{"gene":"CDON","run_date":"2026-06-09T22:57:18","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 the extracellular region, and a 256-amino acid intracellular region. Its mRNA is down-regulated by serum stimulation and constitutively down-regulated in oncogene-transformed cells; CDO protein levels are also regulated post-transcriptionally by cell-substratum adhesion.","method":"Molecular cloning, Northern blot, Western blot, cell adhesion assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with multiple orthogonal expression analyses, single lab","pmids":["9214393"],"is_preprint":false},{"year":1998,"finding":"CDO positively regulates myogenic differentiation: overexpression of CDO in C2C12 myoblasts accelerates differentiation, while soluble extracellular regions of CDO inhibit differentiation. CDO and MyoD are involved in a positive feedback loop — oncogenic Ras down-regulates MyoD, and re-expression of CDO in C2C12/Ras cells induces MyoD; conversely, MyoD induces CDO expression.","method":"Overexpression, dominant-negative constructs, differentiation assays in C2C12 myoblasts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple gain- and loss-of-function experiments with defined molecular readouts, replicated across subsequent studies","pmids":["9786951"],"is_preprint":false},{"year":2002,"finding":"BOC associates with CDO to form cis-acting complexes via both their ectodomains and intracellular domains. BOC accelerates myoblast differentiation in a CDO-dependent manner (a dominant-negative form of CDO inhibits the promyogenic effects of soluble BOC), placing BOC downstream of or in complex with CDO for myogenesis.","method":"Co-immunoprecipitation, soluble fusion protein overexpression, dominant-negative CDO, myoblast differentiation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus functional epistasis with dominant-negative, replicated in subsequent studies","pmids":["11782431"],"is_preprint":false},{"year":2003,"finding":"Mice homozygous for targeted mutations of Cdon display hallmark facial defects associated with microforms of holoprosencephaly (HPE), demonstrating a role for Cdon in facial midline development in vivo.","method":"Targeted gene knockout in mice, morphological analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined developmental phenotype, replicated in subsequent studies","pmids":["12620190"],"is_preprint":false},{"year":2004,"finding":"CDO functions to activate myogenic bHLH factors (MyoD family) via enhanced heterodimer formation, most likely by inducing hyperphosphorylation of E proteins; mice lacking CDO display delayed skeletal muscle development and satellite cells from these mice differentiate defectively in vitro.","method":"CDO knockout mice, satellite cell cultures, co-immunoprecipitation, reporter assays for bHLH heterodimer activity","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout plus mechanistic in vitro assays, multiple orthogonal methods","pmids":["15572127"],"is_preprint":false},{"year":2006,"finding":"Cdo and Boc bind Sonic Hedgehog (Shh) through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. Ectopic expression of Cdo or Boc results in Shh-dependent, cell-autonomous promotion of ventral cell fates. Loss of Cdo produces a Shh dosage-dependent reduction of the floor plate. Cdo and Boc are also transcriptional targets negatively regulated by Hedgehog signaling.","method":"Genetic loss-of-function (knockout mice), gain-of-function (ectopic expression), binding assays, neural tube patterning analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — combined in vivo genetics with in vitro binding assays, replicated across multiple labs","pmids":["16647304"],"is_preprint":false},{"year":2006,"finding":"Cdo-deficient mice display holoprosencephaly with strain-specific severity without limb defects, modeling human HPE. Shh target gene expression is reduced in developing forebrains of Cdo-/- mice. Cdo positively regulates Shh signaling in vitro at multiple levels including signal reception and via a parallel mechanism required at the level of Gli transcription factors. Specific Cdo domains required for promyogenic effects are dispensable for Shh signaling.","method":"Cdo knockout mice, Shh target gene expression analysis (in situ hybridization), cell-based Shh signaling assays, domain-deletion constructs","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout, domain mapping, and cell-based signaling assays; replicated in multiple subsequent studies","pmids":["16647303"],"is_preprint":false},{"year":2006,"finding":"CDO promotes neuronal differentiation and cotransfection of CDO enhances the activity of neurogenic bHLH factor neurogenin1 in reporter assays, enhancing heterodimerization of neurogenin1 and E47. Cdo-/- mice on C57BL/6 background display hydrocephalus and cortical thinning, and primary neural progenitors from Cdo-/- mutants show reduced proliferation.","method":"CDO knockout mice, neuronal precursor cell overexpression/RNAi, reporter assays, co-immunoprecipitation for bHLH heterodimerization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with cellular phenotype plus cell-based mechanistic assays, single lab","pmids":["16648472"],"is_preprint":false},{"year":2006,"finding":"Ihog (Drosophila ortholog of CDON) binds Hedgehog protein through its first extracellular fibronectin type III (FNIII) domain; the second FNIII domain is additionally required for in vivo signaling and for Ihog-enhanced binding of Hh to cells co-expressing Patched. Epistasis analysis places ihog action at or upstream of Patched. Other Ihog family members including mammalian CDO also interact with Hh ligands via a specific FNIII domain.","method":"RNAi in Drosophila cultured cells, in vitro binding assays (pulldown), genetic epistasis analysis, loss-of-function mutations in Drosophila","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain-level binding assays, genetic epistasis, and loss-of-function in vivo, independently corroborated","pmids":["16630821"],"is_preprint":false},{"year":2006,"finding":"The intracellular region of Cdo 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 levels of active p38alpha/beta. Primary myoblasts from Cdo-/- mice are deficient in p38alpha/beta activity, and expression of activated MKK6 rescues differentiation of Cdo-/- cells.","method":"Co-immunoprecipitation, kinase activity assays, Cdo-/- primary myoblasts, rescue experiments with activated MKK6","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic loss-of-function rescue, and kinase activity assays; multiple orthogonal methods","pmids":["17074887"],"is_preprint":false},{"year":2007,"finding":"Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development. Gas1;Cdo double mutant mice show more severe Shh-dependent defects than either single mutant, establishing a genetic interaction between these two Shh-binding cell surface proteins.","method":"Genetic double knockout mice, in situ hybridization for Shh target genes, ectopic expression assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with double-mutant analysis across multiple tissues, replicated","pmids":["17504941"],"is_preprint":false},{"year":2008,"finding":"X-ray crystallography revealed the structure of the ShhN-CDO complex; the ShhN binds to the third FNIII repeat of CDO (not the orthologous FNIII repeat used by Drosophila Ihog). The ShhN-CDO interaction requires calcium, which binds at a previously undetected site on ShhN conserved in nearly all Hh proteins. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with CDO, Ptc, Hip, and Gas1.","method":"X-ray crystallography, biophysical binding assays (ITC, SPR), pulldown experiments, mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple biophysical methods, replicated by subsequent structural studies","pmids":["18794898"],"is_preprint":false},{"year":2008,"finding":"Cdo also interacts with Bnip-2, a regulator of Cdc42, and with JLP; Bnip-2 and JLP are brought together through mutual interaction with Cdo. The Cdo-Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38alpha/beta activity and myoblast differentiation. This defines a Cdo-Bnip-2-Cdc42 signaling pathway upstream of p38 MAPK.","method":"Co-immunoprecipitation, gain- and loss-of-function experiments in myoblasts, Cdc42 activity assays, p38 activity assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple co-IP interactions, gain/loss-of-function pathway dissection, multiple orthogonal methods","pmids":["18678706"],"is_preprint":false},{"year":2009,"finding":"Abl tyrosine kinase associates with both Cdo and JLP during myoblast differentiation. Abl binds a proline-rich motif in the Cdo intracellular domain via its SH3 domain; these regions are required for their promyogenic effects. Cdo is important for full Abl kinase activity, and Abl is necessary for full p38 MAPK activation during myogenic differentiation.","method":"Co-immunoprecipitation, domain-deletion/mutation constructs, kinase activity assays, shRNA knockdown, differentiation rescue assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping plus kinase assays and functional rescue, single lab","pmids":["19470755"],"is_preprint":false},{"year":2009,"finding":"Cdo uses similar regulatory mechanisms in neuronal differentiation as in myogenesis: Cdo-dependent activation of Cdc42 and p38 MAPK promotes neuronal differentiation of C17.2 and P19 cells. Cdc42 and p38 MAPK activities promote heterodimerization of neurogenin1 and E47, suggesting regulation of neural bHLH factor activity as a mechanism.","method":"Overexpression and RNAi knockdown in neural precursor cells, Cdc42 and p38 activity assays, bHLH heterodimerization assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in cell culture, single lab","pmids":["19244314"],"is_preprint":false},{"year":2010,"finding":"N-cadherin ligation activates p38alpha/beta MAPK in myoblasts in a Cdo-, Bnip-2-, and JLP-dependent manner; Cdo, JLP, Bnip-2, and activated Cdc42 cluster at sites of N-cadherin ligation. In contrast, Shh binding to Cdo does not activate p38alpha/beta — JLP and Bnip-2 are not associated with Cdo when bound to Shh — demonstrating mechanistically distinct signaling roles for Cdo depending on the extracellular ligand.","method":"N-cadherin ligation assays, co-immunoprecipitation, p38 MAPK activity assays, immunofluorescence clustering analysis, Shh treatment controls","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods demonstrating ligand-specific signaling, key negative control (Shh does not activate p38)","pmids":["20160094"],"is_preprint":false},{"year":2010,"finding":"GAS1, CDO, and BOC play overlapping and collectively essential roles during HH-mediated ventral neural patterning; they function in cell fate specification of neural progenitors and later in motor neuron progenitor maintenance. Genetic loss-of-function (triple mutant) experiments indicate an obligatory collective requirement for these coreceptors in HH pathway activity in multiple tissues.","method":"Single, double, and triple genetic knockout mice, neural tube patterning analysis, in situ hybridization for HH target genes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic in vivo genetic epistasis through triple knockout, defined molecular and cellular readouts","pmids":["21664576"],"is_preprint":false},{"year":2010,"finding":"All three mammalian Hedgehog proteins (Sonic, Indian, and Desert Hh) bind CDO and BOC in the same manner via the same domain (FNIII repeat 3 of CDO). X-ray crystallography confirmed this conserved mode of binding and revealed that formation of Hh-CDO interaction is weakened at low pH.","method":"X-ray crystallography of Hh-CDO and Hh-BOC complexes, biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of multiple Hh-CDO complexes with biochemical validation","pmids":["20519495"],"is_preprint":false},{"year":2010,"finding":"Cdo interacts with APPL1 (an interacting partner of Akt), and both Cdo and APPL1 are required for efficient Akt activation during myoblast differentiation. Constitutively active Akt rescues differentiation defects of Cdo-depleted cells, whereas APPL1 overexpression alone does not, placing Cdo upstream of Akt via APPL1 for myogenic differentiation.","method":"Co-immunoprecipitation, shRNA knockdown, constitutively active Akt rescue, Akt activity assays, differentiation assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus loss-of-function rescue hierarchy, single lab","pmids":["20484574"],"is_preprint":false},{"year":2010,"finding":"Boc mutation exacerbates HPE in Cdo-deficient mice, indicating that Boc is a silent HPE modifier gene. Cdo and Boc have selective roles in Shh signaling — Cdo;Boc double mutants do not phenocopy Shh-null mice, demonstrating evolutionary divergence from Drosophila where Ihog and Boi are fully essential for all Hh signaling.","method":"Cdo;Boc double-mutant mice, Shh target gene expression analysis, HPE scoring","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double knockout), defined molecular and phenotypic readouts","pmids":["21183473"],"is_preprint":false},{"year":2011,"finding":"Missense mutations in human CDON cause holoprosencephaly (HPE). These mutations diminish CDON's ability to support Shh-dependent gene expression in cell-based signaling assays but do not affect Shh binding. Instead, wild-type CDON associates with PTCH1 and GAS1, but the HPE-associated variants do so inefficiently, indicating that CDON-PTCH1 and CDON-GAS1 interactions are required for signaling and that disruption of these inter-receptor interactions is a mechanism of HPE.","method":"Patient mutation identification, cell-based Shh signaling assays, co-immunoprecipitation of CDON with PTCH1 and GAS1, Shh binding assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics linked to cell-based mechanistic assays with multiple binding partners tested; multiple orthogonal methods","pmids":["21802063"],"is_preprint":false},{"year":2011,"finding":"Gas1 and Cdo are coexpressed in muscle cells, form a complex in differentiating myoblasts, and cooperate to activate p38 MAPK. Gas1 overexpression in Cdo-depleted C2C12 cells restores p38 MAPK activities and differentiation, placing Gas1 as a component of the Cdo/Cadherin multiprotein complex that activates p38.","method":"Co-immunoprecipitation, overexpression, shRNA knockdown, p38 MAPK activity assays, myoblast differentiation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus pathway rescue, single lab","pmids":["21820049"],"is_preprint":false},{"year":2012,"finding":"Cx43 (Connexin 43) physically interacts with Cdo to form dynamic complexes during myoblast differentiation, as demonstrated by co-localization and FRET-based molecular imaging approaches.","method":"Fluorescence imaging, FRET/FLIM analysis, co-immunoprecipitation","journal":"Journal of biophotonics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, imaging-based interaction without functional domain mapping or rescue experiments","pmids":["22930637"],"is_preprint":false},{"year":2012,"finding":"TAK1 and ASK1 associate with the cytoplasmic tail of Cdo and with the scaffold protein JLP, and function as MAP3Ks in Cdo-mediated p38 MAPK activation during myoblast differentiation. Overexpression of TAK1 or ASK1 in Cdo-/- myoblasts restores p38 MAPK activation and myotube formation.","method":"Co-immunoprecipitation, overexpression, shRNA knockdown, p38 kinase activity assays, rescue in Cdo-/- myoblasts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, rescue in knockout cells, and kinase assays; single lab","pmids":["22337877"],"is_preprint":false},{"year":2012,"finding":"Phosphorylation of Stim1 at serine 575 by ERK1/2 (activated via netrin-2/Cdo signaling) is required for myoblast differentiation. Cdo and Stim1 form a complex in differentiating myoblasts, and alanine substitution at S575 fails to rescue differentiation of Stim1-depleted myoblasts. Cdo-/- primary myoblasts display defective NFATc3 activation correlating with reduced Stim1 levels.","method":"Co-immunoprecipitation, site-directed mutagenesis of Stim1 S575, rescue assays, p-ERK and NFATc3 activity assays, Cdo-/- primary myoblasts","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis with functional rescue, co-IP, and knockout cells; single lab","pmids":["22298426"],"is_preprint":false},{"year":2012,"finding":"Cdon mutation synergizes with fetal ethanol exposure to produce defects in early midline patterning, inhibition of Shh signaling in the developing forebrain, and a broad spectrum of HPE phenotypes in 129S6 mice. Loss of Cdon alone or ethanol alone gives little/no phenotype, establishing a gene-environment interaction.","method":"Cdon-/- mouse model with in utero ethanol exposure, Shh target gene expression analysis, HPE scoring","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — controlled in vivo genetic × environment experiment with molecular readouts; replicated in subsequent studies","pmids":["23071453"],"is_preprint":false},{"year":2013,"finding":"Cdo-/- mice are specifically defective in smooth muscle fascicular reorientation in the esophagus, resulting in an aberrantly proximal skeletal-smooth muscle boundary, megaesophagus, achalasia, and lower esophageal sphincter resistance to nitric oxide-induced relaxation.","method":"Cdo knockout mice, histochemistry, immunostaining, morphometric analysis, physiological measurements","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined morphological and physiological phenotypes, mechanistic cellular analysis","pmids":["23569214"],"is_preprint":false},{"year":2013,"finding":"CDON behaves as a SHH dependence receptor: it actively triggers apoptosis in the absence of SHH. The pro-apoptotic activity of unbound CDON requires proteolytic cleavage in its intracellular domain, allowing recruitment and activation of caspase-9. SHH binding to CDON inhibits this pro-apoptotic activity, promoting tumor cell survival.","method":"Cell-based apoptosis assays, caspase-9 activation assays, CDON intracellular domain cleavage analysis, in vivo tumor growth models, SHH-CDON interaction interference experiments","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (caspase assays, cleavage, in vitro and in vivo tumor models), mechanistic domain-level analysis","pmids":["23940460"],"is_preprint":false},{"year":2014,"finding":"In the zebrafish and chick optic vesicle, Cdon acts as a negative Hh signaling regulator (decoy receptor) by predominantly localizing to the basolateral side of neuroepithelial cells, promoting enlargement of the neuroepithelial basal end-foot, trapping Hh protein, and limiting its dispersion in a Patched-independent manner. This protects the retinal primordium from Hh activity.","method":"Zebrafish and chick in vivo genetics, live imaging, subcellular localization assays, Hh protein distribution analysis, genetic rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — two vertebrate models with direct protein localization and Hh distribution assays; mechanistic dissection of Ptc-independent function","pmids":["25001599"],"is_preprint":false},{"year":2014,"finding":"Cdo suppresses canonical Wnt signaling to promote neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6; the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Cdo-deficient dorsal forebrain displays enhanced Wnt signaling, increased proliferation, and elevated Pax6, Gli3, and Axin2 expression.","method":"Co-immunoprecipitation, domain-deletion constructs, Wnt reporter assays, Cdo-/- mouse forebrain analysis, cell proliferation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level co-IP plus in vivo knockout with molecular pathway readouts; multiple orthogonal methods","pmids":["25406935"],"is_preprint":false},{"year":2015,"finding":"CDON and BOC utilize distinct molecular mechanisms to promote HH signaling. CDON requires membrane attachment while BOC does not for full activity. Separate novel extracellular motifs in CDON and BOC are identified as required for their HH-promoting effects, demonstrating non-redundant structural requirements despite functional overlap.","method":"Gain-of-function in developing chicken spinal cord, domain-deletion and mutant constructs, HH target gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo domain dissection in avian model, single lab","pmids":["25848697"],"is_preprint":false},{"year":2015,"finding":"Cdon promotes neural crest cell (NCC) migration in zebrafish; Cdon knockdown results in aberrant trunk NCC migration with reduced directedness and mispositioned protrusions. Cdon is required cell-autonomously for directed NCC migration and regulates localization of N-cadherin to the cell membrane in migratory NCCs.","method":"Morpholino knockdown in zebrafish, live cell imaging, cell transplantation, immunofluorescence for N-cadherin localization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with live imaging and transplantation, single lab","pmids":["26256768"],"is_preprint":false},{"year":2015,"finding":"Syntaxin 4 (Stx4) binds to the cytoplasmic tail of Cdo and is required for cell surface localization of Cdo; Stx4 depletion specifically decreases surface Cdo without altering surface N-cadherin levels. Cdo depletion in turn reduces surface GLUT4 and Stx4, and overall glucose uptake, linking Cdo surface trafficking to metabolic signaling in myoblasts.","method":"Co-immunoprecipitation, surface biotinylation, shRNA knockdown, glucose uptake assays, myoblast differentiation assays","journal":"Skeletal muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, surface biotinylation, and functional assays; single lab","pmids":["26347807"],"is_preprint":false},{"year":2016,"finding":"Cdo forms a complex with Kir2.1 potassium channel during myoblast differentiation and is required for Kir2.1 surface expression and channel activity. Loss of Cdo reduces Kir2.1 surface levels, and this is dependent on p38 MAPK activity (MKK6(EE) expression restores Kir2.1 activity in Cdo-depleted cells).","method":"Co-immunoprecipitation, surface biotinylation, electrophysiology, shRNA knockdown, rescue with activated MKK6","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional channel activity assays and epistasis, single lab","pmids":["27380411"],"is_preprint":false},{"year":2016,"finding":"PKN2 forms complexes with Cdo, APPL1, and AKT via its C-terminal region; this interaction is important for AKT activation and myoblast differentiation. PKN2 levels are decreased in Cdo-depleted cells, and PKN2 overexpression compensates for Cdo deficiency in AKT activation.","method":"Co-immunoprecipitation, shRNA knockdown, overexpression, AKT activity assays, myoblast differentiation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, domain mapping, and functional rescue, single lab","pmids":["27763641"],"is_preprint":false},{"year":2016,"finding":"Cdo-/- mice develop cardiac dysfunction (reduced ejection fraction, ECG abnormalities), fibrosis, and up-regulation and mislocalization of Connexin 43 (Cx43) due to hyperactivation of Wnt/β-catenin signaling. Cdon is localized at intercalated discs in mouse and human hearts. Inhibition of Wnt signaling (by XAV939, IWP2, or DKK1) prevents Cdo-depletion-induced upregulation of collagen 1a and Cx43, placing Cdo as a negative regulator of Wnt/β-catenin in cardiomyocytes.","method":"Cdo-/- mice, echocardiography, histology, immunostaining for Cx43 and β-catenin, gap junction activity assays, Wnt inhibitor treatments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with cardiac phenotype plus pathway rescue by pharmacological Wnt inhibition; multiple orthogonal methods","pmids":["28154134"],"is_preprint":false},{"year":2016,"finding":"Cdo is required for efficient cardiomyogenesis of pluripotent stem cells via activation of Shh signaling. Cdo-/- ES cells display decreased expression of cardiac regulators (Gata4, Nkx2.5, Mef2c) and reduced Shh signaling; Shh agonist treatment restores cardiomyogenesis in Cdo-deficient ES cells.","method":"Cdo-/- mouse ES cells, P19 EC cell differentiation, shRNA knockdown, Shh pathway reporter assays, Shh agonist rescue","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout in stem cells with pathway-specific rescue, single lab","pmids":["26906632"],"is_preprint":false},{"year":2018,"finding":"Ash1L (a Trithorax group epigenetic activator) promotes myoblast fusion by activating Cdon expression. Ash1L is required to counteract Polycomb repressive activity at the Cdon locus; RNA- and ChIP-sequencing identified Cdon as a key target gene of Ash1L in myogenesis.","method":"RNA-seq, ChIP-seq, Ash1L loss-of-function in vitro and in vivo, myoblast fusion assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genomic assays plus functional experiments placing Ash1L upstream of Cdon, single lab","pmids":["30487570"],"is_preprint":false},{"year":2020,"finding":"Satellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis due to decreased satellite cell proliferation and senescence. Mechanistically, Cdon-depleted satellite cells show impaired integrin β1 activation, reduced ERK activation in response to FGF, and Cdon interacts with and regulates cell surface localization of FGFR1 and FGFR4.","method":"Inducible satellite cell-specific Cdon knockout mice (Pax7-CreERT2), cardiotoxin injury, immunostaining, EdU assay, co-immunoprecipitation, FGFR surface expression analysis, RNA-seq","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional tissue-specific knockout with multiple mechanistic readouts including co-IP and surface expression analysis","pmids":["32103583"],"is_preprint":false},{"year":2020,"finding":"Nodal signaling is a major point of synergistic interaction between Cdon mutation and fetal alcohol exposure in HPE. Window-of-sensitivity experiments indicate that brief ethanol exposure during gastrulation transiently inhibits Nodal pathway activity in Cdon mutant embryos, with consequent effects on midline patterning.","method":"Cdon-/- mouse with timed ethanol exposure, Nodal pathway activity assays, genetic epistasis, in vitro Nodal assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic × environment with pathway-specific molecular readouts; single lab","pmids":["32876567"],"is_preprint":false},{"year":2020,"finding":"In endothelial cells, Cdon prevents Desert Hedgehog (Dhh) binding to Ptch1 and thus acts as a decoy receptor for Dhh, negatively regulating Dhh signaling. Cdon deficiency in ECs promotes endothelial junction integrity and decreases inflammatory markers (VCAM-1, ICAM-1), opposite to Gas1 (which is a positive regulator of Dhh in ECs).","method":"siRNA knockdown, EC-specific conditional knockout mice, Dhh-Ptch1 binding assays, VCAM-1/ICAM-1 expression analysis, vascular permeability assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with molecular binding assays and functional vascular readouts, single lab","pmids":["33028094"],"is_preprint":false},{"year":2021,"finding":"Cytoneme-mediated delivery of SHH from ligand-producing cells requires a novel Dispatched (DISP)-BOC/CDON co-receptor complex at the producing cell membrane. Myosin 10 promotes vesicular transport of SHH in mouse cell cytonemes. Cytoneme-deposited SHH induces rapid receptor-dependent signaling within seconds; this is dependent on the DISP-BOC/CDON complex for cytoneme occurrence and ligand delivery.","method":"Live cell imaging, Myo10 knockout mice, neural tube patterning analysis, co-immunoprecipitation of DISP-BOC/CDON complex, time-lapse signaling assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of novel complex plus in vivo knockout and live imaging, single lab","pmids":["33570491"],"is_preprint":false},{"year":2022,"finding":"GAS1, CDON, and BOC are collectively required for HH-dependent digit specification, limb patterning, and long bone growth. Limb-specific conditional deletion of Cdon in a Gas1;Boc null background results in digit loss and limb outgrowth defects.","method":"Limb-specific conditional Cdon knockout in Gas1;Boc null background, skeletal preparations, HH target gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic in vivo combinatorial genetic analysis, defined HH-dependent phenotypes","pmids":["36265686"],"is_preprint":false},{"year":2023,"finding":"Cdon deficiency in vascular smooth muscle cells (VSMCs) causes exacerbated aortic calcification via hyperactivation of Wnt/Runx2 signaling. The Ig2 domain of Cdon ectodomain is required for Wnt suppression; deletion of Ig2 abolishes Cdon-dependent Wnt inhibition and osteogenic conversion. Recombinant Ig2 domain protein suppresses Wnt signaling and VSMC calcification.","method":"Cdon conditional knockout mice (VSMC-specific), Wnt reporter assays, domain-deletion mutants, recombinant Ig2 protein treatment, aortic stiffness measurements, histological calcification analysis","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with domain-level mechanistic analysis and recombinant protein rescue; multiple orthogonal methods","pmids":["36609601"],"is_preprint":false},{"year":2023,"finding":"Motor neuron-specific Cdon ablation causes age-related motor neuron degeneration and impaired sciatic nerve repair. Mechanistically, Cdon-depleted motor neurons show altered ErbB4 and FGFR expression and impaired Akt activation in response to neuregulin-1 (NRG1), linking Cdon to neurotrophin signaling in motor neuron survival.","method":"Motor neuron-specific Cdon knockout (Hb9-Cre), sciatic nerve crush injury model, RNA-seq, immunostaining, electrophysiology, Akt activity assays in Cdon-depleted NSC34 cells","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockout with mechanistic pathway analysis; single lab","pmids":["37559423"],"is_preprint":false}],"current_model":"CDON (CDO) is a multifunctional Ig/fibronectin superfamily cell surface co-receptor that positively regulates Hedgehog (HH) signaling by binding SHH (via its third FNIII repeat in a calcium-dependent interaction) and forming complexes with PTCH1, GAS1, and BOC to transduce the HH signal; it also promotes skeletal myogenesis, neurogenesis, and other differentiation programs by scaffolding intracellular signaling complexes containing N-cadherin, JLP, Bnip-2/Cdc42, Abl, and APPL1 to activate p38α/β MAPK and AKT, while negatively regulating canonical Wnt signaling through its Ig2 domain interaction with LRP6; in specific developmental contexts (optic vesicle, endothelium) it acts as a decoy/sequestration receptor that limits HH ligand dispersion; and in the absence of SHH it functions as a dependence receptor that triggers caspase-9-dependent apoptosis via proteolytic cleavage of its intracellular domain."},"narrative":{"mechanistic_narrative":"CDON (CDO) is a cell-surface co-receptor of the immunoglobulin/fibronectin type III superfamily that integrates Hedgehog (HH) signaling and cell-adhesion cues to drive cell-fate specification and differentiation across multiple developmental contexts [PMID:9214393, PMID:16647304, PMID:20160094]. As a HH co-receptor, CDON binds all three mammalian HH ligands through its third FNIII repeat in a calcium-dependent interaction whose structural details were resolved by crystallography, and it positively transduces the signal by physically associating with PTCH1 and GAS1; HPE-causing missense mutations in human CDON spare SHH binding but disrupt these inter-receptor associations, establishing CDON-PTCH1/GAS1 complexes as essential for signaling [PMID:16647304, PMID:18794898, PMID:20519495, PMID:21802063]. CDON acts collectively and non-redundantly with the related co-receptors BOC and GAS1, and combinatorial mouse genetics show an obligatory requirement for these proteins in HH-dependent ventral neural patterning, craniofacial, vertebral, and limb development [PMID:17504941, PMID:21664576, PMID:36265686]. Loss of CDON in mice produces holoprosencephaly, and this phenotype is exacerbated by fetal ethanol exposure through synergistic inhibition of Shh and Nodal signaling, defining a gene-environment interaction [PMID:12620190, PMID:16647303, PMID:23071453, PMID:32876567]. In a ligand-specific manner CDON also scaffolds an intracellular signaling module: N-cadherin ligation (but not SHH binding) recruits the scaffold JLP together with Bnip-2, which stimulates Cdc42 and downstream TAK1/ASK1-MKK6 to activate p38α/β MAPK and drive myogenic and neuronal differentiation, in part by enhancing bHLH/E-protein heterodimerization; CDON additionally promotes AKT activation through APPL1 and PKN2 [PMID:11782431, PMID:17074887, PMID:18678706, PMID:19244314, PMID:20160094, PMID:20484574, PMID:22337877, PMID:27763641]. Through its Ig2 ectodomain, CDON binds LRP6 and negatively regulates canonical Wnt/β-catenin signaling, a function required to restrain proliferation in the forebrain, prevent Cx43 dysregulation and cardiac fibrosis, and suppress osteogenic VSMC calcification [PMID:25406935, PMID:28154134, PMID:36609601]. In specific tissues such as the optic vesicle and endothelium, CDON instead behaves as a Patched-independent decoy receptor that sequesters HH ligand and limits its dispersion, and in the absence of SHH it acts as a dependence receptor whose intracellular domain is proteolytically cleaved to recruit and activate caspase-9, triggering apoptosis [PMID:23940460, PMID:25001599, PMID:33028094].","teleology":[{"year":1997,"claim":"Establishing CDO as a novel adhesion-regulated Ig-superfamily surface glycoprotein defined the structural platform from which all later co-receptor functions were dissected.","evidence":"Molecular cloning and expression/adhesion analyses identifying five Ig and three FNIII repeats plus a cytoplasmic tail","pmids":["9214393"],"confidence":"Medium","gaps":["No ligand or signaling partner identified at cloning","Functional role undefined"]},{"year":1998,"claim":"Linking CDO to a MyoD positive-feedback loop established it as a positive regulator of differentiation, not merely a structural surface protein.","evidence":"Overexpression, soluble ectodomain inhibition, and dominant-negative constructs in C2C12 myoblasts","pmids":["9786951"],"confidence":"High","gaps":["Molecular mechanism downstream of CDO unknown","Cytoplasmic effectors not identified"]},{"year":2002,"claim":"Identifying cis-complex formation with BOC introduced the concept of a CDO co-receptor network acting in differentiation.","evidence":"Reciprocal co-IP and dominant-negative epistasis in myoblast differentiation assays","pmids":["11782431"],"confidence":"High","gaps":["Shared ligand not yet known","Stoichiometry of CDO-BOC complex undefined"]},{"year":2003,"claim":"The holoprosencephaly-like facial phenotype of Cdon knockout mice provided the first in vivo evidence for a role in midline development, anticipating its HH connection.","evidence":"Targeted knockout and morphological analysis in mice","pmids":["12620190"],"confidence":"High","gaps":["Causative pathway (HH) not yet established","Cellular basis of facial defect unresolved"]},{"year":2006,"claim":"Demonstrating that CDO/BOC bind SHH via a specific FNIII repoat and the Drosophila ortholog Ihog acts at/upstream of Patched defined CDON as a HH-pathway co-receptor operating at the level of signal reception and Gli.","evidence":"Knockout and ectopic-expression mouse genetics, binding assays, neural tube patterning, and Drosophila RNAi/epistasis","pmids":["16647304","16647303","16630821"],"confidence":"High","gaps":["Structural basis of ligand binding unresolved","Mechanism of Gli-level regulation unclear"]},{"year":2006,"claim":"Mapping the CDO intracellular tail to a JLP/p38αβ MAPK module and identifying a parallel role in neuronal bHLH activation revealed a ligand-receptor-independent intracellular signaling output.","evidence":"Co-IP, kinase assays, MKK6 rescue in Cdo-/- myoblasts, and reporter/heterodimerization assays in neural cells","pmids":["17074887","16648472"],"confidence":"High","gaps":["Upstream activating ligand for p38 axis not defined in 2006","Link between p38 and bHLH activity incomplete"]},{"year":2007,"claim":"Genetic cooperation between Gas1 and Cdo established that HH-binding cell-surface proteins function combinatorially rather than independently.","evidence":"Gas1;Cdo double-mutant mice with Shh target gene analysis across multiple tissues","pmids":["17504941"],"confidence":"High","gaps":["Molecular nature of cooperation not defined","Whether the proteins form a physical complex unresolved"]},{"year":2008,"claim":"The ShhN-CDO crystal structure and identification of a Bnip-2-Cdc42 arm provided atomic-level and mechanistic detail for both the HH-binding and intracellular signaling functions.","evidence":"X-ray crystallography with calcium-site mutagenesis (ShhN-CDO) and co-IP/activity assays defining Cdo-Bnip-2-Cdc42-p38","pmids":["18794898","18678706"],"confidence":"High","gaps":["How calcium-site disease mutations differentially affect each co-receptor not fully resolved","Spatial coordination of intracellular complex assembly unclear"]},{"year":2009,"claim":"Adding Abl kinase to the CDO intracellular complex and extending the Cdc42/p38 logic to neurogenesis refined the differentiation signaling cascade.","evidence":"Co-IP/domain mapping with kinase assays in myoblasts and overexpression/RNAi in neural precursors","pmids":["19470755","19244314"],"confidence":"Medium","gaps":["Ordering of Abl relative to other effectors incomplete","Single-lab findings for neural extension"]},{"year":2010,"claim":"Defining the ligand-specific switch (N-cadherin activates p38; SHH does not) plus crystallographic confirmation of a conserved pan-HH binding mode and demonstration of collective co-receptor requirement unified the dual roles of CDON.","evidence":"N-cadherin ligation with co-IP/IF, Hh-CDO/BOC crystal structures, triple-knockout mouse genetics, and APPL1-Akt rescue assays","pmids":["20160094","20519495","21664576","20484574","21183473"],"confidence":"High","gaps":["How the receptor switches partner assembly between ligands mechanistically unresolved","Divergence of vertebrate vs Drosophila co-receptor essentiality not fully explained"]},{"year":2011,"claim":"Human CDON mutations causally linked to HPE through disrupted CDON-PTCH1/GAS1 interactions established the clinical relevance and pinpointed inter-receptor binding as the critical signaling step.","evidence":"Patient mutation analysis, cell-based Shh signaling assays, and co-IP of CDON with PTCH1/GAS1; plus Gas1-Cdo p38 complex in myoblasts","pmids":["21802063","21820049"],"confidence":"High","gaps":["How CDON physically bridges PTCH1 and GAS1 structurally undefined","Variant penetrance/modifiers in patients unresolved"]},{"year":2012,"claim":"Adding TAK1/ASK1 MAP3Ks, Stim1/NFAT, and Cx43 to the CDO complex broadened the intracellular signaling and trafficking repertoire underlying differentiation, while a gene-environment HPE model was established.","evidence":"Co-IP, knockout-cell rescue, phospho-site mutagenesis, FRET imaging, and Cdon-/- ethanol exposure with Shh readouts","pmids":["22337877","22298426","22930637","23071453"],"confidence":"Medium","gaps":["Cx43 interaction lacks functional/domain validation (imaging only)","Integration of Ca2+/NFAT and p38 arms unresolved"]},{"year":2013,"claim":"Defining CDON as a SHH dependence receptor that triggers caspase-9 apoptosis when unbound, plus an esophageal muscle role, revealed pro-apoptotic and morphogenetic functions distinct from canonical signaling promotion.","evidence":"Apoptosis/caspase-9 assays, intracellular-domain cleavage analysis, tumor models, and Cdo-/- esophageal phenotyping","pmids":["23940460","23569214"],"confidence":"High","gaps":["Identity of the protease cleaving the CDON intracellular domain unknown","Physiological contexts where dependence-receptor activity dominates undefined"]},{"year":2014,"claim":"Establishing CDON as a Patched-independent decoy receptor in the optic vesicle and as an LRP6-binding Wnt suppressor revealed negative-regulatory functions opposite to its co-receptor role.","evidence":"Zebrafish/chick localization and Hh-distribution assays; Ig2-LRP6 co-IP, Wnt reporters, and Cdo-/- forebrain analysis","pmids":["25001599","25406935"],"confidence":"High","gaps":["What determines decoy vs co-receptor behavior in a given tissue unresolved","Whether Wnt inhibition and HH decoy functions are mechanistically linked unclear"]},{"year":2015,"claim":"Distinguishing CDON from BOC mechanistically and defining roles in neural crest migration and surface trafficking refined how the co-receptors and their adhesion functions are deployed.","evidence":"Domain dissection in chick spinal cord, zebrafish NCC knockdown/transplantation, and Stx4 co-IP/surface biotinylation","pmids":["25848697","26256768","26347807"],"confidence":"Medium","gaps":["Membrane-attachment requirement of CDON mechanistically unexplained","Single-lab trafficking findings"]},{"year":2016,"claim":"Extending CDON to cardiac Wnt suppression, cardiomyogenesis via Shh, Kir2.1 channel surface delivery, and PKN2-AKT signaling demonstrated broad tissue deployment of its dual signaling modes.","evidence":"Cdo-/- cardiac phenotyping with Wnt-inhibitor rescue, ES/P19 cardiomyogenesis with Shh agonist rescue, electrophysiology, and PKN2 co-IP/AKT assays","pmids":["28154134","26906632","27380411","27763641"],"confidence":"High","gaps":["How CDON simultaneously balances Wnt suppression and Shh promotion in heart unresolved","Mechanism of channel surface stabilization incomplete"]},{"year":2018,"claim":"Identifying Ash1L as a Trithorax activator of Cdon transcription placed CDON within an epigenetic regulatory circuit controlling myoblast fusion.","evidence":"RNA-seq/ChIP-seq and Ash1L loss-of-function with myoblast fusion assays","pmids":["30487570"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional control not fully resolved","Other upstream regulators of Cdon expression unknown"]},{"year":2020,"claim":"Tissue-specific knockouts linked CDON to satellite-cell FGFR/integrin signaling, endothelial Dhh decoy function, and Nodal-dependent HPE synergy, extending its roles into regeneration, vascular biology, and morphogen crosstalk.","evidence":"Conditional Cdon knockouts with co-IP/surface analysis (FGFR), EC binding/permeability assays, and Cdon-/- ethanol Nodal assays","pmids":["32103583","33028094","32876567"],"confidence":"High","gaps":["Whether FGFR/ErbB regulation reflects a general trafficking role unresolved","Mechanism by which CDON discriminates Dhh decoy vs promotion in endothelium unclear"]},{"year":2021,"claim":"Placing BOC/CDON in a Dispatched co-receptor complex on SHH-producing cells revealed a presynaptic-side role in cytoneme-mediated ligand delivery, broadening CDON function beyond the receiving cell.","evidence":"Live imaging, Myo10 knockout mice, DISP-BOC/CDON co-IP, and time-lapse neural tube signaling","pmids":["33570491"],"confidence":"Medium","gaps":["Whether CDON's producing-cell and receiving-cell roles are separable unresolved","Single-lab cytoneme mechanism"]},{"year":2023,"claim":"Demonstrating Ig2-dependent Wnt suppression in VSMC calcification and CDON's requirement in motor neuron survival/neurotrophin signaling consolidated its dual roles in disease-relevant tissues.","evidence":"VSMC-specific knockout with recombinant Ig2 rescue and Wnt reporters; motor neuron-specific knockout with NRG1/Akt and ErbB4/FGFR analysis","pmids":["36609601","37559423"],"confidence":"High","gaps":["How a single Ig2 domain mediates LRP6 binding across diverse tissues structurally undefined","Integration of neurotrophin-receptor regulation with HH functions unclear"]},{"year":null,"claim":"How CDON selects between its opposing molecular outputs—HH co-receptor, HH decoy, Wnt suppressor, intracellular p38/AKT scaffold, and apoptotic dependence receptor—within a given cell remains unresolved at a mechanistic level.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-dependent partner selection","Protease responsible for dependence-receptor cleavage unidentified","Structural basis of CDON-PTCH1/GAS1 and CDON-LRP6 complexes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5,11,17,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,6,15,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,12,18,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[29,35,43]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[15,31]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,15,28,32,35]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,11,20,29,35]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,16,42]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[27]}],"complexes":["CDON-BOC co-receptor complex","CDON-PTCH1-GAS1 HH receptor complex","DISP-BOC/CDON cytoneme complex","CDON-JLP-Bnip-2 p38 signaling complex"],"partners":["BOC","PTCH1","GAS1","LRP6","JLP","BNIP2","APPL1","ABL1"],"other_free_text":[]}},"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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Its mRNA is down-regulated by serum stimulation and constitutively down-regulated in oncogene-transformed cells; CDO protein levels are also regulated post-transcriptionally by cell-substratum adhesion.\",\n      \"method\": \"Molecular cloning, Northern blot, Western blot, cell adhesion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with multiple orthogonal expression analyses, single lab\",\n      \"pmids\": [\"9214393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CDO positively regulates myogenic differentiation: overexpression of CDO in C2C12 myoblasts accelerates differentiation, while soluble extracellular regions of CDO inhibit differentiation. CDO and MyoD are involved in a positive feedback loop — oncogenic Ras down-regulates MyoD, and re-expression of CDO in C2C12/Ras cells induces MyoD; conversely, MyoD induces CDO expression.\",\n      \"method\": \"Overexpression, dominant-negative constructs, differentiation assays in C2C12 myoblasts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple gain- and loss-of-function experiments with defined molecular readouts, replicated across subsequent studies\",\n      \"pmids\": [\"9786951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BOC associates with CDO to form cis-acting complexes via both their ectodomains and intracellular domains. BOC accelerates myoblast differentiation in a CDO-dependent manner (a dominant-negative form of CDO inhibits the promyogenic effects of soluble BOC), placing BOC downstream of or in complex with CDO for myogenesis.\",\n      \"method\": \"Co-immunoprecipitation, soluble fusion protein overexpression, dominant-negative CDO, myoblast differentiation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus functional epistasis with dominant-negative, replicated in subsequent studies\",\n      \"pmids\": [\"11782431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mice homozygous for targeted mutations of Cdon display hallmark facial defects associated with microforms of holoprosencephaly (HPE), demonstrating a role for Cdon in facial midline development in vivo.\",\n      \"method\": \"Targeted gene knockout in mice, morphological analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined developmental phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"12620190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CDO functions to activate myogenic bHLH factors (MyoD family) via enhanced heterodimer formation, most likely by inducing hyperphosphorylation of E proteins; mice lacking CDO display delayed skeletal muscle development and satellite cells from these mice differentiate defectively in vitro.\",\n      \"method\": \"CDO knockout mice, satellite cell cultures, co-immunoprecipitation, reporter assays for bHLH heterodimer activity\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout plus mechanistic in vitro assays, multiple orthogonal methods\",\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 repeat that is essential for activity. Ectopic expression of Cdo or Boc results in Shh-dependent, cell-autonomous promotion of ventral cell fates. Loss of Cdo produces a Shh dosage-dependent reduction of the floor plate. Cdo and Boc are also transcriptional targets negatively regulated by Hedgehog signaling.\",\n      \"method\": \"Genetic loss-of-function (knockout mice), gain-of-function (ectopic expression), binding assays, neural tube patterning analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combined in vivo genetics with in vitro binding assays, replicated across multiple labs\",\n      \"pmids\": [\"16647304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cdo-deficient mice display holoprosencephaly with strain-specific severity without limb defects, modeling human HPE. Shh target gene expression is reduced in developing forebrains of Cdo-/- mice. Cdo positively regulates Shh signaling in vitro at multiple levels including signal reception and via a parallel mechanism required at the level of Gli transcription factors. Specific Cdo domains required for promyogenic effects are dispensable for Shh signaling.\",\n      \"method\": \"Cdo knockout mice, Shh target gene expression analysis (in situ hybridization), cell-based Shh signaling assays, domain-deletion constructs\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout, domain mapping, and cell-based signaling assays; replicated in multiple subsequent studies\",\n      \"pmids\": [\"16647303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDO promotes neuronal differentiation and cotransfection of CDO enhances the activity of neurogenic bHLH factor neurogenin1 in reporter assays, enhancing heterodimerization of neurogenin1 and E47. Cdo-/- mice on C57BL/6 background display hydrocephalus and cortical thinning, and primary neural progenitors from Cdo-/- mutants show reduced proliferation.\",\n      \"method\": \"CDO knockout mice, neuronal precursor cell overexpression/RNAi, reporter assays, co-immunoprecipitation for bHLH heterodimerization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with cellular phenotype plus cell-based mechanistic assays, single lab\",\n      \"pmids\": [\"16648472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ihog (Drosophila ortholog of CDON) binds Hedgehog protein through its first extracellular fibronectin type III (FNIII) domain; the second FNIII domain is additionally required for in vivo signaling and for Ihog-enhanced binding of Hh to cells co-expressing Patched. Epistasis analysis places ihog action at or upstream of Patched. Other Ihog family members including mammalian CDO also interact with Hh ligands via a specific FNIII domain.\",\n      \"method\": \"RNAi in Drosophila cultured cells, in vitro binding assays (pulldown), genetic epistasis analysis, loss-of-function mutations in Drosophila\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain-level binding assays, genetic epistasis, and loss-of-function in vivo, independently corroborated\",\n      \"pmids\": [\"16630821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The intracellular region of Cdo 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 levels of active p38alpha/beta. Primary myoblasts from Cdo-/- mice are deficient in p38alpha/beta activity, and expression of activated MKK6 rescues differentiation of Cdo-/- cells.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, Cdo-/- primary myoblasts, rescue experiments with activated MKK6\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic loss-of-function rescue, and kinase activity assays; multiple orthogonal methods\",\n      \"pmids\": [\"17074887\"],\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. Gas1;Cdo double mutant mice show more severe Shh-dependent defects than either single mutant, establishing a genetic interaction between these two Shh-binding cell surface proteins.\",\n      \"method\": \"Genetic double knockout mice, in situ hybridization for Shh target genes, ectopic expression assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with double-mutant analysis across multiple tissues, replicated\",\n      \"pmids\": [\"17504941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"X-ray crystallography revealed the structure of the ShhN-CDO complex; the ShhN binds to the third FNIII repeat of CDO (not the orthologous FNIII repeat used by Drosophila Ihog). The ShhN-CDO interaction requires calcium, which binds at a previously undetected site on ShhN conserved in nearly all Hh proteins. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with CDO, Ptc, Hip, and Gas1.\",\n      \"method\": \"X-ray crystallography, biophysical binding assays (ITC, SPR), pulldown experiments, mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple biophysical methods, replicated by subsequent structural studies\",\n      \"pmids\": [\"18794898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cdo also interacts with Bnip-2, a regulator of Cdc42, and with JLP; Bnip-2 and JLP are brought together through mutual interaction with Cdo. The Cdo-Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38alpha/beta activity and myoblast differentiation. This defines a Cdo-Bnip-2-Cdc42 signaling pathway upstream of p38 MAPK.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function experiments in myoblasts, Cdc42 activity assays, p38 activity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple co-IP interactions, gain/loss-of-function pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"18678706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Abl tyrosine kinase associates with both Cdo and JLP during myoblast differentiation. Abl binds a proline-rich motif in the Cdo intracellular domain via its SH3 domain; these regions are required for their promyogenic effects. Cdo is important for full Abl kinase activity, and Abl is necessary for full p38 MAPK activation during myogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion/mutation constructs, kinase activity assays, shRNA knockdown, differentiation rescue assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping plus kinase assays and functional rescue, single lab\",\n      \"pmids\": [\"19470755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdo uses similar regulatory mechanisms in neuronal differentiation as in myogenesis: Cdo-dependent activation of Cdc42 and p38 MAPK promotes neuronal differentiation of C17.2 and P19 cells. Cdc42 and p38 MAPK activities promote heterodimerization of neurogenin1 and E47, suggesting regulation of neural bHLH factor activity as a mechanism.\",\n      \"method\": \"Overexpression and RNAi knockdown in neural precursor cells, Cdc42 and p38 activity assays, bHLH heterodimerization assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in cell culture, single lab\",\n      \"pmids\": [\"19244314\"],\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; Cdo, JLP, Bnip-2, and activated Cdc42 cluster at sites of N-cadherin ligation. In contrast, Shh binding to Cdo does not activate p38alpha/beta — JLP and Bnip-2 are not associated with Cdo when bound to Shh — demonstrating mechanistically distinct signaling roles for Cdo depending on the extracellular ligand.\",\n      \"method\": \"N-cadherin ligation assays, co-immunoprecipitation, p38 MAPK activity assays, immunofluorescence clustering analysis, Shh treatment controls\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods demonstrating ligand-specific signaling, key negative control (Shh does not activate p38)\",\n      \"pmids\": [\"20160094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GAS1, CDO, and BOC play overlapping and collectively essential roles during HH-mediated ventral neural patterning; they function in cell fate specification of neural progenitors and later in motor neuron progenitor maintenance. Genetic loss-of-function (triple mutant) experiments indicate an obligatory collective requirement for these coreceptors in HH pathway activity in multiple tissues.\",\n      \"method\": \"Single, double, and triple genetic knockout mice, neural tube patterning analysis, in situ hybridization for HH target genes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic in vivo genetic epistasis through triple knockout, defined molecular and cellular readouts\",\n      \"pmids\": [\"21664576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"All three mammalian Hedgehog proteins (Sonic, Indian, and Desert Hh) bind CDO and BOC in the same manner via the same domain (FNIII repeat 3 of CDO). X-ray crystallography confirmed this conserved mode of binding and revealed that formation of Hh-CDO interaction is weakened at low pH.\",\n      \"method\": \"X-ray crystallography of Hh-CDO and Hh-BOC complexes, biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple Hh-CDO complexes with biochemical validation\",\n      \"pmids\": [\"20519495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdo interacts with APPL1 (an interacting partner of Akt), and both Cdo and APPL1 are required for efficient Akt activation during myoblast differentiation. Constitutively active Akt rescues differentiation defects of Cdo-depleted cells, whereas APPL1 overexpression alone does not, placing Cdo upstream of Akt via APPL1 for myogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, constitutively active Akt rescue, Akt activity assays, differentiation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus loss-of-function rescue hierarchy, single lab\",\n      \"pmids\": [\"20484574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Boc mutation exacerbates HPE in Cdo-deficient mice, indicating that Boc is a silent HPE modifier gene. Cdo and Boc have selective roles in Shh signaling — Cdo;Boc double mutants do not phenocopy Shh-null mice, demonstrating evolutionary divergence from Drosophila where Ihog and Boi are fully essential for all Hh signaling.\",\n      \"method\": \"Cdo;Boc double-mutant mice, Shh target gene expression analysis, HPE scoring\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double knockout), defined molecular and phenotypic readouts\",\n      \"pmids\": [\"21183473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Missense mutations in human CDON cause holoprosencephaly (HPE). These mutations diminish CDON's ability to support Shh-dependent gene expression in cell-based signaling assays but do not affect Shh binding. Instead, wild-type CDON associates with PTCH1 and GAS1, but the HPE-associated variants do so inefficiently, indicating that CDON-PTCH1 and CDON-GAS1 interactions are required for signaling and that disruption of these inter-receptor interactions is a mechanism of HPE.\",\n      \"method\": \"Patient mutation identification, cell-based Shh signaling assays, co-immunoprecipitation of CDON with PTCH1 and GAS1, Shh binding assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics linked to cell-based mechanistic assays with multiple binding partners tested; multiple orthogonal methods\",\n      \"pmids\": [\"21802063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Gas1 and Cdo are coexpressed in muscle cells, form a complex in differentiating myoblasts, and cooperate to activate p38 MAPK. Gas1 overexpression in Cdo-depleted C2C12 cells restores p38 MAPK activities and differentiation, placing Gas1 as a component of the Cdo/Cadherin multiprotein complex that activates p38.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, shRNA knockdown, p38 MAPK activity assays, myoblast differentiation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus pathway rescue, single lab\",\n      \"pmids\": [\"21820049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cx43 (Connexin 43) physically interacts with Cdo to form dynamic complexes during myoblast differentiation, as demonstrated by co-localization and FRET-based molecular imaging approaches.\",\n      \"method\": \"Fluorescence imaging, FRET/FLIM analysis, co-immunoprecipitation\",\n      \"journal\": \"Journal of biophotonics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, imaging-based interaction without functional domain mapping or rescue experiments\",\n      \"pmids\": [\"22930637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TAK1 and ASK1 associate with the cytoplasmic tail of Cdo and with the scaffold protein JLP, and function as MAP3Ks in Cdo-mediated p38 MAPK activation during myoblast differentiation. Overexpression of TAK1 or ASK1 in Cdo-/- myoblasts restores p38 MAPK activation and myotube formation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, shRNA knockdown, p38 kinase activity assays, rescue in Cdo-/- myoblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, rescue in knockout cells, and kinase assays; single lab\",\n      \"pmids\": [\"22337877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphorylation of Stim1 at serine 575 by ERK1/2 (activated via netrin-2/Cdo signaling) is required for myoblast differentiation. Cdo and Stim1 form a complex in differentiating myoblasts, and alanine substitution at S575 fails to rescue differentiation of Stim1-depleted myoblasts. Cdo-/- primary myoblasts display defective NFATc3 activation correlating with reduced Stim1 levels.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of Stim1 S575, rescue assays, p-ERK and NFATc3 activity assays, Cdo-/- primary myoblasts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis with functional rescue, co-IP, and knockout cells; single lab\",\n      \"pmids\": [\"22298426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdon mutation synergizes with fetal ethanol exposure to produce defects in early midline patterning, inhibition of Shh signaling in the developing forebrain, and a broad spectrum of HPE phenotypes in 129S6 mice. Loss of Cdon alone or ethanol alone gives little/no phenotype, establishing a gene-environment interaction.\",\n      \"method\": \"Cdon-/- mouse model with in utero ethanol exposure, Shh target gene expression analysis, HPE scoring\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — controlled in vivo genetic × environment experiment with molecular readouts; replicated in subsequent studies\",\n      \"pmids\": [\"23071453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cdo-/- mice are specifically defective in smooth muscle fascicular reorientation in the esophagus, resulting in an aberrantly proximal skeletal-smooth muscle boundary, megaesophagus, achalasia, and lower esophageal sphincter resistance to nitric oxide-induced relaxation.\",\n      \"method\": \"Cdo knockout mice, histochemistry, immunostaining, morphometric analysis, physiological measurements\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined morphological and physiological phenotypes, mechanistic cellular analysis\",\n      \"pmids\": [\"23569214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDON behaves as a SHH dependence receptor: it actively triggers apoptosis in the absence of SHH. The pro-apoptotic activity of unbound CDON requires proteolytic cleavage in its intracellular domain, allowing recruitment and activation of caspase-9. SHH binding to CDON inhibits this pro-apoptotic activity, promoting tumor cell survival.\",\n      \"method\": \"Cell-based apoptosis assays, caspase-9 activation assays, CDON intracellular domain cleavage analysis, in vivo tumor growth models, SHH-CDON interaction interference experiments\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (caspase assays, cleavage, in vitro and in vivo tumor models), mechanistic domain-level analysis\",\n      \"pmids\": [\"23940460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the zebrafish and chick optic vesicle, Cdon acts as a negative Hh signaling regulator (decoy receptor) by predominantly localizing to the basolateral side of neuroepithelial cells, promoting enlargement of the neuroepithelial basal end-foot, trapping Hh protein, and limiting its dispersion in a Patched-independent manner. This protects the retinal primordium from Hh activity.\",\n      \"method\": \"Zebrafish and chick in vivo genetics, live imaging, subcellular localization assays, Hh protein distribution analysis, genetic rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two vertebrate models with direct protein localization and Hh distribution assays; mechanistic dissection of Ptc-independent function\",\n      \"pmids\": [\"25001599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cdo suppresses canonical Wnt signaling to promote neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6; the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Cdo-deficient dorsal forebrain displays enhanced Wnt signaling, increased proliferation, and elevated Pax6, Gli3, and Axin2 expression.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion constructs, Wnt reporter assays, Cdo-/- mouse forebrain analysis, cell proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level co-IP plus in vivo knockout with molecular pathway readouts; multiple orthogonal methods\",\n      \"pmids\": [\"25406935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDON and BOC utilize distinct molecular mechanisms to promote HH signaling. CDON requires membrane attachment while BOC does not for full activity. Separate novel extracellular motifs in CDON and BOC are identified as required for their HH-promoting effects, demonstrating non-redundant structural requirements despite functional overlap.\",\n      \"method\": \"Gain-of-function in developing chicken spinal cord, domain-deletion and mutant constructs, HH target gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo domain dissection in avian model, single lab\",\n      \"pmids\": [\"25848697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cdon promotes neural crest cell (NCC) migration in zebrafish; Cdon knockdown results in aberrant trunk NCC migration with reduced directedness and mispositioned protrusions. Cdon is required cell-autonomously for directed NCC migration and regulates localization of N-cadherin to the cell membrane in migratory NCCs.\",\n      \"method\": \"Morpholino knockdown in zebrafish, live cell imaging, cell transplantation, immunofluorescence for N-cadherin localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with live imaging and transplantation, single lab\",\n      \"pmids\": [\"26256768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Syntaxin 4 (Stx4) binds to the cytoplasmic tail of Cdo and is required for cell surface localization of Cdo; Stx4 depletion specifically decreases surface Cdo without altering surface N-cadherin levels. Cdo depletion in turn reduces surface GLUT4 and Stx4, and overall glucose uptake, linking Cdo surface trafficking to metabolic signaling in myoblasts.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, shRNA knockdown, glucose uptake assays, myoblast differentiation assays\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, surface biotinylation, and functional assays; single lab\",\n      \"pmids\": [\"26347807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdo forms a complex with Kir2.1 potassium channel during myoblast differentiation and is required for Kir2.1 surface expression and channel activity. Loss of Cdo reduces Kir2.1 surface levels, and this is dependent on p38 MAPK activity (MKK6(EE) expression restores Kir2.1 activity in Cdo-depleted cells).\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, electrophysiology, shRNA knockdown, rescue with activated MKK6\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional channel activity assays and epistasis, single lab\",\n      \"pmids\": [\"27380411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKN2 forms complexes with Cdo, APPL1, and AKT via its C-terminal region; this interaction is important for AKT activation and myoblast differentiation. PKN2 levels are decreased in Cdo-depleted cells, and PKN2 overexpression compensates for Cdo deficiency in AKT activation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, overexpression, AKT activity assays, myoblast differentiation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, domain mapping, and functional rescue, single lab\",\n      \"pmids\": [\"27763641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdo-/- mice develop cardiac dysfunction (reduced ejection fraction, ECG abnormalities), fibrosis, and up-regulation and mislocalization of Connexin 43 (Cx43) due to hyperactivation of Wnt/β-catenin signaling. Cdon is localized at intercalated discs in mouse and human hearts. Inhibition of Wnt signaling (by XAV939, IWP2, or DKK1) prevents Cdo-depletion-induced upregulation of collagen 1a and Cx43, placing Cdo as a negative regulator of Wnt/β-catenin in cardiomyocytes.\",\n      \"method\": \"Cdo-/- mice, echocardiography, histology, immunostaining for Cx43 and β-catenin, gap junction activity assays, Wnt inhibitor treatments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with cardiac phenotype plus pathway rescue by pharmacological Wnt inhibition; multiple orthogonal methods\",\n      \"pmids\": [\"28154134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdo is required for efficient cardiomyogenesis of pluripotent stem cells via activation of Shh signaling. Cdo-/- ES cells display decreased expression of cardiac regulators (Gata4, Nkx2.5, Mef2c) and reduced Shh signaling; Shh agonist treatment restores cardiomyogenesis in Cdo-deficient ES cells.\",\n      \"method\": \"Cdo-/- mouse ES cells, P19 EC cell differentiation, shRNA knockdown, Shh pathway reporter assays, Shh agonist rescue\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in stem cells with pathway-specific rescue, single lab\",\n      \"pmids\": [\"26906632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ash1L (a Trithorax group epigenetic activator) promotes myoblast fusion by activating Cdon expression. Ash1L is required to counteract Polycomb repressive activity at the Cdon locus; RNA- and ChIP-sequencing identified Cdon as a key target gene of Ash1L in myogenesis.\",\n      \"method\": \"RNA-seq, ChIP-seq, Ash1L loss-of-function in vitro and in vivo, myoblast fusion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic assays plus functional experiments placing Ash1L upstream of Cdon, single lab\",\n      \"pmids\": [\"30487570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Satellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis due to decreased satellite cell proliferation and senescence. Mechanistically, Cdon-depleted satellite cells show impaired integrin β1 activation, reduced ERK activation in response to FGF, and Cdon interacts with and regulates cell surface localization of FGFR1 and FGFR4.\",\n      \"method\": \"Inducible satellite cell-specific Cdon knockout mice (Pax7-CreERT2), cardiotoxin injury, immunostaining, EdU assay, co-immunoprecipitation, FGFR surface expression analysis, RNA-seq\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional tissue-specific knockout with multiple mechanistic readouts including co-IP and surface expression analysis\",\n      \"pmids\": [\"32103583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nodal signaling is a major point of synergistic interaction between Cdon mutation and fetal alcohol exposure in HPE. Window-of-sensitivity experiments indicate that brief ethanol exposure during gastrulation transiently inhibits Nodal pathway activity in Cdon mutant embryos, with consequent effects on midline patterning.\",\n      \"method\": \"Cdon-/- mouse with timed ethanol exposure, Nodal pathway activity assays, genetic epistasis, in vitro Nodal assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic × environment with pathway-specific molecular readouts; single lab\",\n      \"pmids\": [\"32876567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In endothelial cells, Cdon prevents Desert Hedgehog (Dhh) binding to Ptch1 and thus acts as a decoy receptor for Dhh, negatively regulating Dhh signaling. Cdon deficiency in ECs promotes endothelial junction integrity and decreases inflammatory markers (VCAM-1, ICAM-1), opposite to Gas1 (which is a positive regulator of Dhh in ECs).\",\n      \"method\": \"siRNA knockdown, EC-specific conditional knockout mice, Dhh-Ptch1 binding assays, VCAM-1/ICAM-1 expression analysis, vascular permeability assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with molecular binding assays and functional vascular readouts, single lab\",\n      \"pmids\": [\"33028094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cytoneme-mediated delivery of SHH from ligand-producing cells requires a novel Dispatched (DISP)-BOC/CDON co-receptor complex at the producing cell membrane. Myosin 10 promotes vesicular transport of SHH in mouse cell cytonemes. Cytoneme-deposited SHH induces rapid receptor-dependent signaling within seconds; this is dependent on the DISP-BOC/CDON complex for cytoneme occurrence and ligand delivery.\",\n      \"method\": \"Live cell imaging, Myo10 knockout mice, neural tube patterning analysis, co-immunoprecipitation of DISP-BOC/CDON complex, time-lapse signaling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of novel complex plus in vivo knockout and live imaging, single lab\",\n      \"pmids\": [\"33570491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GAS1, CDON, and BOC are collectively required for HH-dependent digit specification, limb patterning, and long bone growth. Limb-specific conditional deletion of Cdon in a Gas1;Boc null background results in digit loss and limb outgrowth defects.\",\n      \"method\": \"Limb-specific conditional Cdon knockout in Gas1;Boc null background, skeletal preparations, HH target gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic in vivo combinatorial genetic analysis, defined HH-dependent phenotypes\",\n      \"pmids\": [\"36265686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cdon deficiency in vascular smooth muscle cells (VSMCs) causes exacerbated aortic calcification via hyperactivation of Wnt/Runx2 signaling. The Ig2 domain of Cdon ectodomain is required for Wnt suppression; deletion of Ig2 abolishes Cdon-dependent Wnt inhibition and osteogenic conversion. Recombinant Ig2 domain protein suppresses Wnt signaling and VSMC calcification.\",\n      \"method\": \"Cdon conditional knockout mice (VSMC-specific), Wnt reporter assays, domain-deletion mutants, recombinant Ig2 protein treatment, aortic stiffness measurements, histological calcification analysis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with domain-level mechanistic analysis and recombinant protein rescue; multiple orthogonal methods\",\n      \"pmids\": [\"36609601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Motor neuron-specific Cdon ablation causes age-related motor neuron degeneration and impaired sciatic nerve repair. Mechanistically, Cdon-depleted motor neurons show altered ErbB4 and FGFR expression and impaired Akt activation in response to neuregulin-1 (NRG1), linking Cdon to neurotrophin signaling in motor neuron survival.\",\n      \"method\": \"Motor neuron-specific Cdon knockout (Hb9-Cre), sciatic nerve crush injury model, RNA-seq, immunostaining, electrophysiology, Akt activity assays in Cdon-depleted NSC34 cells\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockout with mechanistic pathway analysis; single lab\",\n      \"pmids\": [\"37559423\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDON (CDO) is a multifunctional Ig/fibronectin superfamily cell surface co-receptor that positively regulates Hedgehog (HH) signaling by binding SHH (via its third FNIII repeat in a calcium-dependent interaction) and forming complexes with PTCH1, GAS1, and BOC to transduce the HH signal; it also promotes skeletal myogenesis, neurogenesis, and other differentiation programs by scaffolding intracellular signaling complexes containing N-cadherin, JLP, Bnip-2/Cdc42, Abl, and APPL1 to activate p38α/β MAPK and AKT, while negatively regulating canonical Wnt signaling through its Ig2 domain interaction with LRP6; in specific developmental contexts (optic vesicle, endothelium) it acts as a decoy/sequestration receptor that limits HH ligand dispersion; and in the absence of SHH it functions as a dependence receptor that triggers caspase-9-dependent apoptosis via proteolytic cleavage of its intracellular domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDON (CDO) is a cell-surface co-receptor of the immunoglobulin/fibronectin type III superfamily that integrates Hedgehog (HH) signaling and cell-adhesion cues to drive cell-fate specification and differentiation across multiple developmental contexts [#0, #5, #15]. As a HH co-receptor, CDON binds all three mammalian HH ligands through its third FNIII repeat in a calcium-dependent interaction whose structural details were resolved by crystallography, and it positively transduces the signal by physically associating with PTCH1 and GAS1; HPE-causing missense mutations in human CDON spare SHH binding but disrupt these inter-receptor associations, establishing CDON-PTCH1/GAS1 complexes as essential for signaling [#5, #11, #17, #20]. CDON acts collectively and non-redundantly with the related co-receptors BOC and GAS1, and combinatorial mouse genetics show an obligatory requirement for these proteins in HH-dependent ventral neural patterning, craniofacial, vertebral, and limb development [#10, #16, #42]. Loss of CDON in mice produces holoprosencephaly, and this phenotype is exacerbated by fetal ethanol exposure through synergistic inhibition of Shh and Nodal signaling, defining a gene-environment interaction [#3, #6, #25, #39]. In a ligand-specific manner CDON also scaffolds an intracellular signaling module: N-cadherin ligation (but not SHH binding) recruits the scaffold JLP together with Bnip-2, which stimulates Cdc42 and downstream TAK1/ASK1-MKK6 to activate p38\\u03b1/\\u03b2 MAPK and drive myogenic and neuronal differentiation, in part by enhancing bHLH/E-protein heterodimerization; CDON additionally promotes AKT activation through APPL1 and PKN2 [#2, #9, #12, #14, #15, #18, #23, #34]. Through its Ig2 ectodomain, CDON binds LRP6 and negatively regulates canonical Wnt/\\u03b2-catenin signaling, a function required to restrain proliferation in the forebrain, prevent Cx43 dysregulation and cardiac fibrosis, and suppress osteogenic VSMC calcification [#29, #35, #43]. In specific tissues such as the optic vesicle and endothelium, CDON instead behaves as a Patched-independent decoy receptor that sequesters HH ligand and limits its dispersion, and in the absence of SHH it acts as a dependence receptor whose intracellular domain is proteolytically cleaved to recruit and activate caspase-9, triggering apoptosis [#27, #28, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing CDO as a novel adhesion-regulated Ig-superfamily surface glycoprotein defined the structural platform from which all later co-receptor functions were dissected.\",\n      \"evidence\": \"Molecular cloning and expression/adhesion analyses identifying five Ig and three FNIII repeats plus a cytoplasmic tail\",\n      \"pmids\": [\"9214393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand or signaling partner identified at cloning\", \"Functional role undefined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linking CDO to a MyoD positive-feedback loop established it as a positive regulator of differentiation, not merely a structural surface protein.\",\n      \"evidence\": \"Overexpression, soluble ectodomain inhibition, and dominant-negative constructs in C2C12 myoblasts\",\n      \"pmids\": [\"9786951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism downstream of CDO unknown\", \"Cytoplasmic effectors not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying cis-complex formation with BOC introduced the concept of a CDO co-receptor network acting in differentiation.\",\n      \"evidence\": \"Reciprocal co-IP and dominant-negative epistasis in myoblast differentiation assays\",\n      \"pmids\": [\"11782431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Shared ligand not yet known\", \"Stoichiometry of CDO-BOC complex undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The holoprosencephaly-like facial phenotype of Cdon knockout mice provided the first in vivo evidence for a role in midline development, anticipating its HH connection.\",\n      \"evidence\": \"Targeted knockout and morphological analysis in mice\",\n      \"pmids\": [\"12620190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causative pathway (HH) not yet established\", \"Cellular basis of facial defect unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that CDO/BOC bind SHH via a specific FNIII repoat and the Drosophila ortholog Ihog acts at/upstream of Patched defined CDON as a HH-pathway co-receptor operating at the level of signal reception and Gli.\",\n      \"evidence\": \"Knockout and ectopic-expression mouse genetics, binding assays, neural tube patterning, and Drosophila RNAi/epistasis\",\n      \"pmids\": [\"16647304\", \"16647303\", \"16630821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand binding unresolved\", \"Mechanism of Gli-level regulation unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapping the CDO intracellular tail to a JLP/p38\\u03b1\\u03b2 MAPK module and identifying a parallel role in neuronal bHLH activation revealed a ligand-receptor-independent intracellular signaling output.\",\n      \"evidence\": \"Co-IP, kinase assays, MKK6 rescue in Cdo-/- myoblasts, and reporter/heterodimerization assays in neural cells\",\n      \"pmids\": [\"17074887\", \"16648472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activating ligand for p38 axis not defined in 2006\", \"Link between p38 and bHLH activity incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic cooperation between Gas1 and Cdo established that HH-binding cell-surface proteins function combinatorially rather than independently.\",\n      \"evidence\": \"Gas1;Cdo double-mutant mice with Shh target gene analysis across multiple tissues\",\n      \"pmids\": [\"17504941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of cooperation not defined\", \"Whether the proteins form a physical complex unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The ShhN-CDO crystal structure and identification of a Bnip-2-Cdc42 arm provided atomic-level and mechanistic detail for both the HH-binding and intracellular signaling functions.\",\n      \"evidence\": \"X-ray crystallography with calcium-site mutagenesis (ShhN-CDO) and co-IP/activity assays defining Cdo-Bnip-2-Cdc42-p38\",\n      \"pmids\": [\"18794898\", \"18678706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How calcium-site disease mutations differentially affect each co-receptor not fully resolved\", \"Spatial coordination of intracellular complex assembly unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Adding Abl kinase to the CDO intracellular complex and extending the Cdc42/p38 logic to neurogenesis refined the differentiation signaling cascade.\",\n      \"evidence\": \"Co-IP/domain mapping with kinase assays in myoblasts and overexpression/RNAi in neural precursors\",\n      \"pmids\": [\"19470755\", \"19244314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ordering of Abl relative to other effectors incomplete\", \"Single-lab findings for neural extension\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the ligand-specific switch (N-cadherin activates p38; SHH does not) plus crystallographic confirmation of a conserved pan-HH binding mode and demonstration of collective co-receptor requirement unified the dual roles of CDON.\",\n      \"evidence\": \"N-cadherin ligation with co-IP/IF, Hh-CDO/BOC crystal structures, triple-knockout mouse genetics, and APPL1-Akt rescue assays\",\n      \"pmids\": [\"20160094\", \"20519495\", \"21664576\", \"20484574\", \"21183473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the receptor switches partner assembly between ligands mechanistically unresolved\", \"Divergence of vertebrate vs Drosophila co-receptor essentiality not fully explained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human CDON mutations causally linked to HPE through disrupted CDON-PTCH1/GAS1 interactions established the clinical relevance and pinpointed inter-receptor binding as the critical signaling step.\",\n      \"evidence\": \"Patient mutation analysis, cell-based Shh signaling assays, and co-IP of CDON with PTCH1/GAS1; plus Gas1-Cdo p38 complex in myoblasts\",\n      \"pmids\": [\"21802063\", \"21820049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDON physically bridges PTCH1 and GAS1 structurally undefined\", \"Variant penetrance/modifiers in patients unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Adding TAK1/ASK1 MAP3Ks, Stim1/NFAT, and Cx43 to the CDO complex broadened the intracellular signaling and trafficking repertoire underlying differentiation, while a gene-environment HPE model was established.\",\n      \"evidence\": \"Co-IP, knockout-cell rescue, phospho-site mutagenesis, FRET imaging, and Cdon-/- ethanol exposure with Shh readouts\",\n      \"pmids\": [\"22337877\", \"22298426\", \"22930637\", \"23071453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cx43 interaction lacks functional/domain validation (imaging only)\", \"Integration of Ca2+/NFAT and p38 arms unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining CDON as a SHH dependence receptor that triggers caspase-9 apoptosis when unbound, plus an esophageal muscle role, revealed pro-apoptotic and morphogenetic functions distinct from canonical signaling promotion.\",\n      \"evidence\": \"Apoptosis/caspase-9 assays, intracellular-domain cleavage analysis, tumor models, and Cdo-/- esophageal phenotyping\",\n      \"pmids\": [\"23940460\", \"23569214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the protease cleaving the CDON intracellular domain unknown\", \"Physiological contexts where dependence-receptor activity dominates undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing CDON as a Patched-independent decoy receptor in the optic vesicle and as an LRP6-binding Wnt suppressor revealed negative-regulatory functions opposite to its co-receptor role.\",\n      \"evidence\": \"Zebrafish/chick localization and Hh-distribution assays; Ig2-LRP6 co-IP, Wnt reporters, and Cdo-/- forebrain analysis\",\n      \"pmids\": [\"25001599\", \"25406935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines decoy vs co-receptor behavior in a given tissue unresolved\", \"Whether Wnt inhibition and HH decoy functions are mechanistically linked unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguishing CDON from BOC mechanistically and defining roles in neural crest migration and surface trafficking refined how the co-receptors and their adhesion functions are deployed.\",\n      \"evidence\": \"Domain dissection in chick spinal cord, zebrafish NCC knockdown/transplantation, and Stx4 co-IP/surface biotinylation\",\n      \"pmids\": [\"25848697\", \"26256768\", \"26347807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Membrane-attachment requirement of CDON mechanistically unexplained\", \"Single-lab trafficking findings\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending CDON to cardiac Wnt suppression, cardiomyogenesis via Shh, Kir2.1 channel surface delivery, and PKN2-AKT signaling demonstrated broad tissue deployment of its dual signaling modes.\",\n      \"evidence\": \"Cdo-/- cardiac phenotyping with Wnt-inhibitor rescue, ES/P19 cardiomyogenesis with Shh agonist rescue, electrophysiology, and PKN2 co-IP/AKT assays\",\n      \"pmids\": [\"28154134\", \"26906632\", \"27380411\", \"27763641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDON simultaneously balances Wnt suppression and Shh promotion in heart unresolved\", \"Mechanism of channel surface stabilization incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Ash1L as a Trithorax activator of Cdon transcription placed CDON within an epigenetic regulatory circuit controlling myoblast fusion.\",\n      \"evidence\": \"RNA-seq/ChIP-seq and Ash1L loss-of-function with myoblast fusion assays\",\n      \"pmids\": [\"30487570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional control not fully resolved\", \"Other upstream regulators of Cdon expression unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tissue-specific knockouts linked CDON to satellite-cell FGFR/integrin signaling, endothelial Dhh decoy function, and Nodal-dependent HPE synergy, extending its roles into regeneration, vascular biology, and morphogen crosstalk.\",\n      \"evidence\": \"Conditional Cdon knockouts with co-IP/surface analysis (FGFR), EC binding/permeability assays, and Cdon-/- ethanol Nodal assays\",\n      \"pmids\": [\"32103583\", \"33028094\", \"32876567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FGFR/ErbB regulation reflects a general trafficking role unresolved\", \"Mechanism by which CDON discriminates Dhh decoy vs promotion in endothelium unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing BOC/CDON in a Dispatched co-receptor complex on SHH-producing cells revealed a presynaptic-side role in cytoneme-mediated ligand delivery, broadening CDON function beyond the receiving cell.\",\n      \"evidence\": \"Live imaging, Myo10 knockout mice, DISP-BOC/CDON co-IP, and time-lapse neural tube signaling\",\n      \"pmids\": [\"33570491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDON's producing-cell and receiving-cell roles are separable unresolved\", \"Single-lab cytoneme mechanism\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating Ig2-dependent Wnt suppression in VSMC calcification and CDON's requirement in motor neuron survival/neurotrophin signaling consolidated its dual roles in disease-relevant tissues.\",\n      \"evidence\": \"VSMC-specific knockout with recombinant Ig2 rescue and Wnt reporters; motor neuron-specific knockout with NRG1/Akt and ErbB4/FGFR analysis\",\n      \"pmids\": [\"36609601\", \"37559423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single Ig2 domain mediates LRP6 binding across diverse tissues structurally undefined\", \"Integration of neurotrophin-receptor regulation with HH functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDON selects between its opposing molecular outputs\\u2014HH co-receptor, HH decoy, Wnt suppressor, intracellular p38/AKT scaffold, and apoptotic dependence receptor\\u2014within a given cell remains unresolved at a mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-dependent partner selection\", \"Protease responsible for dependence-receptor cleavage unidentified\", \"Structural basis of CDON-PTCH1/GAS1 and CDON-LRP6 complexes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5, 11, 17, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 6, 15, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 12, 18, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [29, 35, 43]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [15, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 15, 28, 32, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 11, 20, 29, 35]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 16, 42]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [\n      \"CDON-BOC co-receptor complex\",\n      \"CDON-PTCH1-GAS1 HH receptor complex\",\n      \"DISP-BOC/CDON cytoneme complex\",\n      \"CDON-JLP-Bnip-2 p38 signaling complex\"\n    ],\n    \"partners\": [\n      \"BOC\",\n      \"PTCH1\",\n      \"GAS1\",\n      \"LRP6\",\n      \"JLP\",\n      \"BNIP2\",\n      \"APPL1\",\n      \"ABL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}