{"gene":"CDON","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"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.","method":"Molecular cloning, Northern blot, Western blot, cell fractionation","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — original characterization with multiple biochemical methods in a single lab","pmids":["9214393"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Overexpression and dominant-negative constructs in C2C12 myoblasts, reporter assays, mRNA expression analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal gain- and loss-of-function experiments, replicated across subsequent studies","pmids":["9786951"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation, soluble fusion protein assays, dominant-negative constructs in myoblasts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional rescue experiments with defined constructs","pmids":["11782431"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Gene targeting/knockout mouse, histological and morphological analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific developmental phenotype, foundational in vivo loss-of-function study","pmids":["12620190"],"is_preprint":false},{"year":2004,"finding":"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.","method":"CDO knockout mouse, in vitro satellite cell differentiation assays, reporter assays, protein interaction studies","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO with specific phenotype plus mechanistic dissection of bHLH activation","pmids":["15572127"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Binding assays (pulldown), in vivo ectopic expression in mouse neural tube, genetic loss-of-function","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated plus genetic epistasis in vivo, highly cited foundational paper","pmids":["16647304"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Cdo knockout mouse, in vitro Shh signaling assays, epistasis analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with molecular pathway analysis, multiple methods, highly cited","pmids":["16647303"],"is_preprint":false},{"year":2006,"finding":"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.","method":"RNAi screen, in vitro binding assays, epistasis analysis in Drosophila","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assays with domain mapping plus genetic epistasis, highly cited","pmids":["16630821"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation, kinase activity assays, primary myoblasts from Cdo-/- mice, rescue by activated MKK6","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional rescue experiments with defined pathway components","pmids":["17074887"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Cdo KO mouse, neural progenitor cultures, co-transfection reporter assays, RNAi","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO phenotype plus mechanistic in vitro assays","pmids":["16648472"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Gas1 and Cdo single and double knockout mice, neural tube analysis, genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — compound genetic epistasis in vivo with clear pathway placement","pmids":["17504941"],"is_preprint":false},{"year":2008,"finding":"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.","method":"X-ray crystallography, biochemical and biophysical binding assays, mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with biochemical validation and mutagenesis, highly cited","pmids":["18794898"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, gain- and loss-of-function experiments in myoblasts, Cdc42 activity assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — co-IP plus functional gain/loss-of-function with specific pathway readouts","pmids":["18678706"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Overexpression, RNAi, kinase activity assays in neural precursor cells and P19 cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell-based assays but single lab, mechanistic extension of prior work","pmids":["19244314"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, domain mapping, kinase assays, knockdown/rescue experiments in myoblasts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain-level co-IP plus kinase activity assays with functional rescue","pmids":["19470755"],"is_preprint":false},{"year":2010,"finding":"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.","method":"N-cadherin ligation assays, co-immunoprecipitation, p38 kinase activity assays, myoblast differentiation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with multiple orthogonal assays distinguishing two signaling modes","pmids":["20160094"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Single, double, and triple knockout mice, neural tube patterning analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — compound genetic epistasis in vivo with clear obligatory requirement established, highly cited","pmids":["21664576"],"is_preprint":false},{"year":2010,"finding":"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.","method":"X-ray crystallography, biochemical binding assays with all three mammalian Hh proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures plus biochemical validation, multiple ligand-receptor pairs","pmids":["20519495"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, RNAi, Akt activity assays, rescue with constitutively active Akt","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — co-IP plus functional epistasis with defined pathway rescue","pmids":["20484574"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Single and double knockout mice, Shh target gene expression analysis in developing forebrain","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 — compound genetic epistasis in vivo with molecular pathway readout","pmids":["21183473"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Cell-based SHH signaling assays, co-immunoprecipitation, SHH binding assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays with disease-relevant mutations; functional dissection of binding requirements","pmids":["21802063"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Culture on integrin-independent substrates, FAK overexpression, Western blotting, differentiation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — functional rescue experiments, single lab","pmids":["21397010"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, RNAi, p38 kinase assays, differentiation rescue experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional rescue, single lab","pmids":["21820049"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis, rescue experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — site-directed mutagenesis plus co-IP and functional rescue establishes a specific phosphorylation event","pmids":["22298426"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, RNAi knockdown, kinase assays, rescue in Cdo-/- cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — co-IP with domain mapping plus functional rescue in KO cells","pmids":["22337877"],"is_preprint":false},{"year":2012,"finding":"Cx43 physically interacts with Cdo to form dynamic complexes during myoblast differentiation, as shown by co-localization and FRET/FLIM analysis.","method":"FRET/FLIM imaging, co-immunoprecipitation, co-localization","journal":"Journal of biophotonics","confidence":"Medium","confidence_rationale":"Tier 3 — imaging-based interaction evidence, single lab","pmids":["22930637"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Caspase activity assays, proteolytic cleavage assays, tumor growth in vivo, cell death assays with ligand/receptor manipulation","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic cleavage/caspase assays plus in vivo tumor model, multiple methods","pmids":["23940460"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Cdo KO mouse, histochemistry, live imaging of esophageal development","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific morphogenetic phenotype, single lab","pmids":["23569214"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation with domain mapping, Wnt reporter assays, Cdo-/- mouse forebrain analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — domain-level co-IP plus in vivo genetic and reporter evidence","pmids":["25406935"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vivo imaging, loss/gain-of-function in zebrafish and chick, protein localization studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple organisms and orthogonal methods establishing context-dependent decoy function","pmids":["25001599"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Silencing of CDO in chick embryo model, apoptosis assays, SHH pathway inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo rescue experiment with molecular pathway placement","pmids":["25193697"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vivo gain-of-function assay in chick spinal cord using deletion and chimeric constructs","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping in vivo with multiple constructs, single lab","pmids":["25848697"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, surface biotinylation assays, electrophysiology, p38MAPK inhibitor experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus surface expression and functional channel assays, single lab","pmids":["27380411"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, surface biotinylation, glucose uptake assays, RNAi knockdown","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with domain mapping plus surface expression assays, single lab","pmids":["26347807"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Morpholino knockdown in zebrafish, live cell imaging, transplantation analysis, immunostaining","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging plus transplantation plus localization studies, single lab","pmids":["26256768"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, RNAi, AKT activity assays, chromatin immunoprecipitation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus ChIP and kinase assays, single lab","pmids":["27763641"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Cdo KO mouse, immunostaining, dopamine quantification by HPLC, behavioral analysis","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with specific molecular and cellular phenotypes, single lab","pmids":["27419218"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Cdo KO mouse, co-immunoprecipitation, Wnt reporter assays, pharmacological inhibition of Wnt pathway","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with specific pathway rescue experiments and multiple readouts","pmids":["28154134"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ChIP-sequencing, RNA-sequencing, Ash1L KO mice, in vitro differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq plus genetic KO with specific phenotype linked to Cdon expression","pmids":["30487570"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Inducible satellite cell-specific Cdon KO mouse, co-immunoprecipitation, surface localization assays, EdU incorporation, RNA sequencing","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 — conditional cell-type-specific KO with co-IP establishing receptor interaction and multiple functional readouts","pmids":["32103583"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Cdo KO mouse, timed ethanol exposure, Nodal reporter assays, genetic rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches defining pathway interaction","pmids":["32876567"],"is_preprint":false},{"year":2020,"finding":"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.","method":"EC-specific conditional Cdon KO mouse, siRNA, binding assays, vascular permeability assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mechanistic binding assays, single lab","pmids":["33028094"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Live cell imaging, super-resolution microscopy, co-immunoprecipitation, Myo10 knockout mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging modalities plus co-IP and KO mice with defined cellular phenotype","pmids":["33570491"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Limb-specific conditional Cdon KO in Gas1;Boc null background, skeletal analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — compound conditional KO with specific developmental phenotypes","pmids":["36265686"],"is_preprint":false},{"year":2023,"finding":"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.","method":"VSMC-specific Cdon KO mouse, Wnt reporter assays, domain deletion mutants, recombinant protein treatment","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — conditional KO plus domain-mapping with recombinant protein rescue","pmids":["36609601"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Motor neuron-specific Cdo KO mouse (Hb9-Cre), sciatic nerve crush model, RNA sequencing, immunostaining, Akt activation assays in NSC34 cells","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with mechanistic pathway analysis","pmids":["37559423"],"is_preprint":false}],"current_model":"CDON (CDO) is a multifunctional cell-surface co-receptor of the Ig/fibronectin superfamily that (1) binds Sonic/Indian/Desert Hedgehog ligands via its third FNIII repeat in a calcium-dependent manner and, in complex with PTCH1 and GAS1, positively promotes HH pathway signaling in most developmental contexts but can act as a decoy receptor in specific tissues; (2) activates p38α/β MAPK and Akt signaling during myogenic differentiation by scaffolding Bnip-2/Cdc42, JLP, APPL1, Abl, TAK1, and ASK1 in complexes assembled around its intracellular domain upon N-cadherin ligation; (3) suppresses canonical Wnt/β-catenin signaling via its Ig2 ectodomain binding to LRP6, thereby promoting neuronal and cardiomyocyte differentiation and protecting against vascular calcification; and (4) functions as a dependence receptor that triggers caspase-9-mediated apoptosis through intracellular proteolytic cleavage when its SHH ligand is absent."},"narrative":{"teleology":[{"year":1997,"claim":"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","pmids":["9214393"],"confidence":"Medium","gaps":["No signaling pathway or ligand identified","Functional role inferred only from expression pattern"]},{"year":1998,"claim":"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","pmids":["9786951"],"confidence":"High","gaps":["Intracellular signaling mechanism unknown","Extracellular ligand for promyogenic function not identified"]},{"year":2002,"claim":"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","pmids":["11782431"],"confidence":"High","gaps":["Stoichiometry and structure of CDO-BOC complex unknown","Shared versus distinct signaling outputs not resolved"]},{"year":2003,"claim":"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","pmids":["12620190"],"confidence":"High","gaps":["Which signaling pathway is disrupted in vivo not yet defined","Whether phenotype is Shh-dependent not directly tested"]},{"year":2004,"claim":"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","pmids":["15572127"],"confidence":"High","gaps":["Kinase responsible for E-protein phosphorylation not identified","Direct versus indirect mechanism not resolved"]},{"year":2006,"claim":"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","pmids":["16647304","16647303","16630821","17074887"],"confidence":"High","gaps":["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"]},{"year":2008,"claim":"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","pmids":["18794898"],"confidence":"High","gaps":["Structure of full-length CDO or CDO in complex with PTCH1 not determined","Calcium regulation in vivo not explored"]},{"year":2008,"claim":"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","pmids":["18678706"],"confidence":"High","gaps":["Whether Cdc42 activation also feeds into pathways other than p38 not tested","Structural basis of Bnip-2–CDO interaction unknown"]},{"year":2010,"claim":"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","pmids":["20160094","21664576","20519495"],"confidence":"High","gaps":["How CDO partitions between Hh and N-cadherin complexes at the membrane not defined","Structural basis of triple co-receptor cooperativity unknown"]},{"year":2010,"claim":"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","pmids":["20484574"],"confidence":"High","gaps":["Whether Akt and p38 branches are activated simultaneously or sequentially not resolved","Direct phosphorylation events downstream of CDO-APPL1-Akt not mapped"]},{"year":2011,"claim":"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","pmids":["21802063"],"confidence":"High","gaps":["Whether additional modifiers are needed for human HPE penetrance not resolved","Structural basis of CDO–PTCH1 interaction not determined"]},{"year":2012,"claim":"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","pmids":["22337877"],"confidence":"High","gaps":["Whether TAK1 and ASK1 act redundantly or sequentially not resolved","Direct kinase–substrate relationships within the scaffold not demonstrated by in vitro kinase assays"]},{"year":2013,"claim":"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","pmids":["23940460"],"confidence":"High","gaps":["Identity of the protease cleaving CDO not determined","Physiological tissues where dependence-receptor apoptosis is the dominant function not fully mapped"]},{"year":2014,"claim":"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","pmids":["25406935"],"confidence":"High","gaps":["Whether CDO–LRP6 interaction is constitutive or regulated not known","Structural basis of Ig2–LDLR interaction not determined"]},{"year":2014,"claim":"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","pmids":["25001599"],"confidence":"High","gaps":["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"]},{"year":2020,"claim":"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","pmids":["32103583"],"confidence":"High","gaps":["Mechanism by which CDO controls FGFR surface localization not defined","Whether CDO-FGFR interaction is direct or scaffolded not resolved"]},{"year":2020,"claim":"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","pmids":["32876567"],"confidence":"High","gaps":["Whether CDON directly binds Nodal pathway components or acts indirectly not determined","Mechanism of ethanol–CDON synergy at the molecular level not resolved"]},{"year":2023,"claim":"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","pmids":["36609601","37559423"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,6,7,16,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,12,14,18,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28,37,44]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,15,33,39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7,10,16,17,28,37,44]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,6,9,10,19,43]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[26,30]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[15,34]}],"complexes":["CDO-BOC-GAS1 Hedgehog co-receptor complex","CDO-JLP-p38 MAPK scaffold complex","CDO-APPL1-Akt signaling complex"],"partners":["BOC","GAS1","PTCH1","JLP","BNIP2","ABL1","APPL1","LRP6"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q4KMG0","full_name":"Cell adhesion molecule-related/down-regulated by oncogenes","aliases":[],"length_aa":1287,"mass_kda":139.1,"function":"Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q4KMG0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDON","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDON","total_profiled":1310},"omim":[{"mim_id":"614226","title":"HOLOPROSENCEPHALY 11; HPE11","url":"https://www.omim.org/entry/614226"},{"mim_id":"608708","title":"BROTHER OF CDON; BOC","url":"https://www.omim.org/entry/608708"},{"mim_id":"608707","title":"CELL ADHESION MOLECULE-RELATED/DOWNREGULATED BY ONCOGENES; CDON","url":"https://www.omim.org/entry/608707"},{"mim_id":"600725","title":"SONIC HEDGEHOG SIGNALING MOLECULE; SHH","url":"https://www.omim.org/entry/600725"},{"mim_id":"236100","title":"HOLOPROSENCEPHALY 1; HPE1","url":"https://www.omim.org/entry/236100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":13.5}],"url":"https://www.proteinatlas.org/search/CDON"},"hgnc":{"alias_symbol":["ORCAM","CDO","CDON1","Ihog"],"prev_symbol":[]},"alphafold":{"accession":"Q4KMG0","domains":[{"cath_id":"2.60.40.10","chopping":"27-116","consensus_level":"high","plddt":84.9518,"start":27,"end":116},{"cath_id":"2.60.40.10","chopping":"118-311","consensus_level":"medium","plddt":85.7701,"start":118,"end":311},{"cath_id":"2.60.40.10","chopping":"318-398","consensus_level":"medium","plddt":80.2711,"start":318,"end":398},{"cath_id":"2.60.40.10","chopping":"404-449_474-519","consensus_level":"medium","plddt":81.3257,"start":404,"end":519},{"cath_id":"2.60.40.10","chopping":"582-673","consensus_level":"high","plddt":75.718,"start":582,"end":673},{"cath_id":"2.60.40.10","chopping":"719-820","consensus_level":"medium","plddt":79.5899,"start":719,"end":820},{"cath_id":"2.60.40.10","chopping":"823-928","consensus_level":"medium","plddt":76.0325,"start":823,"end":928}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4KMG0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4KMG0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4KMG0-F1-predicted_aligned_error_v6.png","plddt_mean":62.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDON","jax_strain_url":"https://www.jax.org/strain/search?query=CDON"},"sequence":{"accession":"Q4KMG0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4KMG0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4KMG0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4KMG0"}},"corpus_meta":[{"pmid":"16647304","id":"PMC_16647304","title":"The 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CDO activates myogenic bHLH factors via enhanced heterodimer formation, likely by inducing hyperphosphorylation of E proteins.\",\n      \"method\": \"CDO knockout mouse, in vitro satellite cell differentiation assays, reporter assays, protein interaction studies\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO with specific phenotype plus mechanistic dissection of bHLH activation\",\n      \"pmids\": [\"15572127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Binding assays (pulldown), in vivo ectopic expression in mouse neural tube, genetic loss-of-function\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated plus genetic epistasis in vivo, highly cited foundational paper\",\n      \"pmids\": [\"16647304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo knockout mouse, in vitro Shh signaling assays, epistasis analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with molecular pathway analysis, multiple methods, highly cited\",\n      \"pmids\": [\"16647303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi screen, in vitro binding assays, epistasis analysis in Drosophila\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assays with domain mapping plus genetic epistasis, highly cited\",\n      \"pmids\": [\"16630821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, primary myoblasts from Cdo-/- mice, rescue by activated MKK6\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional rescue experiments with defined pathway components\",\n      \"pmids\": [\"17074887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo KO mouse, neural progenitor cultures, co-transfection reporter assays, RNAi\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO phenotype plus mechanistic in vitro assays\",\n      \"pmids\": [\"16648472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Gas1 and Cdo single and double knockout mice, neural tube analysis, genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — compound genetic epistasis in vivo with clear pathway placement\",\n      \"pmids\": [\"17504941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical and biophysical binding assays, mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with biochemical validation and mutagenesis, highly cited\",\n      \"pmids\": [\"18794898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function experiments in myoblasts, Cdc42 activity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional gain/loss-of-function with specific pathway readouts\",\n      \"pmids\": [\"18678706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression, RNAi, kinase activity assays in neural precursor cells and P19 cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell-based assays but single lab, mechanistic extension of prior work\",\n      \"pmids\": [\"19244314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, kinase assays, knockdown/rescue experiments in myoblasts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-level co-IP plus kinase activity assays with functional rescue\",\n      \"pmids\": [\"19470755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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      \"method\": \"N-cadherin ligation assays, co-immunoprecipitation, p38 kinase activity assays, myoblast differentiation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple orthogonal assays distinguishing two signaling modes\",\n      \"pmids\": [\"20160094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Single, double, and triple knockout mice, neural tube patterning analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — compound genetic epistasis in vivo with clear obligatory requirement established, highly cited\",\n      \"pmids\": [\"21664576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays with all three mammalian Hh proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures plus biochemical validation, multiple ligand-receptor pairs\",\n      \"pmids\": [\"20519495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, Akt activity assays, rescue with constitutively active Akt\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional epistasis with defined pathway rescue\",\n      \"pmids\": [\"20484574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Single and double knockout mice, Shh target gene expression analysis in developing forebrain\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — compound genetic epistasis in vivo with molecular pathway readout\",\n      \"pmids\": [\"21183473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based SHH signaling assays, co-immunoprecipitation, SHH binding assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays with disease-relevant mutations; functional dissection of binding requirements\",\n      \"pmids\": [\"21802063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Culture on integrin-independent substrates, FAK overexpression, Western blotting, differentiation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional rescue experiments, single lab\",\n      \"pmids\": [\"21397010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, p38 kinase assays, differentiation rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional rescue, single lab\",\n      \"pmids\": [\"21820049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis, rescue experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis plus co-IP and functional rescue establishes a specific phosphorylation event\",\n      \"pmids\": [\"22298426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, kinase assays, rescue in Cdo-/- cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping plus functional rescue in KO cells\",\n      \"pmids\": [\"22337877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cx43 physically interacts with Cdo to form dynamic complexes during myoblast differentiation, as shown by co-localization and FRET/FLIM analysis.\",\n      \"method\": \"FRET/FLIM imaging, co-immunoprecipitation, co-localization\",\n      \"journal\": \"Journal of biophotonics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — imaging-based interaction evidence, single lab\",\n      \"pmids\": [\"22930637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Caspase activity assays, proteolytic cleavage assays, tumor growth in vivo, cell death assays with ligand/receptor manipulation\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic cleavage/caspase assays plus in vivo tumor model, multiple methods\",\n      \"pmids\": [\"23940460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo KO mouse, histochemistry, live imaging of esophageal development\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific morphogenetic phenotype, single lab\",\n      \"pmids\": [\"23569214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, Wnt reporter assays, Cdo-/- mouse forebrain analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-level co-IP plus in vivo genetic and reporter evidence\",\n      \"pmids\": [\"25406935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo imaging, loss/gain-of-function in zebrafish and chick, protein localization studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple organisms and orthogonal methods establishing context-dependent decoy function\",\n      \"pmids\": [\"25001599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Silencing of CDO in chick embryo model, apoptosis assays, SHH pathway inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo rescue experiment with molecular pathway placement\",\n      \"pmids\": [\"25193697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo gain-of-function assay in chick spinal cord using deletion and chimeric constructs\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping in vivo with multiple constructs, single lab\",\n      \"pmids\": [\"25848697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation assays, electrophysiology, p38MAPK inhibitor experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus surface expression and functional channel assays, single lab\",\n      \"pmids\": [\"27380411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, glucose uptake assays, RNAi knockdown\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with domain mapping plus surface expression assays, single lab\",\n      \"pmids\": [\"26347807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown in zebrafish, live cell imaging, transplantation analysis, immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging plus transplantation plus localization studies, single lab\",\n      \"pmids\": [\"26256768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, AKT activity assays, chromatin immunoprecipitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus ChIP and kinase assays, single lab\",\n      \"pmids\": [\"27763641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo KO mouse, immunostaining, dopamine quantification by HPLC, behavioral analysis\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"27419218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo KO mouse, co-immunoprecipitation, Wnt reporter assays, pharmacological inhibition of Wnt pathway\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with specific pathway rescue experiments and multiple readouts\",\n      \"pmids\": [\"28154134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-sequencing, RNA-sequencing, Ash1L KO mice, in vitro differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus genetic KO with specific phenotype linked to Cdon expression\",\n      \"pmids\": [\"30487570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible satellite cell-specific Cdon KO mouse, co-immunoprecipitation, surface localization assays, EdU incorporation, RNA sequencing\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional cell-type-specific KO with co-IP establishing receptor interaction and multiple functional readouts\",\n      \"pmids\": [\"32103583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Cdo KO mouse, timed ethanol exposure, Nodal reporter assays, genetic rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches defining pathway interaction\",\n      \"pmids\": [\"32876567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"EC-specific conditional Cdon KO mouse, siRNA, binding assays, vascular permeability assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic binding assays, single lab\",\n      \"pmids\": [\"33028094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Live cell imaging, super-resolution microscopy, co-immunoprecipitation, Myo10 knockout mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities plus co-IP and KO mice with defined cellular phenotype\",\n      \"pmids\": [\"33570491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Limb-specific conditional Cdon KO in Gas1;Boc null background, skeletal analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — compound conditional KO with specific developmental phenotypes\",\n      \"pmids\": [\"36265686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"VSMC-specific Cdon KO mouse, Wnt reporter assays, domain deletion mutants, recombinant protein treatment\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO plus domain-mapping with recombinant protein rescue\",\n      \"pmids\": [\"36609601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Motor neuron-specific Cdo KO mouse (Hb9-Cre), sciatic nerve crush model, RNA sequencing, immunostaining, Akt activation assays in NSC34 cells\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with mechanistic pathway analysis\",\n      \"pmids\": [\"37559423\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDON (CDO) is a multifunctional cell-surface co-receptor of the Ig/fibronectin superfamily that (1) binds Sonic/Indian/Desert Hedgehog ligands via its third FNIII repeat in a calcium-dependent manner and, in complex with PTCH1 and GAS1, positively promotes HH pathway signaling in most developmental contexts but can act as a decoy receptor in specific tissues; (2) activates p38α/β MAPK and Akt signaling during myogenic differentiation by scaffolding Bnip-2/Cdc42, JLP, APPL1, Abl, TAK1, and ASK1 in complexes assembled around its intracellular domain upon N-cadherin ligation; (3) suppresses canonical Wnt/β-catenin signaling via its Ig2 ectodomain binding to LRP6, thereby promoting neuronal and cardiomyocyte differentiation and protecting against vascular calcification; and (4) functions as a dependence receptor that triggers caspase-9-mediated apoptosis through intracellular proteolytic cleavage when its SHH ligand is absent.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"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.\",\n      \"evidence\": \"Molecular cloning, Northern/Western blotting in transformed vs. normal fibroblasts\",\n      \"pmids\": [\"9214393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No signaling pathway or ligand identified\", \"Functional role inferred only from expression pattern\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that CDO positively regulates skeletal myogenesis and participates in a positive feedback loop with MyoD established CDO's first defined biological function.\",\n      \"evidence\": \"Overexpression and dominant-negative constructs in C2C12 myoblasts with differentiation and reporter assays\",\n      \"pmids\": [\"9786951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling mechanism unknown\", \"Extracellular ligand for promyogenic function not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and dominant-negative rescue in myoblasts\",\n      \"pmids\": [\"11782431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of CDO-BOC complex unknown\", \"Shared versus distinct signaling outputs not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gene targeting/knockout mouse with morphological analysis\",\n      \"pmids\": [\"12620190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which signaling pathway is disrupted in vivo not yet defined\", \"Whether phenotype is Shh-dependent not directly tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cdo KO mouse muscle phenotype, satellite cell differentiation assays, reporter and interaction studies\",\n      \"pmids\": [\"15572127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for E-protein phosphorylation not identified\", \"Direct versus indirect mechanism not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"16647304\", \"16647303\", \"16630821\", \"17074887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis and biophysical binding assays\",\n      \"pmids\": [\"18794898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length CDO or CDO in complex with PTCH1 not determined\", \"Calcium regulation in vivo not explored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, Cdc42 activity assays, and gain/loss-of-function in myoblasts\",\n      \"pmids\": [\"18678706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cdc42 activation also feeds into pathways other than p38 not tested\", \"Structural basis of Bnip-2–CDO interaction unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"N-cadherin ligation vs. Shh treatment with co-IP in myoblasts; triple KO mouse with neural tube analysis\",\n      \"pmids\": [\"20160094\", \"21664576\", \"20519495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDO partitions between Hh and N-cadherin complexes at the membrane not defined\", \"Structural basis of triple co-receptor cooperativity unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, RNAi, constitutively active Akt rescue of Cdo-depleted myoblasts\",\n      \"pmids\": [\"20484574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Akt and p38 branches are activated simultaneously or sequentially not resolved\", \"Direct phosphorylation events downstream of CDO-APPL1-Akt not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-based SHH signaling assays, co-IP, and SHH binding assays with patient-derived missense mutations\",\n      \"pmids\": [\"21802063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional modifiers are needed for human HPE penetrance not resolved\", \"Structural basis of CDO–PTCH1 interaction not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of TAK1 and ASK1 as the MAP3Ks operating within the CDO/JLP scaffold completed the kinase cascade from CDO to p38 MAPK activation.\",\n      \"evidence\": \"Co-IP with domain mapping, RNAi, and rescue of p38 activation in Cdo−/− myoblasts by TAK1/ASK1 overexpression\",\n      \"pmids\": [\"22337877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TAK1 and ASK1 act redundantly or sequentially not resolved\", \"Direct kinase–substrate relationships within the scaffold not demonstrated by in vitro kinase assays\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Caspase activity and proteolytic cleavage assays, in vivo tumor model, cell death assays with ligand manipulation\",\n      \"pmids\": [\"23940460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the protease cleaving CDO not determined\", \"Physiological tissues where dependence-receptor apoptosis is the dominant function not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain-mapping co-IP, Wnt reporter assays, increased Wnt signaling in Cdo−/− forebrain\",\n      \"pmids\": [\"25406935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDO–LRP6 interaction is constitutive or regulated not known\", \"Structural basis of Ig2–LDLR interaction not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo imaging and gain/loss-of-function in zebrafish and chick optic vesicle\",\n      \"pmids\": [\"25001599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inducible satellite cell-specific Cdon KO mouse, co-IP, surface localization assays, muscle regeneration analysis\",\n      \"pmids\": [\"32103583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CDO controls FGFR surface localization not defined\", \"Whether CDO-FGFR interaction is direct or scaffolded not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cdo KO mouse with timed ethanol exposure, Nodal reporter assays, genetic rescue\",\n      \"pmids\": [\"32876567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDON directly binds Nodal pathway components or acts indirectly not determined\", \"Mechanism of ethanol–CDON synergy at the molecular level not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"VSMC-specific and motor neuron-specific Cdon KO mice with pathway analysis and domain-mapping rescue\",\n      \"pmids\": [\"36609601\", \"37559423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 6, 7, 16, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 12, 14, 18, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28, 37, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 15, 33, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7, 10, 16, 17, 28, 37, 44]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 6, 9, 10, 19, 43]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [26, 30]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [15, 34]}\n    ],\n    \"complexes\": [\n      \"CDO-BOC-GAS1 Hedgehog co-receptor complex\",\n      \"CDO-JLP-p38 MAPK scaffold complex\",\n      \"CDO-APPL1-Akt signaling complex\"\n    ],\n    \"partners\": [\n      \"BOC\",\n      \"GAS1\",\n      \"PTCH1\",\n      \"JLP\",\n      \"BNIP2\",\n      \"ABL1\",\n      \"APPL1\",\n      \"LRP6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}