Affinage

CHRD

Chordin · UniProt Q9H2X0

Length
955 aa
Mass
102.0 kDa
Annotated
2026-06-09
61 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHRD encodes chordin, a secreted BMP antagonist that limits BMP signaling during early development by sequestering BMP ligands extracellularly (PMID:12397106, PMID:16894609). In mouse embryos, chordin acts cooperatively with Noggin to restrict BMP activity across multiple patterning events: compound Chrd;Nog mutants lose SHH and FGF8 expression from rostral organizing centers and show heightened BMP sensitivity in cephalic explants (PMID:12397106), display expanded neural crest domains followed by neural crest apoptosis and craniofacial defects (PMID:16894609), and exhibit bilaterally elevated BMP signaling that abolishes Nodal in the lateral plate mesoderm, with ectopic Noggin restoring Nodal asymmetry—establishing a requirement in left-right axis establishment (PMID:18550712). Chordin loss alone produces aortic arch and venous patterning defects culminating in persistent truncus arteriosus, demonstrating a role in cardiovascular patterning (PMID:17685487), and chordin-driven BMP antagonism in the interdigital region suppresses interdigital cell death to produce syndactyly when overexpressed (PMID:29255029). Chordin transcription is controlled at the chrd promoter by activating inputs from Smad2/Smad3 via distinct activin response elements (PMID:33945994) and from Goosecoid acting through Wnt/TCF7-dependent elements (PMID:36980215), and by repressive inputs from Ventx1.1 and from Foxd4l1.1, the latter both binding its own response element and physically blocking Smad2/3 (PMID:34685759, PMID:36980215). Chordin's antagonist activity is modulated by partners and proteolysis: TWSG1 enhances its inhibition of BMP2/4/7 and GDF5 (PMID:34517078), whereas BMP1—whose secretion and CHRD binding are promoted by O-fucosylation—cleaves CHRD to release sequestered BMP4 and reactivate BMP/Smad signaling (PMID:37338142).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 Medium

    Establishing the human CHRD genomic locus and testing it as a candidate disease gene defined its chromosomal context and excluded one clinical hypothesis.

    Evidence Genomic sequencing and radiation hybrid mapping placing CHRD at 3q27 in a cluster with THPO/CLCN2/EIF4G1, plus mutation screening in Cornelia de Lange patients

    PMID:10480362 PMID:9782094

    Open questions at the time
    • No functional consequence of the locus organization shown
    • Negative disease screen does not exclude regulatory variants
  2. 2001 Medium

    Whether human chordin variants retain antagonist function was unknown; alternatively spliced C-truncated forms were shown to still antagonize BMP, indicating functional diversification.

    Evidence cDNA cloning, RT-PCR tissue profiling, and Xenopus axis-duplication assay

    PMID:11472837

    Open questions at the time
    • BMP ligand binding specificity of variants not resolved
    • Physiological role of tissue-specific splicing untested
  3. 2002 High

    It was unclear what maintains rostral organizing centers; chordin and Noggin were shown to limit BMP activity to sustain SHH and FGF8 in the prechordal plate and anterior neural ridge.

    Evidence Chrd;Nog compound mutant analysis, in situ hybridization, and ectopic BMP2 explant assays in mouse

    PMID:12397106

    Open questions at the time
    • Direct chordin-BMP binding not demonstrated in this system
    • Relative contributions of chordin vs Noggin not separated
  4. 2006 High

    The role of BMP antagonism in neural crest and cardiovascular development was undefined; genetic studies showed chordin (with Noggin) regulates neural crest generation/emigration and is required for aortic arch and venous patterning.

    Evidence Single and compound mutant analysis with BMP signaling readouts, and vascular resin injection imaging in Chrd-null embryos

    PMID:16894609 PMID:17685487

    Open questions at the time
    • Cell-autonomous vs non-autonomous action not dissected
    • Downstream effectors of derepressed BMP not identified
  5. 2006 Medium

    Whether chordin influences epithelial cell behavior beyond development was unknown; CHRD was shown to reduce motility and invasion and enhance adhesion in ovarian cancer cells.

    Evidence CHRD transfection with migration, invasion, and adhesion assays in BG1 and PEO14 cell lines

    PMID:16449796

    Open questions at the time
    • Mechanistic link to BMP signaling in this context not established
    • Single cell-line panel, single study
  6. 2008 High

    How left-right asymmetry is established was incompletely understood; chordin and Noggin were shown to restrict BMP in the left lateral plate mesoderm to derepress Nodal.

    Evidence Compound mutants, ectopic Noggin/Bmp4 expression, rescue, and in situ hybridization in mouse

    PMID:18550712

    Open questions at the time
    • Direct molecular link between node morphology defect and Nodal loss not fully resolved
  7. 2017 High

    The driver of interdigital cell survival in a syndactyly model was unknown; ectopic Shh-driven Chrd upregulation was shown to antagonize BMP and suppress interdigital cell death.

    Evidence CRISPR deletion mapping, transcriptomics, and Chrd-overexpressing transgenic mice phenocopying Hammer toe

    PMID:29255029

    Open questions at the time
    • Endogenous requirement of Chrd in normal interdigital apoptosis not tested by loss-of-function
  8. 2021 Medium

    How chrd transcription is controlled was undefined; Smad2/3 were shown to directly bind distinct activin response elements to activate the promoter, while Foxd4l1.1 represses it by both DNA binding and Smad sequestration.

    Evidence Reporter assays, site-directed mutagenesis, ChIP, and co-immunoprecipitation in Xenopus embryos

    PMID:33945994 PMID:34685759

    Open questions at the time
    • Combinatorial logic among activators and repressors not modeled
    • Findings limited to Xenopus promoter context
  9. 2021 Medium

    Whether chordin antagonist activity is modulated by cofactors and which BMPs it acts on were open; TWSG1 was shown to enhance CHRD antagonism of BMP2/4/7 and GDF5, while CHRD failed to antagonize BMP effects in bovine theca cells.

    Evidence Recombinant CHRD/TWSG1 BMP bioactivity assays, and BMP co-treatment androstenedione assays in primary bovine theca cells

    PMID:30400042 PMID:34517078

    Open questions at the time
    • Cell-context dependence of CHRD activity unexplained
    • Structural basis of TWSG1-CHRD cooperation unknown
  10. 2023 Medium

    How the chrd promoter integrates organizer and Wnt inputs, and how sequestered BMP is released, were unresolved; Gsc (Wnt/TCF7-dependent) and Ventx1.1 were shown to directly activate and repress transcription, and BMP1 cleavage of CHRD was shown to release BMP4.

    Evidence Reporter assays, mutagenesis, ChIP-PCR in Xenopus; and poFUT1/BMP1 co-expression with Co-IP and decidualization assays in human endometrial stromal cells

    PMID:36980215 PMID:37338142

    Open questions at the time
    • Direct CHRD cleavage products not biochemically mapped in these studies
    • In vivo relevance of poFUT1-BMP1-CHRD axis not tested by loss-of-function

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of chordin-BMP recognition and the rules governing its context-dependent BMP-ligand selectivity remain unresolved.
  • No structural model of chordin-BMP complexes in the timeline
  • Mechanism behind tissue-specific antagonist activity (active in ovary/cancer cells but inactive in theca cells) unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
BMP1BMP4NOGSMAD2SMAD3TWSG1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Mouse chordin (Chrd) is expressed at high levels in 7-day post-coitum mouse embryos and at lower levels in adult tissues including liver and cerebellum; the human CHRD gene was mapped to chromosome 3q27 by radiation hybrid mapping and mouse Chrd to chromosome 16. RNA blot analysis, radiation hybrid mapping, interspecific crosses Genomics Medium 9782094
1999 The human CHRD gene resides at 3q27 in a gene cluster with THPO, CLCN2, and EIF4G1; CHRD and THPO are transcribed from opposing DNA strands from promoters spaced less than 2 kb apart. Mutation screening of CHRD in Cornelia de Lange syndrome patients found no disease-specific mutations. Genomic sequencing, radiation hybrid mapping, mutation screening Human genetics Medium 10480362
2001 Human CHRD encodes multiple alternatively spliced variants that produce C-truncated forms of chordin protein; these splice variants are expressed in tissue-specific patterns in fetal and adult tissues (notably liver, cerebellum, female genital tract) and can antagonize BMP activity when tested in a Xenopus axis-duplication assay. cDNA cloning, RT-PCR, Xenopus axis-duplication assay Mechanisms of development Medium 11472837
2002 Chordin (Chrd) and Noggin function as BMP antagonists in the mouse prechordal plate and anterior neural ridge; Chrd−/−;Nog+/− compound mutants show loss of SHH expression from the prechordal plate and reduced FGF8 from the anterior neural ridge, and cephalic explants from double mutants show increased sensitivity to exogenous BMP, establishing that these factors limit BMP activity to maintain rostral organizing centers. Genetic compound mutant analysis, in situ hybridization, ectopic BMP2 application to wild-type and mutant cephalic explants Development (Cambridge, England) High 12397106
2006 Chordin (CHRD) reduces tumor cell motility and invasion, and enhances cell adhesion, in ovarian cancer cell lines (BG1 and PEO14), consistent with a role in regulating BMP activity in ovarian surface epithelium. CHRD transfection into cancer cell lines; migration/invasion assays, adhesion assay FASEB journal Medium 16449796
2006 Chordin (Chrd) and Noggin act together as BMP antagonists to promote neural crest cell generation and regulate their emigration from the neural tube in mammals; loss of both factors expands the early neural crest domain and ultimately causes neural crest cell apoptosis, peripheral nervous system defects, and craniofacial skeletal defects. Chrd and Nog single and compound mutant analysis, BMP signaling assays in dorsal tissue Developmental dynamics High 16894609
2007 Genetic inactivation of Chordin (Chrd−/−) in mice results in severe aortic arch defects developing into persistent truncus arteriosus, as well as multiple venous patterning defects of the anterior cardinal veins, demonstrating that BMP pathway antagonism by Chordin is required for cardiovascular patterning. Genetic knockout, pigmented methylsalicylate resin vascular injection in fixed transparent embryos Developmental dynamics Medium 17685487
2008 In Chrd;Nog double mutants, BMP signaling is elevated bilaterally and Nodal expression is absent from the lateral plate mesoderm (LPM). Ectopic Noggin expression in the left LPM restores Nodal expression; ectopic Bmp4 in the left LPM represses Nodal; ectopic Noggin in the right LPM induces ectopic Nodal. This establishes that chordin and noggin limit BMP signaling in the left LPM to derepress Nodal and are required for proper node morphology for left-right axis establishment. Genetic compound mutant analysis, conditional/ectopic gene expression, in situ hybridization, BMP signaling assays Development (Cambridge, England) High 18550712
2017 In the Hammer toe (Hm) mouse, ectopic Shh expression driven by inserted enhancers upregulates Chordin (Chrd) in interdigital regions; Chrd-overexpressing transgenic mice recapitulate syndactyly with webbing, establishing that Chrd antagonizes BMP signaling in the interdigital region to suppress interdigital cell death. CRISPR/Cas9 deletion mapping, transcriptome analysis, Chrd-overexpressing transgenic mice Proceedings of the National Academy of Sciences of the United States of America High 29255029
2021 Smad2 and Smad3 directly bind distinct activin response elements (ARE1 and ARE2) in the distal region of the chordin (chrd) promoter to activate transcription in Xenopus gastrula embryos; Smad2 acts on both ARE1 and ARE2 while Smad3 acts only on ARE2, providing differential transcriptional control. Reporter gene assays, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) Biochemical and biophysical research communications Medium 33945994
2021 Foxd4l1.1 negatively regulates chrd transcription by two mechanisms: (1) direct binding to Foxd4l1.1 response elements (FRE) in the chrd promoter, and (2) physical interaction with Smad2/Smad3 to block their binding to activin response elements (AREs) in the chrd promoter. Mutagenesis of FRE abolishes the repressor activity. Reporter gene assays, site-directed mutagenesis, co-immunoprecipitation, RT-PCR in Xenopus embryos Cells Medium 34685759
2023 Goosecoid (Gsc) activates chrd transcription by binding to Gsc response elements (GRE) in the chrd promoter in a manner dependent on an adjacent Wnt/TCF7 response element (WRE); Ventx1.1 represses chrd by direct binding to Ventx1.1 response elements (VRE). ChIP-PCR confirmed direct binding of both transcription factors to their respective elements. Reporter gene assays, site-directed mutagenesis, ChIP-PCR, RT-PCR in Xenopus gastrula Cells Medium 36980215
2023 O-fucosylation of BMP1 by poFUT1 promotes its secretion and enhances binding of BMP1 to CHRD. This BMP1–CHRD interaction releases BMP4 that was previously sequestered by CHRD, activating BMP/Smad signaling and accelerating decidualization of human endometrial stromal cells. poFUT1/BMP1 co-expression in hESCs, Co-IP of BMP1 and CHRD, BMP/Smad signaling assays, decidualization assay Biology of reproduction Medium 37338142
2021 TWSG1 enhances the ability of CHRD to antagonize BMP2, BMP4, BMP7, and GDF5 in bioactivity assays, indicating cooperative/synergistic action between TWSG1 and CHRD in modulating BMP signaling in the ovary. BMP signaling bioactivity assays with recombinant CHRD and TWSG1 proteins Molecular and cellular endocrinology Medium 34517078
2019 Chordin (CHRD) did not antagonize the BMP-induced suppression of androstenedione secretion by bovine theca cells for any of BMP2, BMP4, BMP6, or BMP7, in contrast to gremlin, noggin, and follistatin which showed selective antagonism. Primary bovine theca cell culture, androstenedione ELISA, BMP co-treatment assays Journal of molecular endocrinology Medium 30400042

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development (Cambridge, England) 194 11566865
2002 Chordin and noggin promote organizing centers of forebrain development in the mouse. Development (Cambridge, England) 157 12397106
2009 PCSK9 as a therapeutic target of dyslipidemia. Expert opinion on therapeutic targets 112 19063703
2016 De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS genetics 93 27058611
2003 CRIM1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface. The Journal of biological chemistry 90 12805376
2016 Differential expression of TGF-β superfamily members and role of Smad1/5/9-signalling in chondral versus endochondral chondrocyte differentiation. Scientific reports 65 27848974
2012 The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. The Journal of biological chemistry 64 23105118
2008 BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment. Development (Cambridge, England) 55 18550712
2017 Endothelial microparticles act as novel diagnostic and therapeutic biomarkers of circulatory hypoxia-related diseases: a literature review. Journal of cellular and molecular medicine 52 28316143
2012 Microarray expression analysis of genes and pathways involved in growth plate cartilage injury responses and bony repair. Bone 51 22387305
2006 Endogenous bone morphogenetic protein antagonists regulate mammalian neural crest generation and survival. Developmental dynamics : an official publication of the American Association of Anatomists 50 16894609
2008 Altered transforming growth factor-beta signaling in a murine model of thoracic aortic aneurysm. Journal of vascular research 38 18434745
2001 Defects of the body plan of mutant embryos lacking Lim1, Otx2 or Hnf3beta activity. The International journal of developmental biology 37 11291865
2011 Identification and regulation of bone morphogenetic protein antagonists associated with preantral follicle development in the ovary. Endocrinology 35 21791559
2006 Chordin is underexpressed in ovarian tumors and reduces tumor cell motility. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 16449796
2010 Distinct functionalities of bone morphogenetic protein antagonists during fracture healing in mice. Journal of anatomy 30 20298438
2022 Integrative analyses of biomarkers and pathways for heart failure. BMC medical genomics 29 35346191
2016 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation. The Journal of biological chemistry 29 27284008
1998 Coding sequence and expression patterns of mouse chordin and mapping of the cognate mouse chrd and human CHRD genes. Genomics 29 9782094
2016 BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2. Molecular human reproduction 28 27385727
2022 The landscape of promoter-centred RNA-DNA interactions in rice. Nature plants 27 35115727
2017 Spore surface proteins of Brevibacillus laterosporus are involved in insect pathogenesis. Scientific reports 26 28256631
2001 The human chordin gene encodes several differentially expressed spliced variants with distinct BMP opposing activities. Mechanisms of development 25 11472837
1999 Molecular mechanisms underlying carotenogenesis in the chromoplast: multilevel regulation of carotenoid-associated genes. The Plant journal : for cell and molecular biology 25 10607295
2021 BMP antagonists in tissue development and disease. Matrix biology plus 24 34435185
2008 PerioGlas regulates osteoblast RNA interfering. Journal of prosthodontics : official journal of the American College of Prosthodontists 24 18573151
2019 Gremlin, noggin, chordin and follistatin differentially modulate BMP-induced suppression of androgen secretion by bovine ovarian theca cells. Journal of molecular endocrinology 23 30400042
2015 A semi-automated mass spectrometric immunoassay coupled to selected reaction monitoring (MSIA-SRM) reveals novel relationships between circulating PCSK9 and metabolic phenotypes in patient cohorts. Methods (San Diego, Calif.) 22 25770357
2013 Chromatin dynamics in living cells: identification of oscillatory motion. Journal of cellular physiology 22 22886456
2009 Chromatin dynamics is correlated with replication timing. Chromosoma 22 19296120
2018 Evaluation of Gene-Based Family-Based Methods to Detect Novel Genes Associated With Familial Late Onset Alzheimer Disease. Frontiers in neuroscience 21 29670507
2015 Osteogenic differentiation of bone marrow stromal cells is hindered by the presence of intervertebral disc cells. Arthritis research & therapy 21 26809343
2017 The BMP2 variant L51P restores the osteogenic differentiation of human mesenchymal stromal cells in the presence of intervertebral disc cells. European cells & materials 19 28266688
2018 Effects of acute and chronic methamphetamine administration on cynomolgus monkey hippocampus structure and cellular transcriptome. Toxicology and applied pharmacology 18 29802913
2010 The expression of twisted gastrulation in postnatal mouse brain and functional implications. Neuroscience 18 20493240
1999 Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes. Human genetics 17 10480362
2022 Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels. Molecular metabolism 16 36566984
2021 Smad2 and Smad3 differentially modulate chordin transcription via direct binding on the distal elements in gastrula Xenopus embryos. Biochemical and biophysical research communications 13 33945994
2021 PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs. Stem cell reports 13 34739847
2017 Enhancer adoption caused by genomic insertion elicits interdigital Shh expression and syndactyly in mouse. Proceedings of the National Academy of Sciences of the United States of America 13 29255029
2023 SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2. Viruses 10 36851576
2021 The culture microenvironment of juvenile idiopathic arthritis synovial fibroblasts is favorable for endochondral bone formation through BMP4 and repressed by chondrocytes. Pediatric rheumatology online journal 9 33980237
1997 Isolation and regulation of accumulation of a minor chromoplast-specific protein from cucumber corollas. Plant physiology 9 9008387
2021 Foxd4l1.1 Negatively Regulates Chordin Transcription in Neuroectoderm of Xenopus Gastrula. Cells 7 34685759
2023 Two Homeobox Transcription Factors, Goosecoid and Ventx1.1, Oppositely Regulate Chordin Transcription in Xenopus Gastrula Embryos. Cells 6 36980215
2020 Thymosin β4 Identified by Transcriptomic Analysis from HF Anagen to Telogen Promotes Proliferation of SHF-DPCs in Albas Cashmere Goat. International journal of molecular sciences 6 32218218
2023 O-Fucosylation of BMP1 promotes endometrial decidualization by activating BMP/Smad signaling pathway. Biology of reproduction 5 37338142
2007 Abnormal venous and arterial patterning in Chordin mutants. Developmental dynamics : an official publication of the American Association of Anatomists 5 17685487
2023 The developmental gene Chordin is amplified and expressed in human cancers. Molecular & cellular oncology 4 37260544
2021 Expression profiling of ovarian BMP antagonists reveals the potential interaction between TWSG1 and the chordin subfamily in the ovary. Molecular and cellular endocrinology 4 34517078
2025 PRDM14 is essential for vertebrate gastrulation and safeguards avian germ cell identity. Developmental biology 3 39938772
2024 Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis. Oncogene 3 38698265
2024 Exploration of transcriptional regulation network between buffalo oocytes and granulosa cells and its impact on different diameter follicles. BMC genomics 3 39462339
2022 ccr7 affects both morphogenesis and differentiation during early Xenopus embryogenesis. Development, growth & differentiation 3 35581152
2023 ccl19 and ccl21 affect cell movements and differentiation in early Xenopus development. Development, growth & differentiation 2 36861303
2022 RNA sequence analysis identified bone morphogenetic protein-2 (BMP2) as a biomarker underlying form deprivation myopia. Biochemistry and biophysics reports 2 35494490
2025 Maternal provisioning and zygotic activation: transcriptomic dynamics of early atlantic halibut (Hippoglossus hippoglossus) embryogenesis. Frontiers in cell and developmental biology 1 41445585
2024 The secreted protein FonCHRD is essential for vegetative growth, asexual reproduction, and pathogenicity in watermelon Fusarium wilt fungus. Crop health 1 41649655
2017 Isolation and characterization of a stress-responsive gene encoding a CHRD domain-containing protein from a halotolerant green alga. Gene 1 29017964
2026 ChRD-PET: A Method for Mapping RNA-DNA Interactions. Methods in molecular biology (Clifton, N.J.) 0 41174197
2025 Simultaneous Capture of Chromatin-Associated RNA and Global RNA-RNA Interactions With Reduced Input Requirements. Bio-protocol 0 40948898

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