Affinage

GDF6

Growth/differentiation factor 6 · UniProt Q6KF10

Length
455 aa
Mass
50.7 kDa
Annotated
2026-06-10
57 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF6 (BMP13) is a secreted BMP-family ligand that patterns skeletal joints, eye, cochlea, tendon, and renal structures, where it acts as a context-dependent brake on terminal differentiation and apoptosis (PMID:12606286, PMID:22693558, PMID:32369452). It binds the BMP antagonist noggin and forms heterodimers with BMP2, and engages canonical type I (BMPR1A/ALK6) and type II (BMPR2, ACVR2A) receptors to activate SMAD1/5/8, while in parallel signaling through ERK1/2 and p38 MAPK (PMID:10393114, PMID:23527555, PMID:32992671). The relative weight of these pathways is tissue-specific: GDF6 promotes neural/retinal differentiation and cell survival through SMAD1/5/8 (PMID:17010201, PMID:21070663), drives anabolic matrix synthesis in nucleus pulposus cells via combined SMAD1/5/8 and ERK1/2 (PMID:32992671), and induces tenogenic gene expression and tendon-like tissue in a manner dissociated from canonical SMAD1/5/8 despite normal receptor binding (PMID:21702718). Developmentally GDF6 suppresses osteogenic and chondrogenic differentiation to maintain joints and the coronal suture, inhibiting Runx2 and alkaline phosphatase activity in suture mesenchyme (PMID:19240811, PMID:22693558), and is positioned downstream of Wnt/PCP (Ror2) signaling to induce neural crest at the neural plate border (PMID:27578181). Distinct from its BMP-domain ligand activity, the GDF6 prodomain is a ligand for the transmembrane receptor CD99, recruiting CSK to inhibit Src kinase (PMID:33147457). Human and mouse genetics establish that GDF6 gain-of-function mutations reducing noggin antagonism cause multiple synostoses syndrome (SYNS4) through enhanced BMP signaling, while loss-of-function or regulatory disruption causes ocular coloboma/microphthalmia, Klippel-Feil vertebral fusions, and cochlear aplasia (PMID:18425797, PMID:26643732, PMID:32369452, PMID:36744814). GDF6 mRNA is post-transcriptionally regulated through m6A methylation, with METTL3 stabilizing and FTO destabilizing the transcript (PMID:37041485, PMID:39474078), and GDF6 additionally exerts cardioprotective anti-hypertrophic effects via cAMP/Epac1/AMPKα signaling (PMID:41462947).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established GDF6 as a bona fide BMP ligand whose activity is constrained by an extracellular antagonist, defining the ligand-antagonist axis central to its later disease mechanism.

    Evidence Direct binding assay (GDF6-noggin), dissociated cell fate assay, and heterodimer formation by cotranslation in Xenopus

    PMID:10393114

    Open questions at the time
    • Receptor identity and downstream signaling not addressed
    • In vivo developmental role not yet defined
  2. 2003 High

    Defined GDF6's in vivo developmental role and its non-redundancy with the paralog Gdf5 in skeletal joint patterning.

    Evidence Single and double Gdf5/Gdf6 knockout mice with skeletal phenotype analysis

    PMID:12606286

    Open questions at the time
    • Molecular signaling mechanism at affected joints not resolved
    • Cell-type origin of defects not pinpointed
  3. 2006 Medium

    Connected GDF6 to eye development and demonstrated it signals through the canonical SMAD1/5/8 pathway to promote retinal differentiation and survival.

    Evidence Morpholino knockdown in zebrafish and Xenopus; phospho-Smad1/5/8 staining; Pax6 expression; TUNEL apoptosis assays

    PMID:17010201 PMID:17236135

    Open questions at the time
    • Morpholino off-target effects not excluded
    • Receptor complex mediating retinal signaling not identified
  4. 2009 Medium

    Extended GDF6 function to tendon matrix and to in vitro lineage control, showing it suppresses osteogenic differentiation while promoting chondrogenic/proteoglycan programs.

    Evidence Gdf6 null mouse tendon biochemistry and mechanical testing; in vitro MSC and C3H10T1/2 differentiation assays; human/zebrafish ocular-vertebral genetics with SOX9 reporter

    PMID:14753743 PMID:19129173 PMID:19240811 PMID:19248159

    Open questions at the time
    • Signaling pathway underlying lineage outcomes not dissected in these studies
    • Variable penetrance mechanism in Gdf6+/- ocular phenotypes unexplained
  5. 2011 High

    Revealed that GDF6's tenogenic activity is dissociated from canonical SMAD1/5/8 signaling despite BMP2-comparable receptor binding, establishing pathway-selective, tissue-specific output.

    Evidence Receptor binding affinity assays, SMAD signaling assays, and in vivo ectopic expression with tendon-marker readouts in C3H10T1/2 cells

    PMID:21702718

    Open questions at the time
    • Identity of the non-SMAD effector driving tenogenesis not established
    • Mechanism selecting SMAD-independent output unknown
  6. 2012 High

    Defined a mechanistic basis for joint/suture maintenance: GDF6 inhibits premature osteogenic differentiation by restraining Runx2 and ALP in suture mesenchyme.

    Evidence Gdf6-/- mouse with ALP activity assay, Runx2 expression, and precise embryonic staging

    PMID:22693558

    Open questions at the time
    • Direct transcriptional targets of GDF6 in suture cells not mapped
    • Receptor mediating suppression not identified
  7. 2013 Medium

    Dissected the receptor and pathway requirements for a GDF6 lineage decision, implicating BMPR1A/BMPR2/ACVR2A and both SMAD and p38 MAPK with Runx1t1 as a downstream node.

    Evidence Overexpression and RNAi of receptor subunits, Smad4, p38, and Runx1t1 in C3H10T1/2 adipogenic commitment assays

    PMID:23527555

    Open questions at the time
    • Direct GDF6-receptor binding not biochemically confirmed in this system
    • Relevance of adipocytic commitment to in vivo phenotypes unclear
  8. 2015 High

    Established the molecular mechanism of SYNS4 gain-of-function: a missense variant makes GDF6 a more potent BMP agonist resistant to noggin antagonism.

    Evidence Patient genetics with BMP signaling and noggin antagonism assays comparing wild-type vs p.Y444N GDF6

    PMID:26643732

    Open questions at the time
    • Structural basis of noggin resistance not directly determined
    • In vivo confirmation pending at this stage
  9. 2016 Medium

    Placed GDF6 downstream of Wnt/PCP (Ror2) signaling for localized BMP activity required in neural crest induction.

    Evidence Ror2 morpholino knockdown and GDF6 rescue epistasis in Xenopus with phospho-Smad staining and neural plate border markers

    PMID:27578181

    Open questions at the time
    • Direct transcriptional link from Ror2/PCP to gdf6 not defined
    • Mammalian conservation of this circuit untested
  10. 2020 High

    Uncovered a non-BMP signaling modality: the GDF6 prodomain acts as a CD99 ligand recruiting CSK to inhibit Src, with KFS prodomain mutants being hyperactive.

    Evidence Co-IP, domain-specific constructs, CSK recruitment and Src activity assays, siRNA knockdown and p21 analysis in Ewing sarcoma

    PMID:33147457

    Open questions at the time
    • Physiological contexts where prodomain-CD99 signaling operates beyond Ewing sarcoma not mapped
    • Relationship between prodomain and BMP-domain activities of secreted GDF6 unresolved
  11. 2020 High

    Solidified GDF6's requirement in cochlear and renal development and added non-canonical VEGFR2-mediated angiogenic and ERK1/2-dependent anabolic functions.

    Evidence iPSC otic cells and Gdf6 KO mice (cochlear aplasia); CRISPR KO migration assay with rescue (renal); lncRNA SCDAL/SNF5 promoter regulation and VEGFR2 angiogenesis assays; recombinant GDF6 on nucleus pulposus cells

    PMID:32369452 PMID:32737436 PMID:32992671 PMID:34319658

    Open questions at the time
    • Receptor mediating VEGFR2 transactivation not defined
    • How a single ligand selects among SMAD, ERK, and VEGFR2 outputs unresolved
  12. 2023 Medium

    Identified post-transcriptional control of GDF6 by m6A methylation, with METTL3 stabilizing and FTO destabilizing the transcript across distinct biological settings.

    Evidence MeRIP-seq, RNA stability assays, METTL3 and FTO manipulation in dental pulp stem cells and antiviral models

    PMID:37041485 PMID:39474078

    Open questions at the time
    • Stimuli that toggle m6A writers/erasers on GDF6 not defined
    • Whether m6A regulation affects developmental GDF6 levels untested
  13. 2024 Medium

    Embedded GDF6 in mechanotransduction and disease signaling circuits: a PIEZO1/miR-155-5p/GDF6/SMAD2/3 axis in chondrocyte senescence and TGF-β/SMAD3-driven EMT in gastric cancer.

    Evidence Mouse OA models with miR-155-5p mimics/inhibitors and recombinant GDF6 rescue; bidirectional overexpression/knockdown EMT assays in gastric cancer cells

    PMID:38508350 PMID:38850874

    Open questions at the time
    • Direct receptor engagement in SMAD2/3 versus SMAD1/5/8 contexts not clarified
    • Causality versus correlation in cancer EMT not fully established
  14. 2025 Medium

    Demonstrated a cardioprotective role wherein GDF6 suppresses cardiac hypertrophy through cAMP/Epac1/AMPKα signaling.

    Evidence AAV9 cardiac GDF6 overexpression and knockdown in TAC mice with Epac1 knockdown and AMPKα inhibition

    PMID:41462947

    Open questions at the time
    • Receptor linking secreted GDF6 to cAMP/Epac1 not identified
    • Single-lab finding awaiting independent replication
  15. 2023 High

    Confirmed in vivo that enhanced GDF6/BMP signaling causes SYNS4 joint fusions via interzone defects and excess chondrogenesis.

    Evidence SYNS4-orthologous p.Tyr443Asn knock-in mouse with skeletal phenotyping, joint interzone analysis, and forelimb bud RNA-seq

    PMID:36744814

    Open questions at the time
    • Direct BMP target genes mediating interzone loss not pinpointed
    • Therapeutic reversibility not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GDF6 selects among its multiple, sometimes opposing, downstream outputs (SMAD1/5/8, ERK1/2, p38, SMAD2/3, VEGFR2, prodomain-CD99-Src, cAMP/Epac1) in a tissue-specific manner remains unresolved.
  • No unified model linking receptor context to pathway choice
  • Whether prodomain and BMP-domain activities are coordinately deployed in the same cell is unknown
  • Structural determinants of noggin resistance not directly resolved by experiment

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4
Partners
ACVR2ABMP2BMPR1ABMPR2CD99CSKNOG

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Gdf6 null mutation in mice causes defects in joint, ligament, and cartilage formation at specific skeletal sites (wrist, ankle, middle ear, coronal suture), distinct from Gdf5 mutant sites; double Gdf5/Gdf6 mutants show additive/synergistic skeletal defects including severe limb element reduction, scoliosis, and intervertebral cartilage alterations, establishing non-redundant and partially overlapping roles of Gdf6 and Gdf5 in joint patterning. Single and double knockout mice; skeletal phenotype analysis Developmental biology High 12606286
1999 Xenopus GDF6 directly binds the BMP antagonist noggin, as demonstrated by direct binding assay; GDF6 induces epidermis and inhibits neural tissue in dissociated cells, and this activity is blocked by noggin. GDF6 and BMP2 form heterodimers requiring cotranslation in the same cells. Direct binding assay (GDF6-noggin), dissociated cell fate assay, heterodimer formation by cotranslation Development (Cambridge, England) High 10393114
2006 Morpholino knockdown of gdf6a in zebrafish recapitulates chorioretinal coloboma, microphthalmia, and anophthalmia in a dose-dependent manner, establishing GDF6 as required for ocular closure and size during eye development. Morpholino knockdown in zebrafish; phenotypic analysis American journal of human genetics Medium 17236135
2006 GDF6 morpholino knockdown in Xenopus reduces eye size, disrupts retinal laminar structure and differentiated neural cell types, reduces Smad1/5/8 phosphorylation (indicating reduced BMP signaling), shrinks the Pax6 expression domain, reduces NCAM expression, and increases apoptosis along the neural tube and retina, demonstrating that GDF6 signals through the canonical BMP/Smad1/5/8 pathway to promote neural and retinal differentiation and cell survival. Morpholino knockdown in Xenopus; phospho-Smad1/5/8 staining; Pax6 expression analysis; TUNEL assay BMC developmental biology Medium 17010201
2008 GDF6 knockdown in Xenopus causes anterior axial defects consistent with Klippel-Feil syndrome; a missense mutation (p.Leu289Pro) at a conserved residue and an inversion disrupting GDF6 expression are associated with familial/sporadic KFS including vertebral, carpal, and tarsal fusions. GDF6 is expressed at boundaries of developing carpals, tarsals, and vertebrae and within the adult vertebral disc. Xenopus morpholino knockdown; mutation identification in KFS patients; expression analysis Human mutation Medium 18425797
2009 Seven heterozygous GDF6 mutations identified in patients with ocular and vertebral anomalies were characterized using a SOX9-reporter assay and western analysis, demonstrating altered GDF6 signaling activity. Morphant zebrafish (reduced Gdf6) display ocular and skeletal anomalies including altered expression of somite markers noggin1 and noggin2. Gdf6+/- mice exhibit variable ocular phenotypes, establishing incomplete penetrance and variable expressivity. SOX9-reporter assay; western blot; zebrafish morpholino knockdown; Gdf6+/- mice phenotyping Human molecular genetics Medium 19129173
2009 Null mutation in Gdf6 causes substantially lower tail tendon collagen content (−33%) in 4-week-old male mice, with direct functional consequences: 45–50% reduction in mechanical properties, demonstrating a role for GDF6 in tendon matrix modeling. Gdf6 null mouse; collagen quantification; mechanical testing Anatomical record (Hoboken, N.J. : 2007) Medium 19248159
2009 BMP-13 (GDF6) inhibits osteogenic differentiation of human bone marrow MSCs in vitro, suppressing alkaline phosphatase activity and matrix mineralization while increasing proteoglycan synthesis, suggesting GDF6 opposes terminal osteogenic differentiation. In vitro osteogenic differentiation assay with exogenous BMP-13; ALP assay; calcium staining; proteoglycan staining; real-time PCR International journal of biological sciences Medium 19240811
2004 Adenoviral expression of BMP-13 (GDF6) in C3H10T1/2 mesenchymal progenitor cells induces chondrogenic differentiation (Alcian blue staining, cartilage-specific gene markers, proteoglycan upregulation) but fails to support hypertrophic chondrocyte differentiation or endochondral ossification, unlike BMP-2. BMP receptor BMPR-IB/ALK-6 expression is not constitutive but all other tested BMP receptors are constitutively expressed and unaffected by BMP-13. Adenoviral gene transfer; RT-PCR; histological and biochemical analyses; ALP activity assay Journal of bone and mineral research Medium 14753743
2011 Ectopic expression of rhBMP12 and rhBMP13 (GDF6) induces tendon-like tissue formation in vivo and tendon-specific gene (Thbs4) expression in C3H10T1/2 cells, but does not activate SMAD 1/5/8 signaling in these cells, despite binding type I (ALK-3, ALK6) and type II (ACVR2A, ACVR2B, BMPR2) BMP receptors with affinities similar to BMP2. This demonstrates that GDF6's tenogenic activity is dissociated from canonical SMAD1/5/8 signaling even with comparable receptor binding. Receptor binding affinity assays; SMAD signaling assays; gene expression (Thbs4, osteocalcin) in C3H10T1/2 cells; in vivo ectopic expression Growth factors (Chur, Switzerland) High 21702718
2012 Coronal suture fusion in Gdf6-/- mice results from accelerated differentiation of suture mesenchyme prior to calvarial ossification onset. Gdf6 is expressed in frontal bone primordia from E10.5–12.5. In Gdf6-/- embryos, increased alkaline phosphatase activity and Runx2 expression in the suture mesenchyme demonstrate that Gdf6 normally inhibits osteogenic differentiation to maintain the suture, revealing an inhibitory role for a BMP family member in preventing premature ossification. Gdf6-/- mouse; ALP activity assay; Runx2 expression analysis; embryonic staging PloS one High 22693558
2013 Overexpression of Gdf6 induces commitment of pluripotent mesenchymal C3H10T1/2 cells to the adipocyte lineage. This is mediated by type I receptor Bmpr1a and type II receptors Bmpr2 and Acvr2a. Both Smad and p38 MAPK pathways are required. Runx1t1 is downregulated in committed pre-adipocytes, and forced Runx1t1 expression blocks adipocytic commitment. Overexpression in C3H10T1/2 cells; RNAi knockdown of Smad4, p38 MAPK, receptor subunits, Runx1t1; differentiation assays The FEBS journal Medium 23527555
2015 A GDF6 missense variant (p.Y444N) in a conserved residue at the receptor/antagonist binding interface causes gain-of-function: mutant GDF6 is a more potent stimulator of canonical BMP signaling and is resistant to NOG-mediated antagonism compared to wild-type GDF6, resulting in synostoses (SYNS4) due to enhanced BMP signaling and loss of joint formation. Patient genetics; BMP signaling assays; NOG antagonism assays comparing wild-type and mutant GDF6 Journal of bone and mineral research High 26643732
2016 In Xenopus, Ror2-dependent planar cell polarity signaling is required during gastrulation to upregulate gdf6 at the neural plate border. Local GDF6-mediated BMP signaling (Smad1/5/8 phosphorylation) at the neural plate border is necessary for neural crest induction, and GDF6 overexpression rescues neural plate border specification in Ror2 morphant embryos, placing GDF6 downstream of Wnt/PCP signaling in neural crest specification. Ror2 morpholino knockdown in Xenopus; epistasis (GDF6 rescue of Ror2 morphants); phospho-Smad staining; neural plate border gene expression Development (Cambridge, England) Medium 27578181
2020 GDF6 prodomain (not the BMP domain) is a ligand for CD99 transmembrane protein. The GDF6 prodomain binds the CD99 extracellular domain, recruiting CSK (C-terminal Src kinase) to the YQKKK motif in the CD99 intracellular domain, thereby inhibiting Src activity. GDF6 silencing causes Src hyperactivation and p21-dependent growth arrest in Ewing sarcoma. Two KFS-associated GDF6 prodomain mutants are hyperactive in CD99-Src signaling. Co-IP; domain-specific constructs; CSK recruitment assay; Src activity assay; siRNA knockdown; p21 analysis Cell reports High 33147457
2020 GDF6 promotes angiogenesis via non-canonical VEGFR2 activation. The lncRNA SCDAL induces GDF6 expression through direct interaction with SNF5 at the GDF6 promoter, and secreted GDF6 promotes endothelial angiogenesis via non-canonical VEGFR2 activation in vitro and in vivo. lncRNA-chromatin interaction assay (SNF5/GDF6 promoter); GDF6 knockdown/overexpression in endothelial cells; VEGFR2 signaling assay; in vivo cardiac ischemia model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34319658
2020 Recombinant GDF6 stimulates an anabolic response in degenerate human nucleus pulposus cells (increased matrix and NP-phenotypic marker expression, increased glycosaminoglycan production, no change in catabolic enzyme expression) via SMAD1/5/8 and ERK1/2 phosphorylation, both validated by blocking studies, identifying SMAD-dependent and SMAD-independent (ERK1/2) signaling mechanisms. Recombinant GDF6 treatment of human NP cells; phospho-SMAD1/5/8 and phospho-ERK1/2 western blot; signaling inhibitor blocking studies; GAG quantification; gene expression International journal of molecular sciences Medium 32992671
2020 Long-range cis-regulatory elements located approximately 350 kb downstream of GDF6 are required for GDF6 expression in otic lineage cells; deletion of these elements in humans causes cochlear aplasia, and Gdf6 knockout mice recapitulate cochlear aplasia, establishing GDF6 as necessary for early cochlear development. Genome sequencing; iPSC-derived otic lineage cells from affected individual (GDF6 expression reduced); Gdf6 knockout mouse (cochlear aplasia phenotype) The Journal of clinical investigation High 32369452
2020 GDF6 CRISPR/Cas9 knockout attenuates migration of murine IMCD3 cells, an effect rescued by wild-type but not mutant GDF6, indicating that GDF6 function is required for a fundamental developmental cell migration process relevant to renal development. Xenopus gdf6 knockdown impairs pronephros development. CRISPR/Cas9 knockout in IMCD3 cells; wild-type vs. mutant GDF6 rescue; Xenopus morpholino knockdown European journal of human genetics : EJHG Medium 32737436
2023 METTL3-mediated m6A methylation increases GDF6 mRNA stability in dental pulp stem cells, promoting dentinogenesis differentiation. METTL3 knockdown impairs, and overexpression promotes, DPSC dentinogenesis; METTL3-mediated m6A directly regulates GDF6 (and STC1) mRNA stability as shown by RNA stability assay. MeRIP-seq; RNA stability assay (actinomycin D); lentiviral METTL3 knockdown/overexpression; ALP and alizarin red staining; direct pulp capping model in rats BMC oral health Medium 37041485
2023 A GDF6 gain-of-function knock-in mouse (p.Tyr443Asn, orthologous to human SYNS4 p.Tyr444Asn) recapitulates human SYNS4 joint fusions; analysis reveals joint interzone formation defects, excess chondrogenesis, and transcriptome profiling shows enhanced BMP signaling and upregulated bone formation pathways, confirming that enhanced GDF6/BMP signaling disrupts joint morphogenesis both prenatally and postnatally. Knock-in mouse model; skeletal phenotyping; RNA sequencing of forelimb buds; joint interzone analysis Journal of bone and mineral research High 36744814
2024 GDF6 promotes EMT in gastric cancer cells via the TGF-β/SMAD3 signaling pathway: GDF6 overexpression upregulates TGF-β and phospho-SMAD3, elevates mesenchymal markers (N-cadherin, vimentin) and reduces epithelial markers (E-cadherin, cytokeratins), while GDF6 silencing reverses these effects. GDF6 overexpression and siRNA knockdown in gastric cancer cell lines; western blot for SMAD3 phosphorylation, EMT markers; CCK-8, scratch, Transwell, colony assays Pathology, research and practice Medium 38850874
2024 The PIEZO1/miR-155-5p/GDF6/SMAD2/3 axis regulates chondrocyte senescence under mechanical overloading: mechanical stress activates PIEZO1 to upregulate miR-155-5p, which suppresses GDF6-SMAD2/3 signaling, disrupting joint metabolic homeostasis. Intra-articular injection of miR-155-5p inhibitor or recombinant GDF6 mitigates overloading-induced OA in vivo. Mouse DMM model, hindlimb weight-bearing model; miR-155-5p mimics/inhibitors; recombinant GDF6 injection; SMAD2/3 western blot; qPCR; SA-β-gal staining; in vivo intra-articular injection Cellular signalling Medium 38508350
2024 FTO-mediated m6A demethylation destabilizes GDF6 mRNA; FTO depletion stabilizes GDF6 mRNA, increasing GDF6 protein and type I interferon production while reducing pro-inflammatory factors, thereby exerting antiviral effects against RSV. IGF2BP1 binding protein loss decreases GDF6 expression and reduces interferon production, placing GDF6 in an m6A-regulated antiviral signaling axis. FTO depletion; m6A profiling; GDF6 mRNA stability assay; type I interferon measurement; IGF2BP1 binding assay iScience Medium 39474078
2025 GDF6 overexpression attenuates, and GDF6 knockdown aggravates, pressure overload-induced cardiac hypertrophy in mice. Mechanistically, GDF6 activates AMPKα through the cAMP/Epac1 pathway; Epac1 knockdown abolishes the cardioprotective effects of GDF6, and AMPKα inhibition blocks GDF6's anti-hypertrophic effects. AAV9-mediated cardiac GDF6 overexpression and knockdown in TAC mice; phenylephrine-induced NRVM hypertrophy; AMPKα inhibition; Epac1 knockdown; echocardiography; histology; molecular analysis Biomedicines Medium 41462947
2010 Severe reduction of eye size in the zebrafish out of sight (outm233) mutant is caused by a mutation in the zebrafish gdf6a gene. Despite small eye size, overall retinal architecture is largely intact but apoptosis is abnormally high in mutant eyes during early neurogenesis, suggesting GDF6 regulates eye size by controlling apoptosis at the onset of neurogenesis rather than gross retinal patterning. Positional cloning; acridine orange and TUNEL staining; immunohistochemistry of retinal cell types BMC genetics Medium 21070663
2018 A GDF6 N399K mutation (SYNS4) is located in a hydrophobic pocket critical for noggin binding; structural modeling indicates N399K renders GDF6 more similar to noggin-resistant BMP family members (GDF2, BMP10, which have lysine at the equivalent position), suggesting noggin resistance as the mechanism of gain-of-function for this SYNS4 variant, while BMPR2 binding is predicted unaffected. Structural modelling; patient genetics; sequence/family comparison Molecular syndromology Low 30733656

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Developmental biology 272 12606286
2008 Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Human mutation 149 18425797
2006 GDF6, a novel locus for a spectrum of ocular developmental anomalies. American journal of human genetics 91 17236135
2009 Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Human molecular genetics 84 19129173
1999 Xenopus GDF6, a new antagonist of noggin and a partner of BMPs. Development (Cambridge, England) 80 10393114
2003 A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome research 77 12915490
2010 BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anterior cruciate ligament cells. Cytotherapy 64 20334610
2010 Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases. The British journal of ophthalmology 64 20494911
2009 BMP-13 emerges as a potential inhibitor of bone formation. International journal of biological sciences 57 19240811
2009 BMP13 prevents the effects of annular injury in an ovine model. International journal of biological sciences 55 19521550
2011 Bone morphogenetic protein (BMP)1-3 enhances bone repair. Biochemical and biophysical research communications 52 21453682
2004 Adenovirus mediated BMP-13 gene transfer induces chondrogenic differentiation of murine mesenchymal progenitor cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 51 14753743
2006 Eye and neural defects associated with loss of GDF6. BMC developmental biology 46 17010201
2006 Structure and protective effect of exopolysaccharide from P. Agglomerans strain KFS-9 against UV radiation. Microbiological research 43 16580187
2010 Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies. BMC genetics 40 21070663
2011 Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities. Growth factors (Chur, Switzerland) 39 21702718
2023 Exosomal miRNA-155-5p from M1-polarized macrophages suppresses angiogenesis by targeting GDF6 to interrupt diabetic wound healing. Molecular therapy. Nucleic acids 35 38074896
2009 Identification of a tendon phenotype in GDF6 deficient mice. Anatomical record (Hoboken, N.J. : 2007) 33 19248159
2014 Distinct effects of platelet-rich plasma and BMP13 on rotator cuff tendon injury healing in a rat model. The American journal of sports medicine 32 25193888
2012 In vitro effects of bmp-2, bmp-7, and bmp-13 on proliferation and differentation of mouse mesenchymal stem cells. Biomedical sciences instrumentation 31 22846268
2015 A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29 26643732
2012 The BMP ligand Gdf6 prevents differentiation of coronal suture mesenchyme in early cranial development. PloS one 28 22693558
2008 Unveiling the bmp13 enigma: redundant morphogen or crucial regulator? International journal of biological sciences 28 18797508
2021 A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 34319658
2020 GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth. Cell reports 23 33147457
2017 Differentiation of MSC and annulus fibrosus cells on genetically engineered silk fleece-membrane-composites enriched for GDF-6 or TGF-β3. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20 29058815
2014 Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis. Annals of the rheumatic diseases 19 24442880
2013 Gdf6 induces commitment of pluripotent mesenchymal C3H10T1/2 cells to the adipocyte lineage. The FEBS journal 19 23527555
2018 Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats. Growth factors (Chur, Switzerland) 17 29482391
2020 miR-98 is involved in missed abortion by targeting GDF6 and FAPP2. Reproduction (Cambridge, England) 16 32045359
2024 The PIEZO1/miR-155-5p/GDF6/SMAD2/3 signaling axis is involved in inducing the occurrence and progression of osteoarthritis under excessive mechanical stress. Cellular signalling 15 38508350
2020 Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation. International journal of molecular sciences 15 32992671
2005 Detection of potential GDF6 regulatory elements by multispecies sequence comparisons and identification of a skeletal joint enhancer. Genomics 15 15979840
2020 Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development. The Journal of clinical investigation 14 32369452
2016 Combined effects of engineered tendon matrix and GDF-6 on bone marrow mesenchymal stem cell-based tendon regeneration. Biotechnology letters 14 26956234
2016 Ror2 signaling is required for local upregulation of GDF6 and activation of BMP signaling at the neural plate border. Development (Cambridge, England) 14 27578181
2020 High BMPR2 expression leads to enhanced SMAD1/5/8 signalling and GDF6 responsiveness in human adipose-derived stem cells: implications for stem cell therapies for intervertebral disc degeneration. Journal of tissue engineering 12 32489577
2020 Exoproduction and characterization of a detergent-stable alkaline keratinase from Arthrobacter sp. KFS-1. Biochimie 12 32835736
2019 Lytic KFS-SE2 phage as a novel bio-receptor for Salmonella Enteritidis detection. Journal of microbiology (Seoul, Korea) 12 30706346
2017 Further delineation of the GDF6 related multiple synostoses syndrome. American journal of medical genetics. Part A 12 29130651
2013 A novel extended-spectrum β-lactamase, SGM-1, from an environmental isolate of Sphingobium sp. Antimicrobial agents and chemotherapy 11 23716045
2012 Klippel-Feil syndrome associated with situs inversus: description of a new case and exclusion of GDF1, GDF3 and GDF6 as causal genes. European journal of medical genetics 11 22522086
2023 METTL3 enhances dentinogenesis differentiation of dental pulp stem cells via increasing GDF6 and STC1 mRNA stability. BMC oral health 10 37041485
2021 GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment. Genes 10 34573339
2004 Comparative sequence analysis of the Gdf6 locus reveals a duplicon-mediated chromosomal rearrangement in rodents and rapidly diverging coding and regulatory sequences. Genomics 8 15475260
2025 Effects of GDF6 on active protein synthesis by cells of degenerated intervertebral disc. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 7 39920317
2020 Rare heterozygous GDF6 variants in patients with renal anomalies. European journal of human genetics : EJHG 7 32737436
2018 A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss. Molecular syndromology 6 30733656
2025 IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A. Cell death discovery 4 39820341
2024 GDF6 in gastric cancer upregulated by helicobacter pylori induces epithelial-mesenchymal translation via the TGF-β/SMAD3 signaling pathway. Pathology, research and practice 4 38850874
2024 The GDF6-FTO axis modulates the innate immune and inflammatory response to human respiratory syncytial virus. iScience 4 39474078
2023 Defective Joint Development and Maintenance in GDF6-Related Multiple Synostoses Syndrome. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 4 36744814
2025 Therapeutic Effects of GDF6-Overexpressing Mesenchymal Stem Cells through Upregulation of the GDF15/SIRT1 Axis in Age-Related Hearing Loss. Frontiers in bioscience (Landmark edition) 3 39862101
2024 Transcriptomic profiling reveals key early response genes during GDF6-mediated differentiation of human adipose-derived stem cells to nucleus pulposus cells. JOR spine 3 38249721
2014 Association of rs6982567 near GDF6 with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Han Chinese cohort. BMC ophthalmology 3 25416513
2025 Dual-Faced Role of GDF6 in Cancer: Mechanistic Insights into Its Context-Dependent Regulation of Metastasis and Immune Evasion Across Human Malignancies. Current issues in molecular biology 1 40699648
2025 GDF6 Alleviates Pathological Cardiac Hypertrophy via AMPKα Signaling Pathway. Biomedicines 0 41462947

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