cell death assays with ligand/receptor manipulation PLoS biology High 23940460
2013 Cdo-deficient mice display megaesophagus and impaired esophageal smooth muscle fascicular reorientation; Cdo is specifically required for the morphogenetic process by which smooth muscle fascicles change orientation to allow the skeletal muscle transition zone to migrate distally. Cdo KO mouse, histochemistry, live imaging of esophageal development The Journal of cell biology Medium 23569214
2014 Cdon suppresses canonical Wnt signaling by interacting with LRP6 via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6; this interaction is necessary and sufficient for Cdo-dependent Wnt inhibition; Cdo-deficient dorsal forebrain displays enhanced Wnt signaling and increased cell proliferation. Co-immunoprecipitation with domain mapping, Wnt reporter assays, Cdo-/- mouse forebrain analysis Nature communications High 25406935
2014 In the developing zebrafish and chick optic vesicle, Cdon acts as a negative Hh signaling regulator by localizing predominantly to the basolateral side of neuroepithelial cells, promoting basal end-foot enlargement, and trapping Hh protein to limit its dispersion—a Patched-independent function. In vivo imaging, loss/gain-of-function in zebrafish and chick, protein localization studies Nature communications High 25001599
2014 SHH promotes survival of neural crest cells in the first branchial arch by inhibiting CDO pro-apoptotic activity; silencing CDO rescues neural crest cells from apoptosis induced by SHH inhibition in the ventral foregut endoderm. Silencing of CDO in chick embryo model, apoptosis assays, SHH pathway inhibition Biochemical and biophysical research communications Medium 25193697
2015 CDON and BOC use distinct molecular mechanisms for HH signaling: CDON requires membrane attachment and specific extracellular motifs distinct from those of BOC; these distinct structural requirements were mapped by in vivo gain-of-function in the developing chicken spinal cord. In vivo gain-of-function assay in chick spinal cord using deletion and chimeric constructs Developmental biology Medium 25848697
2015 Cdo regulates surface expression of the potassium channel Kir2.1 during early myoblast differentiation via p38MAPK signaling; Cdo forms a complex with Kir2.1, and Cdo depletion reduces Kir2.1 channel surface expression and activity. Co-immunoprecipitation, surface biotinylation assays, electrophysiology, p38MAPK inhibitor experiments PloS one Medium 27380411
2015 Syntaxin 4 (Stx4) binds to the cytoplasmic tail of Cdo and regulates Cdo surface localization; Stx4 depletion specifically decreases cell surface Cdo without affecting surface N-cadherin levels; conversely, Cdo depletion reduces GLUT4 and Stx4 at the cell surface and impairs glucose uptake. Co-immunoprecipitation, surface biotinylation, glucose uptake assays, RNAi knockdown Skeletal muscle Medium 26347807
2015 Cdon regulates N-cadherin localization in zebrafish neural crest cells; cdon knockdown results in mislocalized N-cadherin and aberrant trunk NCC migration with reduced directedness and mispositioned protrusions; cdon is required cell-autonomously for directed NCC migration. Morpholino knockdown in zebrafish, live cell imaging, transplantation analysis, immunostaining Developmental biology Medium 26256768
2016 PKN2 (protein kinase C-related kinase 2) forms complexes with Cdo, APPL1, and Akt via its C-terminal region; PKN2 expression is dependent on Cdo during differentiation; PKN2 promotes AKT activity and myoblast differentiation and facilitates MyoD/BAF60c recruitment to the myogenin promoter. Co-immunoprecipitation, RNAi, AKT activity assays, chromatin immunoprecipitation Cell death & disease Medium 27763641
2016 Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and its loss leads to increased proliferating cells in this region; Cdon-/- mice have increased VTA (but not SNc) TH-positive neurons at birth and adulthood, and greater mesocortical dopamine presynaptic sites. Cdo KO mouse, immunostaining, dopamine quantification by HPLC, behavioral analysis eNeuro Medium 27419218
2017 Cdon deficiency causes hyperactive Wnt/β-catenin signaling in the heart, leading to β-catenin accumulation, Axin2 upregulation, and aberrant Connexin 43 (Cx43) expression and mislocalization; Cdon is localized at intercalated discs; inhibition of Wnt/β-catenin signaling prevents Cdon depletion-induced collagen 1a and Cx43 upregulation. Cdo KO mouse, co-immunoprecipitation, Wnt reporter assays, pharmacological inhibition of Wnt pathway Proceedings of the National Academy of Sciences of the United States of America High 28154134
2018 Ash1L (a Trithorax group epigenetic activator) is required to counteract Polycomb repression at the Cdon locus to allow Cdon expression during myoblast fusion; Ash1L-mediated activation of Cdon is required for myoblast fusion. ChIP-sequencing, RNA-sequencing, Ash1L KO mice, in vitro differentiation assays Nature communications High 30487570
2020 Cdon in satellite cells interacts with and regulates cell surface localization of FGFR1 and FGFR4; satellite cell-specific Cdon ablation causes impaired integrin β1 activation and FGF responsiveness, decreased satellite cell proliferation, and impaired muscle regeneration. Inducible satellite cell-specific Cdon KO mouse, co-immunoprecipitation, surface localization assays, EdU incorporation, RNA sequencing Journal of cachexia, sarcopenia and muscle High 32103583
2020 In a mouse model of HPE, Cdon mutation and fetal alcohol exposure synergistically inhibit Nodal signaling (not just HH signaling) during gastrulation; window-of-sensitivity experiments show that brief ethanol exposure during gastrulation transiently inhibits Nodal pathway activity. Cdo KO mouse, timed ethanol exposure, Nodal reporter assays, genetic rescue experiments eLife High 32876567
2020 In endothelial cells, Cdon acts as a decoy receptor for Desert Hedgehog (Dhh), preventing Dhh binding to Ptch1, whereas Gas1 promotes Dhh binding to Smo; EC-specific Cdon knockout promotes endothelial junction integrity. EC-specific conditional Cdon KO mouse, siRNA, binding assays, vascular permeability assays Arteriosclerosis, thrombosis, and vascular biology Medium 33028094
2021 A Dispatched (DISP)-BOC/CDON co-receptor complex functions in ligand-producing cells to promote cytoneme occurrence and facilitate SHH ligand delivery; Myosin 10 promotes vesicular transport of SHH in mouse cell cytonemes; cytoneme-mediated SHH deposition triggers rapid receptor-dependent signaling within seconds. Live cell imaging, super-resolution microscopy, co-immunoprecipitation, Myo10 knockout mice eLife High 33570491
2022 CDON collectively functions with GAS1 and BOC in HH-dependent limb patterning; limb-specific conditional deletion of Cdon in a Gas1;Boc null background results in digit loss and defects in limb outgrowth and long bone patterning. Limb-specific conditional Cdon KO in Gas1;Boc null background, skeletal analysis Developmental biology High 36265686
2023 Cdon in vascular smooth muscle cells suppresses Wnt/Runx2-driven osteogenic transdifferentiation and vascular calcification; the Ig2 domain of Cdon ectodomain is required for Wnt suppression; recombinant Ig2 domain protein can suppress Wnt signaling and VSMC calcification. VSMC-specific Cdon KO mouse, Wnt reporter assays, domain deletion mutants, recombinant protein treatment Experimental & molecular medicine High 36609601
2023 Motor neuron-specific Cdon ablation causes aging-related motor neuron degeneration, impaired sciatic nerve repair and reinnervation, and myelination defects; mechanistically, Cdon-depleted motor neurons show altered ErbB4 and FGFR expression and impaired Akt activation in response to neuregulin-1. Motor neuron-specific Cdo KO mouse (Hb9-Cre), sciatic nerve crush model, RNA sequencing, immunostaining, Akt activation assays in NSC34 cells Journal of cachexia, sarcopenia and muscle High 37559423

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Developmental cell 298 16647304
2011 Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Developmental cell 227 21664576
2007 The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes & development 224 17504941
2006 Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Developmental cell 206 16647303
2006 The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 179 16630821
2002 BOC, an Ig superfamily member, associates with CDO to positively regulate myogenic differentiation. The EMBO journal 125 11782431
2008 The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 124 18794898
2011 Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. American journal of human genetics 108 21802063
2006 Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. The Journal of cell biology 103 17074887
2012 Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS genetics 100 23071453
2008 A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38alpha/beta MAPK activity and myogenic differentiation. The Journal of cell biology 91 18678706
2003 Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Current biology : CB 91 12620190
2010 The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development (Cambridge, England) 89 20501592
1998 CDO, a robo-related cell surface protein that mediates myogenic differentiation. The Journal of cell biology 89 9786951
2004 Positive regulation of myogenic bHLH factors and skeletal muscle development by the cell surface receptor CDO. Developmental cell 85 15572127
1997 CDO: an oncogene-, serum-, and anchorage-regulated member of the Ig/fibronectin type III repeat family. The Journal of cell biology 81 9214393
2012 Balancing Hedgehog, a retention and release equilibrium given by Dally, Ihog, Boi and shifted/DmWif. Developmental biology 64 23276604
2010 Boc modifies the holoprosencephaly spectrum of Cdo mutant mice. Disease models & mechanisms 57 21183473
2010 N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38alpha/beta MAPK signaling in skeletal myoblasts. Proceedings of the National Academy of Sciences of the United States of America 55 20160094
2010 All mammalian Hedgehog proteins interact with cell adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner. The Journal of biological chemistry 54 20519495
2017 Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America 51 28154134
2010 Cdo interacts with APPL1 and activates Akt in myoblast differentiation. Molecular biology of the cell 50 20484574
2021 Cytoneme delivery of Sonic Hedgehog from ligand-producing cells requires Myosin 10 and a Dispatched-BOC/CDON co-receptor complex. eLife 49 33570491
2013 Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity. PLoS biology 49 23940460
2014 Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle. Nature communications 47 25001599
2010 Ihog and Boi are essential for Hedgehog signaling in Drosophila. Neural development 42 21044292
2000 Developmental expression pattern of the cdo gene. Developmental dynamics : an official publication of the American Association of Anatomists 42 10974670
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2009 Cdo promotes neuronal differentiation via activation of the p38 mitogen-activated protein kinase pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 19244314
2015 A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome. The Journal of clinical endocrinology and metabolism 39 26529631
2014 Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation. Nature communications 39 25406935
2018 Sublethal effects of chronic exposure to CdO or PbO nanoparticles or their binary mixture on the honey bee (Apis millefera L.). Environmental science and pollution research international 36 30280346
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2021 ZnO-CdO nanocomposites incorporated with graphene oxide nanosheets for efficient photocatalytic degradation of bisphenol A, thymol blue and ciprofloxacin. Journal of hazardous materials 35 34607025
2016 PKN2 and Cdo interact to activate AKT and promote myoblast differentiation. Cell death & disease 35 27763641
2012 TGF-β-activated kinase 1 (TAK1) and apoptosis signal-regulating kinase 1 (ASK1) interact with the promyogenic receptor Cdo to promote myogenic differentiation via activation of p38MAPK pathway. The Journal of biological chemistry 35 22337877
2006 Cortical thinning and hydrocephalus in mice lacking the immunoglobulin superfamily member CDO. Molecular and cellular biology 35 16648472
2011 Promyogenic function of Integrin/FAK signaling is mediated by Cdo, Cdc42 and MyoD. Cellular signalling 33 21397010
2020 Satellite cell-specific ablation of Cdon impairs integrin activation, FGF signalling, and muscle regeneration. Journal of cachexia, sarcopenia and muscle 30 32103583
2020 Consequences of a short-term exposure to a sub lethal concentration of CdO nanoparticles on key life history traits in the fruit fly (Drosophila melanogaster). Journal of hazardous materials 30 33349477
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2014 Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma. Journal of the National Cancer Institute 28 25313246
2010 Brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish. Development (Cambridge, England) 28 21115611
2012 Phosphorylation of Stim1 at serine 575 via netrin-2/Cdo-activated ERK1/2 is critical for the promyogenic function of Stim1. Molecular biology of the cell 27 22298426
2012 CdO nanoparticle toxicity on growth, morphology, and cell division in Escherichia coli. Langmuir : the ACS journal of surfaces and colloids 27 23137198
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2016 Prenatal ethanol exposure in mice phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia. Disease models & mechanisms 25 27935818
2015 Cdon promotes neural crest migration by regulating N-cadherin localization. Developmental biology 25 26256768
2005 BOC, brother of CDO, is a dorsoventral axon-guidance molecule in the embryonic vertebrate brain. The Journal of comparative neurology 24 15776441
2013 Rescue of holoprosencephaly in fetal alcohol-exposed Cdon mutant mice by reduced gene dosage of Ptch1. PloS one 22 24244464
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2017 Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs. Nature communications 20 29097673
2013 Smooth muscle fascicular reorientation is required for esophageal morphogenesis and dependent on Cdo. The Journal of cell biology 20 23569214
2023 Cdon suppresses vascular smooth muscle calcification via repression of the Wnt/Runx2 Axis. Experimental & molecular medicine 19 36609601
2015 Distinct structural requirements for CDON and BOC in the promotion of Hedgehog signaling. Developmental biology 19 25848697
2018 The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression. Nature communications 18 30487570
2014 Sonic Hedgehog promotes the survival of neural crest cells by limiting apoptosis induced by the dependence receptor CDON during branchial arch development. Biochemical and biophysical research communications 18 25193697
2016 Cdo Regulates Surface Expression of Kir2.1 K+ Channel in Myoblast Differentiation. PloS one 17 27380411
2014 Shifting redox states of the iron center partitions CDO between crosslink formation or cysteine oxidation. Archives of biochemistry and biophysics 16 24929188
2011 Identification of transmembrane protein in prostate cancer by the Escherichia coli ampicillin secretion trap: expression of CDON is involved in tumor cell growth and invasion. Pathobiology : journal of immunopathology, molecular and cellular biology 16 21849809
2020 Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly. eLife 15 32876567
2020 Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes). Arteriosclerosis, thrombosis, and vascular biology 15 33028094
2014 The Shh coreceptor Cdo is required for differentiation of midbrain dopaminergic neurons. Stem cell research 15 25117422
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2016 A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells. Journal of molecular and cellular cardiology 14 26906632
2014 CDO, an Hh-coreceptor, mediates lung cancer cell proliferation and tumorigenicity through Hedgehog signaling. PloS one 14 25369201
2012 A molecular imaging analysis of Cx43 association with Cdo during skeletal myoblast differentiation. Journal of biophotonics 14 22930637
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2012 The Drosophila WIF1 homolog Shifted maintains glypican-independent Hedgehog signaling and interacts with the Hedgehog co-receptors Ihog and Boi. Development (Cambridge, England) 13 23154411
2006 Mutational screening of FGFR1, CER1, and CDON in a large cohort of trigonocephalic patients. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 13 16526918
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2003 Overexpression of the immunoglobulin superfamily members CDO and BOC enhances differentiation of the human rhabdomyosarcoma cell line RD. Molecular carcinogenesis 12 12720294
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2019 Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis. American journal of medical genetics. Part A 9 31502381
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2021 Enhanced photocatalytic and photodynamic activity of chitosan and garlic loaded CdO-TiO2 hybrid bionanomaterials. Scientific reports 7 34675259
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2023 Mutations in cdon and boc affect trunk neural crest cell migration and slow-twitch muscle development in zebrafish. Development (Cambridge, England) 6 37390228
2022 Exposure to a sublethal concentration of CdO nanoparticles impairs the vision of the fruit fly (Drosophila melanogaster) by disrupting histamine synthesis and recycling mechanisms. Environmental science and pollution research international 6 36394804
2021 Formation Mechanism of Cofactor Cys-Tyr in the Cysteine Dioxygenases (CDO and F2-CDO) and Its Influence on Catalysis: A QM/MM Study. Inorganic chemistry 6 34008401
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2018 Experimental and computational assessment of mycosynthesized CdO nanoparticles towards biomedical applications. Journal of photochemistry and photobiology. B, Biology 5 29448204
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2016 Toxicity and efficacy of CdO nanostructures on the MDCK and Caki-2 cells. Journal of photochemistry and photobiology. B, Biology 5 27689742
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