Affinage

GDF9

Growth/differentiation factor 9 · UniProt O60383

Length
454 aa
Mass
51.4 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 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

GDF9 is an oocyte-secreted TGF-β superfamily ligand that drives follicular somatic cell proliferation and differentiation through type I receptor ALK5 (TGFBR1) and SMAD2/3 signaling (PMID:17959852). Its transcription is directly controlled at the oocyte promoter by opposing factors: NOBOX activates GDF9 by binding defined NOBOX-binding elements, while germ cell nuclear factor (GCNF) represses it through DR0 elements (PMID:16997917, PMID:12912906). Acting cooperatively with the related oocyte ligand BMP15, GDF9 synergistically stimulates granulosa cell DNA synthesis and SMAD3 signaling in a manner dependent on SMAD2/3, ERK1/2 (MAPK), and SRC kinase pathways, with non-SMAD pathway requirements differing between species (PMID:21911477, PMID:21474603). This GDF9/BMP15 paracrine axis programs cumulus cell metabolism — inducing cholesterol biosynthetic enzymes that supply the cholesterol-deficient oocyte — and orchestrates antrum formation and somatic gene expression including AMH, which it induces by recruiting p300 to the AMH promoter to deposit H3K27 acetylation (PMID:18045843, PMID:30033985, PMID:30060157). GDF9 also shapes the follicular signaling environment by inducing the BMP antagonist NBL1/DAN and follistatin transcription, and promotes follicle survival through PI3K/Akt/FOXO3a signaling (PMID:22357543, PMID:23567549, PMID:33409876). Human GDF9 is secreted as a latent promature protein whose activity is gated by the proregion's affinity for the mature domain; a single mature-domain residue (Gly391) confers latency, and substitution to Arg activates it (PMID:22234469, PMID:28733348). The interaction between the prodomain and mature domain is central to human ovarian physiology: prodomain mutations that reduce this affinity activate GDF9, expression-abrogating variants associate with dizygotic twinning, and loss-of-function variants (e.g. p.R146C) cause premature ovarian failure and diminished ovarian reserve (PMID:24438375, PMID:23851219).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2003 High

    Established how GDF9 transcription is restrained in oocytes, identifying GCNF as a direct repressor acting through promoter DR0 elements.

    Evidence Chromatin binding and reporter assays with an oocyte-specific GCNF conditional knockout mouse

    PMID:12912906

    Open questions at the time
    • Does not establish the activating side of the promoter switch
    • Repression dynamics across follicle stages not resolved
  2. 2006 High

    Identified NOBOX as the direct transcriptional activator of Gdf9, defining the positive arm of oocyte-specific GDF9 promoter control during early folliculogenesis.

    Evidence SELEX, mutation analysis, luciferase reporter assays, and ChIP for NOBOX binding elements in the Gdf9 promoter

    PMID:16997917

    Open questions at the time
    • Combinatorial logic with GCNF repression not directly tested
    • In vivo contribution of each NBE not dissected
  3. 2007 High

    Defined the GDF9 receptor/SMAD pathway and a cell-context-dependent response, showing GDF9 signals via ALK5/SMAD2/3 to drive theca cell proliferation while inhibiting steroidogenesis.

    Evidence Primary bovine theca cell proliferation and steroid assays, SMAD CAGA reporter, ALK5 mRNA correlation

    PMID:17959852

    Open questions at the time
    • Mechanism linking ALK5 abundance to follicle-size-dependent responsiveness not resolved
    • Type II receptor identity not addressed here
  4. 2007 High

    Revealed a metabolic function for the oocyte ligands, showing GDF9 and BMP15 together program cumulus cells to synthesize cholesterol that the oocyte cannot make itself.

    Evidence Bmp15/Gdf9 mutant mouse models with oocytectomy rescue and de novo cholesterol synthesis assays

    PMID:18045843

    Open questions at the time
    • Direct transcriptional mechanism on cholesterol enzyme genes not defined
    • Relative contribution of GDF9 vs BMP15 not separated
  5. 2008 High

    Characterized the molecular basis of GDF9/BMP15 cooperativity, showing heteromeric interactions involving the BMP15 proregion that are species-specific and signal through defined type II/type I receptors.

    Evidence Co-IP, non-reducing Western blot, granulosa cell bioassay, and immunoneutralization

    PMID:18633140

    Open questions at the time
    • Stoichiometry of the active complex unresolved
    • Whether the complex is obligate for signaling not settled
  6. 2011 High

    Reconstituted the synergy with purified proteins and mapped its signaling requirements, establishing dependence on SMAD2/3, ERK1/2, and SRC but not NF-κB.

    Evidence Purified mature GDF9/BMP15 on murine granulosa cells with pathway-specific inhibitors and SMAD3 reporter

    PMID:21911477

    Open questions at the time
    • How SRC and ERK integrate with SMAD output not mechanistically linked
    • Receptor complex composition driving non-SMAD arms not defined
  7. 2011 Medium

    Showed species-specific non-SMAD signaling requirements, with ovine GDF9+BMP15 requiring NF-κB/p38 and murine requiring ERK, correlating with distinct molecular complex forms.

    Evidence Rat granulosa cell bioassay with pathway inhibitors and Western blot of molecular forms

    PMID:21474603

    Open questions at the time
    • Structural basis of species-specific complexes not resolved
    • Single lab, single readout
  8. 2011 High

    Connected GDF9/BMP15 signaling to chromatin regulation of AMH, showing induction via SMAD2/3 and PI3K/Akt with p300 recruitment and H3K27ac, antagonized by FSH.

    Evidence ChIP for p300 and H3K27ac, siRNA, and Fshβ-null mouse with transgenic rescue

    PMID:30060157

    Open questions at the time
    • Direct SMAD binding to the AMH promoter not delineated here
    • GDF9-only versus synergistic contribution not separated
  9. 2011 Medium

    Demonstrated an in vivo regulatory role for the secreted GDF9 proregion in setting ovulation rate and litter size.

    Evidence Active immunization of mice against GDF9 proregion with corpora lutea and litter size counts

    PMID:22106408

    Open questions at the time
    • Molecular mechanism by which proregion antibody alters signaling unclear
    • Single lab in vivo endpoint
  10. 2011 Medium

    Showed GDF9 induces antrum-like structures and suppresses fibroblast-like dedifferentiation of granulosa cells, most potently with BMP15.

    Evidence Bovine oocyte-granulosa complex culture with oocytectomy and recombinant ligands, morphological readout

    PMID:30033985

    Open questions at the time
    • Molecular drivers of antrum formation not defined
    • Morphological readout only
  11. 2012 High

    Identified the molecular cause of human GDF9 latency, pinpointing Gly391 in the mature domain as the residue gating receptor affinity and activity.

    Evidence Site-directed mutagenesis with adrenocortical luciferase and granulosa proliferation assays, EC50 analysis

    PMID:22234469

    Open questions at the time
    • Structural detail of the receptor binding interface not solved
    • Physiological mechanism that overcomes latency in vivo unknown
  12. 2012 Medium

    Placed GDF9 upstream of a BMP antagonist gradient, showing it upregulates NBL1/DAN which selectively antagonizes BMP2/BMP4 in granulosa cells.

    Evidence Granulosa cell culture with recombinant GDF9, RT-PCR, and DAN bioassays with steroidogenesis readout

    PMID:22357543

    Open questions at the time
    • Direct transcriptional control of NBL1 by GDF9 not shown
    • In vivo relevance of the gradient untested
  13. 2013 Medium

    Defined GDF9/SMAD3 regulation of follistatin and its modulation by FOXL2, including ablation by the tumor-associated FOXL2C134W mutant.

    Evidence Primary granulosa reporter assays with promoter mutations and FOXL2 siRNA

    PMID:23567549

    Open questions at the time
    • Mechanism of FOXL2-SMAD3 antagonism on the promoter not fully resolved
    • Single lab reporter-based
  14. 2013 High

    Genetic epistasis revealed a stage-dependent dual role for GDF9, promoting defective folliculogenesis early but suppressing granulosa tumor initiation in the inhibin-null background.

    Evidence Inha−/−Gdf9−/− double knockout mice with follicular histology, tumor assessment, and Inhbb expression analysis

    PMID:23446452

    Open questions at the time
    • Mechanism of tumor suppression by GDF9 undefined
    • Relationship to activin βB signaling not mechanistically dissected
  15. 2013 Medium

    Provided functional evidence that a human loss-of-function variant (p.R146C) impairs GDF9 secretion and SMAD2 signaling, linking GDF9 to diminished ovarian reserve.

    Evidence Mutagenesis with secretion Western blot, human granulosa proliferation, Smad2 phosphorylation, and structural modeling

    PMID:23851219

    Open questions at the time
    • Patient genotype-phenotype causality from a single variant
    • Structural prediction not experimentally validated
  16. 2014 Medium

    Distinguished GDF9 from BMP15 functionally, showing only BMP15 downregulates connexin43 and gap junction communication via SMAD1/5/8, whereas GDF9 does not.

    Evidence Human granulosa cell GJIC assays with Smad4 siRNA and BMP type I receptor inhibitor

    PMID:24413384

    Open questions at the time
    • Does not address GDF9-specific roles in gap junctions
    • Single lab
  17. 2014 High

    Systematically established the proregion–mature domain affinity as the human disease-relevant switch, with POF-associated prodomain mutations activating GDF9 and other variants abrogating expression.

    Evidence Mutagenesis of multiple variants in HEK293T with granulosa bioassay and structural modeling

    PMID:24438375

    Open questions at the time
    • In vivo consequence of constitutive activation not modeled
    • Structural models not experimentally confirmed
  18. 2014 Low

    Linked a GDF9 promoter tandem duplication disrupting NOBOX-binding and E-box elements to primary ovarian insufficiency.

    Evidence Array CGH, PCR breakpoint mapping, and MLPA in a POI patient

    PMID:24939957

    Open questions at the time
    • No functional experiments confirming altered promoter activity were performed
    • Single patient observation
  19. 2015 Medium

    Connected GDF9 promoter activation to human fetal ovarian development, identifying a fetal NOBOX isoform that upregulates GDF9 and transient pre-follicular GDF9 expression.

    Evidence Human fetal ovary immunohistochemistry, qRT-PCR, and reporter assay with a novel NOBOX isoform

    PMID:25790371

    Open questions at the time
    • In vivo requirement of the fetal isoform untested
    • Functional consequence of pre-follicular GDF9 unclear
  20. 2017 Medium

    Showed human BMP15 disease variants reduce BMP15/GDF9 synergy, reinforcing the GDF9-BMP15 interaction as central to human ovarian physiology.

    Evidence Mutagenesis of multiple BMP15 variants with granulosa bioassays and synergy assays

    PMID:28359091

    Open questions at the time
    • Direct interaction interface of synergy-disrupting variants not mapped
    • Single lab
  21. 2017 Medium

    Revised the model of the secreted ligand, demonstrating native ovine/bovine GDF9 and BMP15 are predominantly monomeric promature proteins rather than dimers or heterodimers.

    Evidence Western blot with monoclonal antibodies under non-reducing/reducing/cross-linking conditions on native oocyte secretions plus in silico modeling

    PMID:28733348

    Open questions at the time
    • How monomeric forms assemble at receptors not experimentally resolved
    • Species generalization to human not directly tested
  22. 2010 Medium

    Extended GDF9 signaling beyond the ovary, showing it promotes prostate cancer invasion and EMT through ALK5.

    Evidence GDF9 overexpression, knockdown, and recombinant protein in PC-3 cells with invasion assays and ALK5 inhibitor

    PMID:21116689

    Open questions at the time
    • Source of GDF9 in prostate tumors not defined
    • Single cell line, single lab
  23. 2010 Medium

    Demonstrated a conserved role in gonadal sex differentiation, with zebrafish Gdf9 suppressing amh and promoting ovarian fate.

    Evidence Recombinant Gdf9 on gonadal cells with RT-qPCR and vivo-morpholino knockdown sex ratio phenotype

    PMID:28203731

    Open questions at the time
    • Receptor pathway in zebrafish not mapped
    • Relevance to mammalian sex determination unclear
  24. 2021 Medium

    Identified a pro-survival mechanism, showing GDF9 reduces follicular apoptosis and activates primordial follicles via PI3K/Akt/FOXO3a.

    Evidence Ovine cortical slice culture with recombinant GDF9, PI3K inhibitor, and p-Akt/p-FOXO3a immunohistochemistry

    PMID:33409876

    Open questions at the time
    • Direct receptor coupling to PI3K not shown
    • Single lab, ex vivo model
  25. 2022 Medium

    Characterized native human GDF9/BMP15 secretion dynamics during oocyte maturation, showing GDF9 dominates over BMP15 and signaling components are upregulated at MII.

    Evidence Western blot, ELISA of spent IVM media, and RT-qPCR of cumulus cell signaling genes from human oocytes

    PMID:35986324

    Open questions at the time
    • Causal role of declining homodimer levels in maturation not tested
    • Correlative signaling-gene readout

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the active GDF9/BMP15 receptor-engaging complex and how proregion-gated latency is physiologically relieved in vivo remain unresolved.
  • No experimental structure of the GDF9-BMP15-receptor assembly
  • Mechanism that activates latent human GDF9 in the follicle unknown
  • Whether monomeric promature forms are the obligate signaling species not settled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
ACVR1BACVR1CBMP15BMPR2TGFBR1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 GCNF (germ cell nuclear factor) directly represses GDF9 transcription by binding to DR0 elements within the GDF9 gene promoter, as shown by molecular binding studies and reporter assays in an oocyte-specific GCNF knockout mouse model. Chromatin binding assays, reporter gene assays, oocyte-specific conditional knockout mouse model The EMBO journal High 12912906
2006 NOBOX transcription factor directly binds to specific NOBOX binding elements (NBEs: TAATTG, TAGTTG, TAATTA) in the Gdf9 promoter at positions -786, -967, and -1259, and augments transcriptional activity of Gdf9 in oocytes during early folliculogenesis, as confirmed by chromatin immunoprecipitation. SELEX (cyclic amplification of sequence target assay), mutation analysis, luciferase reporter assays, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 16997917
2007 GDF9 stimulates proliferation and inhibits steroidogenesis in bovine theca cells from small (3-6 mm) follicles, decreasing progesterone and androstenedione production, and activates SMAD2/3-mediated CAGA promoter signaling via ALK5 (TGFBR1); theca cells from large follicles show little response, correlated with lower ALK5 mRNA abundance. Primary bovine theca cell culture, [3H]-thymidine incorporation, steroid RIA, transfected SMAD reporter assay, RT-PCR Biology of reproduction High 17959852
2007 BMP15 and GDF9 together (but not alone) control cumulus cell cholesterol biosynthesis by promoting expression of cholesterol biosynthetic enzyme transcripts (Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol, Ebp); oocytes are deficient in cholesterol synthesis and depend on cumulus cells for cholesterol supply via GDF9/BMP15 paracrine signaling. Bmp15−/− and Bmp15−/−Gdf9+/− double mutant mouse models, oocytectomy, wild-type oocyte co-culture rescue experiments, de novo cholesterol synthesis assays, transcript analysis Development (Cambridge, England) High 18045843
2008 Recombinant mouse GDF9 is secreted as a dimer of mature protein (in both the presence and absence of BMP15), while BMP15 proregion noncovalently interacts with GDF9 mature protein (co-immunoprecipitation), forming heteromeric BMP15/GDF9 complexes; these cooperative interactions are species-specific and dependent on the BMP15 proregion, and signal through BMPR2 and ACVR1B/TGFBR1/ACVR1C receptor pathways. Co-immunoprecipitation, Western blot under non-reducing conditions, rat granulosa cell [3H]-thymidine incorporation bioassay, immunoneutralization experiments Biology of reproduction High 18633140
2011 Purified mature GDF9 and BMP15 synergistically stimulate granulosa cell DNA synthesis and SMAD3 signaling; this synergy is specific (neither can be replaced by analogous TGF-β family members) and is dependent on SMAD2/3 phosphorylation, ERK1/2 (MAPK), and SRC kinase signaling pathways, but not NF-κB. Primary murine granulosa cell culture, [3H]-thymidine incorporation, SMAD3 transcriptional reporter assay, pharmacological inhibitors (SB431542, MEK/ERK inhibitor, SRC inhibitor, NF-κB inhibitor) Molecular human reproduction High 21911477
2011 GDF9 and BMP15 synergistically activate Smad2/3 and PI3K/Akt pathways in granulosa cells to induce AMH/Amh expression by recruiting the coactivator p300 to the AMH promoter, promoting H3K27 acetylation; FSH antagonizes this via PKA/SF1-mediated induction of GIOT-1, which recruits HDAC2 to deacetylate H3K27ac and suppress AMH expression. Primary mouse granulosa cell and KGN cell line experiments, chromatin immunoprecipitation (ChIP) for p300 and H3K27ac, siRNA knockdown, Fshβ-null mouse model with FSHβ transgenic rescue, in vivo serum AMH measurement Endocrinology High 30060157
2011 Immunization of mice against the full-length GDF9 proregion increases ovulation rate (more corpora lutea) but also decreases litter size, suggesting the GDF9 proregion plays a physiologically important role in regulating ovulation rate and litter size in vivo after secretion. Active immunization of mice with GDF9 proregion peptide-KLH conjugates, ovarian histology (corpora lutea count), litter size counts Reproduction (Cambridge, England) Medium 22106408
2011 Ovine and murine GDF9+BMP15 cooperatively stimulate granulosa cell [3H]-thymidine uptake through SMAD2/3 signaling (required for both species); ovine GDF9+BMP15 also requires NF-κB and partially p38-MAPK; murine GDF9+BMP15 requires ERK-MAPK; neither requires SMAD1/5/8 pathway. Species-specific differences in non-SMAD signaling correlate with differences in molecular complex forms detected by Western blot. Rat granulosa cell [3H]-thymidine incorporation, pharmacological pathway inhibitors, Western blot analysis of molecular complexes Reproduction (Cambridge, England) Medium 21474603
2012 Human GDF9 (hGDF9) is secreted in a latent form, whereas mouse GDF9 is active; a single residue, Gly391 in the mature domain of hGDF9 (part of the type I receptor binding site), confers latency by reducing receptor affinity. Substituting Gly391 with Arg (as in mouse GDF9) activates hGDF9 to levels comparable to mGDF9 in both adrenocortical cell luciferase assay and granulosa cell proliferation assay. Site-directed mutagenesis, adrenocortical cell luciferase reporter assay, murine granulosa cell proliferation assay, dose-response curves (EC50) Endocrinology High 22234469
2012 GDF9 upregulates NBL1 (DAN) mRNA expression in granulosa cells; DAN specifically antagonizes BMP2 and BMP4 signaling in granulosa cells, modulating their actions during folliculogenesis; GDF9 thus indirectly establishes a BMP antagonist gradient in granulosa cells. Granulosa cell culture with recombinant GDF9, RT-PCR for NBL1 expression, cell expression system bioassays with recombinant DAN against multiple TGF-β members, progesterone production assay with BMP4 ± DAN Biology of reproduction Medium 22357543
2013 The GDF9 p.R146C mutation (found in women with diminished ovarian reserve) reduces GDF9 mature protein secretion in cultured cells, decreases GDF9-stimulated granulosa cell proliferation, and impairs activation of the Smad2 pathway; structural modeling predicts disruption of an α-helix in the GDF9 proregion. Site-directed mutagenesis and expression in cultured cells, Western blot for secreted mature protein, human granulosa cell proliferation assay, Smad2 phosphorylation assay, protein structure modeling Human reproduction (Oxford, England) Medium 23851219
2013 In primary granulosa cells, GDF-9 (with Smad3) stimulates follistatin transcription; FOXL2 negatively regulates GDF-9-induced follistatin transcription; the granulosa cell tumor-associated mutant FOXL2C134W completely ablates GDF-9-induced follistatin expression. Both the Smad binding element and forkhead binding element in the follistatin promoter are required for GDF-9/Smad3 action. Primary granulosa cell transfection/reporter assays, siRNA knockdown of FOXL2, promoter mutation analysis Molecular and cellular endocrinology Medium 23567549
2013 Deletion of Gdf9 from inhibin-null (Inha−/−) mice rescues initial granulosa cell/oocyte growth defects at early follicle stages in Inha−/− ovaries, normalizes granulosa-oocyte growth dynamics, and reduces levels of Inhbb (activin βB subunit) that are upregulated in Inha−/−. However, Gdf9 deletion enhances onset of pre-tumor lesions in young mice, indicating GDF9 has a sequential role: promoting defective folliculogenesis early but suppressing tumor initiation. Inha−/− Gdf9−/− double knockout mouse model, histological analysis of follicle stages, tumor assessment, gene expression analysis Biology of reproduction High 23446452
2014 Oocyte-derived BMP15, but not GDF9, down-regulates connexin43 (Cx43) expression and decreases gap junction intercellular communication (GJIC) activity in human granulosa cells via Smad1/5/8 phosphorylation and a Smad4-dependent pathway (blocked by dorsomorphin, a BMP type I receptor inhibitor, and Smad4 siRNA). GDF9 did not affect Cx43 or GJIC. Human granulosa cell line (SVOG) and primary human granulosa-lutein cells, Cx43 mRNA/protein measurement, GJIC functional assay, siRNA knockdown of Smad4, pharmacological inhibition of BMP type I receptor Molecular human reproduction Medium 24413384
2014 Multiple human GDF9 prodomain mutations associated with premature ovarian failure (S186Y, V216M, T238A) result in activation of hGDF9 by reducing the affinity of the prodomain for mature hGDF9, allowing it to more readily signal. Two mutations found in mothers of dizygotic twins (P103S, P374L) completely abrogate GDF9 expression. These were identified by site-directed mutagenesis and in vitro granulosa cell proliferation bioassays. Site-directed mutagenesis, expression in HEK293T cells, Western blot for mature protein, in vitro granulosa cell proliferation bioassay, homology structural modeling The Journal of clinical endocrinology and metabolism High 24438375
2017 Multiple BMP15 mutations associated with primary ovarian insufficiency reduce mature BMP15 protein production, BMP15 activity on granulosa cells, or the synergistic activity of BMP15 with GDF9; three variants (R68W, F194S, N196K) specifically reduce BMP15/GDF9 synergy, suggesting the GDF9-BMP15 interaction is central to human ovarian physiology. Site-directed mutagenesis, expression assays for protein production, granulosa cell bioassays, GDF9/BMP15 synergy assays The Journal of clinical endocrinology and metabolism Medium 28359091
2017 The major oocyte-secreted molecular forms of ovine and bovine BMP15 and GDF9 are cleaved and uncleaved monomeric promature proteins (not dimers or heterodimers under native conditions), as determined by Western blot with specific monoclonal antibodies under non-reducing, reducing, and cross-linking conditions; in silico modelling proposes monomeric forms interact with type II and type I receptors to initiate synergistic signaling. Western blot with monoclonal antibodies (non-reducing, reducing, reducing+cross-linking conditions), recombinant protein controls including cysteine mutants and heterodimer, isolated oocyte in vitro secretion, in silico structural modelling Reproduction (Cambridge, England) Medium 28733348
2010 GDF9 promotes invasiveness of prostate cancer PC-3 cells and induces epithelial-mesenchymal transition (EMT) markers (SNAI1, RhoC, ROCK-1, N-cadherin upregulation; E-cadherin downregulation); this effect is dependent on ALK-5 (activin-like kinase 5) signaling, as demonstrated by ALK-5 inhibitor treatment. GDF9 overexpression, knockdown, and recombinant GDF9 protein treatment in PC-3 cells; invasion assay; gene expression analysis; ALK-5 inhibitor pharmacological experiment Molecular and cellular biochemistry Medium 21116689
2010 In zebrafish, recombinant Gdf9 suppresses amh expression and increases expression of activin beta subunits (inhbaa, inhbb) in somatic cells in vitro; vivo-morpholino knockdown of gdf9 causes male-skewed sex ratio, indicating GDF9 promotes oocyte/ovary differentiation partly through suppression of amh. Recombinant zebrafish Gdf9 treatment of gonadal cells in vitro, RT-qPCR gene expression, vivo-morpholino knockdown with sex ratio phenotype Biology of reproduction Medium 28203731
2011 GDF9 and BMP15 (exogenously supplied) induce antrum-like structure formation by bovine granulosa cells in oocytectomized complexes, and the combination is more potent than either factor alone; GDF9+BMP15 suppresses fibroblast-like differentiation of granulosa cells after oocyte removal. Bovine oocyte-granulosa cell complex culture, oocytectomy, recombinant GDF9 and BMP15 treatment, morphological assessment The Journal of reproduction and development Medium 30033985
2021 GDF-9 reduces follicular apoptosis and promotes granulosa cell proliferation in ovine preantral follicles via the PI3K/Akt/FOXO3a pathway; LY294002 (PI3K inhibitor) blocks GDF-9-induced primordial follicle activation and reduces p-Akt immunostaining, while GDF-9 treatment maintains nuclear exclusion of p-FOXO3a. In vitro culture of ovine ovarian cortical slices with recombinant GDF-9, PI3K inhibitor (LY294002), immunohistochemistry for p-Akt and p-FOXO3a, apoptosis and proliferation assays Reproductive sciences (Thousand Oaks, Calif.) Medium 33409876
2014 A tandem duplication of 475 bp containing part of the GDF9 gene promoter region (including three NOBOX-binding elements and an E-box) was identified in a woman with primary ovarian insufficiency, suggesting that disruption of these regulatory elements in the GDF9 promoter is causative of POI. Array comparative genomic hybridization (CGH), PCR breakpoint characterization, MLPA probe development for confirmation Human reproduction (Oxford, England) Low 24939957
2015 A novel NOBOX isoform expressed in the human fetal ovary is capable of upregulating the GDF9 promoter in reporter assays; GDF9 protein is transiently expressed in oocytes before follicle formation during human fetal ovarian development. Immunohistochemistry in human fetal ovary sections, qRT-PCR, luciferase reporter assay with novel NOBOX isoform PloS one Medium 25790371
2022 Native human pro-mature GDF9 (~47 kDa) and BMP15 (~43 kDa) are detected in human oocytes by Western blot; GDF9 and BMP15 are secreted by oocytes during IVM, with GDF9 concentrations ~10-fold higher than BMP15; concentrations of both GDF9 and BMP15 homodimers are significantly lower in spent media from MII oocytes than GV oocytes; BMPR2, SMAD3, and SMAD5 are upregulated in cumulus cells from MII oocytes, indicating active GDF9/BMP15 signaling during meiotic resumption. Western blot, immunofluorescence, ELISA of spent IVM media (GDF9, BMP15, heterodimer), RT-qPCR for signaling pathway genes in cumulus cells Reproductive biology and endocrinology Medium 35986324

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in the genes for oocyte-derived growth factors GDF9 and BMP15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries). Biology of reproduction 485 14627550
2007 Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development (Cambridge, England) 303 18045843
2004 Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop. Developmental biology 284 15531364
2011 Integral role of GDF-9 and BMP-15 in ovarian function. Molecular reproduction and development 266 21226076
2006 Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European journal of endocrinology 202 16645022
2018 GDF-9 and BMP-15 direct the follicle symphony. Journal of assisted reproduction and genetics 152 30039232
2010 The role of oocyte-secreted factors GDF9 and BMP15 in follicular development and oogenesis. Reproduction in domestic animals = Zuchthygiene 135 21198974
2004 Spatio-temporal expression of the germ cell marker genes MATER, ZAR1, GDF9, BMP15,andVASA in adult bovine tissues, oocytes, and preimplantation embryos. Biology of reproduction 129 15189828
2014 Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans. Reproductive biology and endocrinology : RB&E 114 25139161
2018 Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function. Vitamins and hormones 107 29544636
2007 Growth differentiation factor 9 (GDF9) stimulates proliferation and inhibits steroidogenesis by bovine theca cells: influence of follicle size on responses to GDF9. Biology of reproduction 106 17959852
2005 Expression of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), and BMP receptors in the ovaries of goats. Molecular reproduction and development 103 15515056
1999 Localization of growth differentiation factor-9 (GDF-9) mRNA and protein in rat ovaries and cDNA cloning of rat GDF-9 and its novel homolog GDF-9B. Molecular and cellular endocrinology 100 10612437
2004 Physiology of GDF9 and BMP15 signalling molecules. Animal reproduction science 99 15271472
2009 Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. Reproduction (Cambridge, England) 96 19713444
2005 The art and artifact of GDF9 activity: cumulus expansion and the cumulus expansion-enabling factor. Biology of reproduction 87 15917343
2010 Estrogen promotes the development of mouse cumulus cells in coordination with oocyte-derived GDF9 and BMP15. Molecular endocrinology (Baltimore, Md.) 85 21047911
2011 Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertility and sterility 83 21496799
2018 Oocyte-Derived Factors (GDF9 and BMP15) and FSH Regulate AMH Expression Via Modulation of H3K27AC in Granulosa Cells. Endocrinology 80 30060157
2009 Temporal regulation of BMP2, BMP6, BMP15, GDF9, BMPR1A, BMPR1B, BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig. Reproduction (Cambridge, England) 79 19359354
2003 GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility. The EMBO journal 79 12912906
2011 A new polymorphism in the Growth and Differentiation Factor 9 (GDF9) gene is associated with increased ovulation rate and prolificacy in homozygous sheep. Animal genetics 76 20528846
2011 Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15 both activate development of human primordial follicles in vitro, with seemingly more beneficial effects of GDF9. The Journal of clinical endocrinology and metabolism 75 21632818
2006 Characterization of NOBOX DNA binding specificity and its regulation of Gdf9 and Pou5f1 promoters. The Journal of biological chemistry 75 16997917
2018 Two strongly linked single nucleotide polymorphisms (Q320P and V397I) in GDF9 gene are associated with litter size in cashmere goats. Theriogenology 73 30414564
2011 Signalling pathways mediating specific synergistic interactions between GDF9 and BMP15. Molecular human reproduction 71 21911477
2004 Are BMP-15 and GDF-9 primary determinants of ovulation quota in mammals? Trends in endocrinology and metabolism: TEM 71 15380806
2008 The proregion of mouse BMP15 regulates the cooperative interactions of BMP15 and GDF9. Biology of reproduction 68 18633140
2007 Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertility and sterility 66 17482612
2006 The effects of immunizing sheep with different BMP15 or GDF9 peptide sequences on ovarian follicular activity and ovulation rate. Biology of reproduction 62 17093201
2014 Oocyte-derived BMP15 but not GDF9 down-regulates connexin43 expression and decreases gap junction intercellular communication activity in immortalized human granulosa cells. Molecular human reproduction 61 24413384
2004 A deletion mutation in GDF9 in sisters with spontaneous DZ twins. Twin research : the official journal of the International Society for Twin Studies 56 15607004
2009 Polymorphism of BMPR1B, BMP15 and GDF9 fecundity genes in prolific Garole sheep. Tropical animal health and production 54 20020203
2010 Expression of GDF-9, BMP-15 and their receptors in mammalian ovary follicles. Journal of molecular histology 53 20857181
2014 Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome. Journal of assisted reproduction and genetics 52 25172094
2017 Expression analysis of growth differentiation factor 9 (Gdf9/gdf9), anti-müllerian hormone (Amh/amh) and aromatase (Cyp19a1a/cyp19a1a) during gonadal differentiation of the zebrafish, Danio rerio. Biology of reproduction 51 28203731
2013 Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women. Human reproduction (Oxford, England) 50 23851219
2007 Patterns of expression of messenger RNAs encoding GDF9, BMP15, TGFBR1, BMPR1B, and BMPR2 during follicular development and characterization of ovarian follicular populations in ewes carrying the Woodlands FecX2W mutation. Biology of reproduction 50 17715428
2017 BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. The Journal of clinical endocrinology and metabolism 48 28359091
2019 The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency. Human fertility (Cambridge, England) 43 31607184
2014 Identification of a duplication within the GDF9 gene and novel candidate genes for primary ovarian insufficiency (POI) by a customized high-resolution array comparative genomic hybridization platform. Human reproduction (Oxford, England) 40 24939957
2015 GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript. PloS one 39 25790371
2011 Signalling pathways involved in the cooperative effects of ovine and murine GDF9+BMP15-stimulated thymidine uptake by rat granulosa cells. Reproduction (Cambridge, England) 39 21474603
2012 DAN (NBL1) specifically antagonizes BMP2 and BMP4 and modulates the actions of GDF9, BMP2, and BMP4 in the rat ovary. Biology of reproduction 38 22357543
2009 Oogenesis specific genes (Nobox, Oct4, Bmp15, Gdf9, Oogenesin1 and Oogenesin2) are differentially expressed during natural and gonadotropin-induced mouse follicular development. Molecular reproduction and development 36 19480014
2018 Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 29587293
2012 Activation of latent human GDF9 by a single residue change (Gly 391 Arg) in the mature domain. Endocrinology 35 22234469
2017 BMP15 and GDF9 Gene Mutations in Premature Ovarian Failure. Journal of reproduction & infertility 34 28377898
2020 Growth differentiation factor 9 (gdf9) and bone morphogenetic protein 15 (bmp15) are potential intraovarian regulators of steroidogenesis in Japanese flounder (Paralichthys olivaceus). General and comparative endocrinology 33 32659273
2018 GDF9 and BMP15 induce development of antrum-like structures by bovine granulosa cells without oocytes. The Journal of reproduction and development 33 30033985
2018 Expression Analysis of the Prolific Candidate Genes, BMPR1B, BMP15, and GDF9 in Small Tail Han Ewes with Three Fecundity (FecB Gene) Genotypes. Animals : an open access journal from MDPI 33 30274220
2017 Regulatory Role of miRNA-375 in Expression of BMP15/GDF9 Receptors and its Effect on Proliferation and Apoptosis of Bovine Cumulus Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 28214889
2009 Polymorphisms in GDF9 and BMP15 associated with fertility and ovulation rate in Moghani and Ghezel sheep in Iran. Reproduction in domestic animals = Zuchthygiene 33 19144040
2018 Genome-wide analysis of circular RNAs in bovine cumulus cells treated with BMP15 and GDF9. Scientific reports 32 29786687
2010 Polymorphisms of caprine GDF9 gene and their association with litter size in Jining Grey goats. Molecular biology reports 32 21181498
2014 Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes. Animal genetics 31 25039891
2022 Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries. The Journal of clinical endocrinology and metabolism 30 35511085
2021 Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders. Journal of ovarian research 30 33397408
2015 Quantitative expression patterns of GDF9 and BMP15 genes in sheep ovarian follicles grown in vivo or cultured in vitro. Theriogenology 30 26474685
2012 Polymorphism identification in goat GNRH1 and GDF9 genes and their association analysis with litter size. Animal genetics 30 22812579
2008 Expression pattern of zygote arrest 1 (ZAR1), maternal antigen that embryo requires (MATER), growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes in ovine oocytes and in vitro-produced preimplantation embryos. Reproduction, fertility, and development 30 19007555
2007 The role of growth differentiation factor-9 (GDF-9) and its analog, GDF-9b/BMP-15, in human breast cancer. Annals of surgical oncology 30 17453295
2021 miR-23b-3p inhibits chicken granulosa cell proliferation and steroid hormone synthesis via targeting GDF9. Theriogenology 29 34687940
2012 Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. Journal of assisted reproduction and genetics 29 22825968
2014 Aberrant GDF9 expression and activation are associated with common human ovarian disorders. The Journal of clinical endocrinology and metabolism 28 24438375
2013 Association of BMPR-1B and GDF9 genes polymorphisms and secondary protein structure changes with reproduction traits in Mehraban ewes. Gene 28 23583795
2024 The Roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in Folliculogenesis and In Vitro Fertilization. Journal of clinical medicine 27 38999341
2017 Molecular forms of ruminant BMP15 and GDF9 and putative interactions with receptors. Reproduction (Cambridge, England) 27 28733348
2010 GDF9 as a candidate gene for prolificacy of Small Tail Han sheep. Molecular biology reports 27 21184179
2020 Novel Variants in GDF9 Gene Affect Promoter Activity and Litter Size in Mongolia Sheep. Genes 26 32235645
2013 Differential ovarian morphometry and follicular expression of BMP15, GDF9 and BMPR1B influence the prolificacy in goat. Reproduction in domestic animals = Zuchthygiene 26 23581245
2011 Exogenous GDF9 but not Activin A, BMP15 or TGFβ alters tight junction protein transcript abundance in zebrafish ovarian follicles. General and comparative endocrinology 26 21291886
2021 Polymorphism Detection of GDF9 Gene and Its Association with Litter Size in Luzhong Mutton Sheep (Ovis aries). Animals : an open access journal from MDPI 25 33671790
2013 Importance of the GDF9 signaling pathway on cumulus cell expansion and oocyte competency in sheep. Theriogenology 24 23764009
2022 Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM. Reproductive biology and endocrinology : RB&E 23 35986324
2019 Serum Concentrations of Oocyte-Secreted Factors BMP15 and GDF9 During IVF and in Women With Reproductive Pathologies. Endocrinology 23 31211369
2019 Genetic Effects of Single Nucleotide Polymorphisms in the Goat GDF9 Gene on Prolificacy: True or False Positive? Animals : an open access journal from MDPI 23 31683597
2014 Direct evidence on the contribution of a missense mutation in GDF9 to variation in ovulation rate of Finnsheep. PloS one 23 24751660
2011 Active immunization against the proregions of GDF9 or BMP15 alters ovulation rate and litter size in mice. Reproduction (Cambridge, England) 23 22106408
2004 Differential expression of bone morphogenetic protein 4-6 (BMP-4, -5, and -6) and growth differentiation factor-9 (GDF-9) during ovarian development in neonatal pigs. Domestic animal endocrinology 23 15519042
2013 Differential expression of GDF9, TGFB1, TGFB2 and TGFB3 in porcine oocytes isolated from follicles of different size before and after culture in vitro. Acta veterinaria Hungarica 22 23439295
2018 Polymorphism of GDF9 and BMPR1B genes and their association with litter size in Markhoz goats. Reproduction in domestic animals = Zuchthygiene 21 29696699
2021 Involvement of Phosphorylated Akt and FOXO3a in the Effects of Growth and Differentiation Factor-9 (GDF-9) on Inhibition of Follicular Apoptosis and Induction of Granulosa Cell Proliferation After In Vitro Culture of Sheep Ovarian Tissue. Reproductive sciences (Thousand Oaks, Calif.) 20 33409876
2010 Growth and differentiation factor 9 (GDF-9) induces epithelial-mesenchymal transition in prostate cancer cells. Molecular and cellular biochemistry 20 21116689
2004 Bromodomain containing 2 (Brd2) is expressed in distinct patterns during ovarian folliculogenesis independent of FSH or GDF9 action. Molecular reproduction and development 20 15112318
2017 Genetic polymorphism of growth differentiation factor 9 (GDF9) gene related to fecundity in two Egyptian sheep breeds. Journal of assisted reproduction and genetics 19 28762037
2013 Granulosa cell tumor mutant FOXL2C134W suppresses GDF-9 and activin A-induced follistatin transcription in primary granulosa cells. Molecular and cellular endocrinology 19 23567549
2020 Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT. Experimental biology and medicine (Maywood, N.J.) 18 32223330
2016 Temporal expression of GDF-9 and BMP-15 mRNAs in canine ovarian follicles. Theriogenology 18 27341772
2013 Expression of growth differentiation factor 9 (GDF-9) during in vitro maturation in canine oocytes. Theriogenology 18 23849650
2019 Association of BMP15 and GDF9 variants to premature ovarian insufficiency. Journal of assisted reproduction and genetics 17 31392662
2016 Differential expression of GDF-9 and BMP- 15 during follicular development in canine ovaries evaluated by flow cytometry. Animal reproduction science 17 26876149
2013 GDF9 modulates the reproductive and tumor phenotype of female inha-null mice. Biology of reproduction 17 23446452
2013 Differential expression dynamics of Growth differentiation factor9 (GDF9) and Bone morphogenetic factor15 (BMP15) mRNA transcripts during in vitro maturation of buffalo (Bubalus bubalis) cumulus-oocyte complexes. SpringerPlus 17 23724366
2013 Anti-Müllerian hormone (AMH), inhibin-α, growth differentiation factor 9 (GDF9), and bone morphogenic protein-15 (BMP15) mRNA and protein are influenced by photoperiod-induced ovarian regression and recrudescence in Siberian hamster ovaries. Molecular reproduction and development 17 23877969
2020 BMPR-1B, BMP-15 and GDF-9 genes structure and their relationship with litter size in six sheep breeds reared in Egypt. BMC research notes 16 32299511
2017 Endometriosis-associated infertility: GDF-9, AMH, and AMHR2 genes polymorphisms. Journal of assisted reproduction and genetics 16 28831646
2017 GDF9 and BMP15 Expressions and Fine Structure Changes During Folliculogenesis in Polycystic Ovary Syndrome. Balkan medical journal 16 28903889
2013 Investigation of prolific sheep from UK and Ireland for evidence on origin of the mutations in BMP15 (FecX(G), FecX(B)) and GDF9 (FecG(H)) in Belclare and Cambridge sheep. PloS one 16 23301039
2013 Inhibitory effects of controlled ovarian stimulation on the expression of GDF9 and BMP15 in oocytes from women with PCOS. Journal of assisted reproduction and genetics 16 23912750

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