Affinage

GDF9

Growth/differentiation factor 9 · UniProt O60383

Length
454 aa
Mass
51.4 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF9 is an oocyte-secreted TGF-β superfamily ligand that orchestrates folliculogenesis by driving granulosa and theca cell proliferation, cumulus expansion, cholesterol biosynthesis, and suppression of apoptosis. Unlike most TGF-β family members, GDF9 lacks the conserved inter-subunit cysteine and is processed into a prodomain–mature protein complex whose activity is species-specifically regulated: human GDF9 is secreted in a latent form conferred by Gly391 in the type I receptor-binding site, whereas murine GDF9 is constitutively active (PMID:8429021, PMID:22234469). GDF9 signals through ALK4/5/7 type I receptors and BMPR2 to activate SMAD2/3 in target cells, and synergizes with BMP15 to additionally engage ERK1/2 and SRC kinase pathways, stimulating cumulus cell cholesterol synthesis, AMH expression (via p300-mediated H3K27 acetylation), and follistatin transcription (regulated by FOXL2/Smad3) (PMID:21911477, PMID:18045843, PMID:30060157, PMID:23567549). GDF9 transcription in oocytes is directly activated by NOBOX and STAT3 and repressed by GCNF, and upstream Rac1–STAT3 signaling coordinates GDF9/BMP15 expression to control primordial follicle assembly via mTORC1–Notch2 signaling in pregranulosa cells (PMID:16997917, PMID:12912906, PMID:27050391).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Identification of GDF9 as a novel TGF-β superfamily member lacking the conserved inter-subunit cysteine established it as a structurally distinct secreted growth factor with potentially unique dimerization properties.

    Evidence cDNA cloning and sequence analysis from mouse libraries

    PMID:8429021

    Open questions at the time
    • Native quaternary structure unknown
    • No bioactivity data at this stage
    • Tissue expression pattern not yet characterized beyond Northern blot
  2. 1999 High

    Demonstration that recombinant GDF9 stimulates preantral follicle growth and inhibin production established GDF9 as a functional oocyte-derived growth factor acting on surrounding somatic cells.

    Evidence Bacterially produced recombinant GDF9 tested in rat preantral follicle culture and neonatal ovary explants

    PMID:10067849

    Open questions at the time
    • Receptor identity unknown
    • Downstream signaling pathway not defined
    • In vivo relevance not yet tested
  3. 2000 High

    In vivo GDF9 treatment promoted primordial-to-primary follicle transition and theca cell development, establishing its non-redundant role in early folliculogenesis distinct from FSH.

    Evidence Recombinant GDF9 injection in immature rats with histomorphometry and CYP17 immunoblot

    PMID:11014238

    Open questions at the time
    • Mechanism of theca recruitment unknown
    • Dose-response and receptor requirements not addressed
  4. 2003 High

    Discovery that GCNF directly represses GDF9 transcription via DR0 promoter elements, with oocyte-specific GCNF knockout causing GDF9 upregulation and double-oocyte follicles, defined the first transcriptional control mechanism for GDF9 in oocytes.

    Evidence Oocyte-specific Cre/loxP knockout of GCNF, promoter reporter and binding assays

    PMID:12912906

    Open questions at the time
    • Positive transcriptional regulators not yet identified
    • Whether GCNF regulation is conserved in humans unknown
  5. 2006 High

    Identification of NOBOX as a direct transcriptional activator of GDF9 through promoter NBE elements provided the first positive oocyte-specific transcription factor for GDF9.

    Evidence CAST, ChIP, and luciferase reporter assays on Gdf9 promoter

    PMID:16997917

    Open questions at the time
    • NOBOX–GCNF interplay at the GDF9 promoter not resolved
    • Chromatin context and epigenetic regulation not addressed
  6. 2007 High

    Parallel discoveries that GDF9 signals via ALK5/SMAD2/3 in theca cells to stimulate proliferation and suppress steroidogenesis, and that GDF9 cooperates with BMP15 to drive cumulus cell cholesterol biosynthesis, delineated its dual paracrine roles and pathway specificity in distinct follicular cell types.

    Evidence SMAD reporter assays and pathway inhibitors in bovine theca cells; genetic Bmp15/Gdf9 mutant mice with oocytectomy rescue and metabolic profiling in cumulus cells

    PMID:17959852 PMID:18045843

    Open questions at the time
    • Type II receptor identity not yet defined
    • Mechanism of GDF9-BMP15 cooperative signaling at receptor level unresolved
  7. 2008 High

    Co-immunoprecipitation of GDF9 mature protein with BMP15 proregion and demonstration that cooperative signaling operates through BMPR2 and ALK4/5/7 receptors established the biochemical basis of the GDF9–BMP15 heteromeric interaction.

    Evidence Co-IP, proregion immunoneutralization, granulosa cell bioassay with recombinant proteins

    PMID:18633140

    Open questions at the time
    • Whether a stable GDF9:BMP15 heterodimer forms or signaling occurs through independent monomers remained debated
    • Structural basis of interaction unknown
  8. 2010 High

    Systematic pathway inhibitor studies resolved that GDF9+BMP15 synergistic granulosa cell proliferation requires SMAD2/3 universally, plus ERK1/2 and SRC kinase in murine cells, defining species-specific non-SMAD pathway engagement.

    Evidence Pathway inhibitor panel (SB431542, PD98059, PP2, BAY11-7082) in rat and murine granulosa cell thymidine incorporation assays

    PMID:21474603 PMID:21911477

    Open questions at the time
    • Direct receptor-to-kinase cascade intermediates not mapped
    • SRC substrate in this context unidentified
  9. 2010 High

    Demonstration that GDF9 suppresses Nrip1 in cumulus cells provided a molecular mechanism for oocyte–estrogen crosstalk during follicle maturation.

    Evidence Oocytectomy and recombinant GDF9 rescue in preantral granulosa–oocyte complexes with transcript analysis

    PMID:21047911

    Open questions at the time
    • Whether Nrip1 suppression is SMAD2/3-dependent not tested
    • Relevance to human cumulus expansion not confirmed
  10. 2012 High

    Identification of Gly391 as the residue conferring latency to human GDF9 (versus constitutively active murine GDF9) resolved the long-standing species difference in bioactivity and pinpointed the type I receptor-binding interface as the latency determinant.

    Evidence Site-directed mutagenesis with functional assays in adrenocortical and granulosa cells

    PMID:22234469

    Open questions at the time
    • Full structural model of prodomain–mature domain interaction lacking
    • Mechanism of latency release in vivo unknown
  11. 2013 High

    Characterization of human GDF9 mutations linked to dizygotic twinning (P103S, P374L ablating protein expression) and premature ovarian insufficiency (S186Y, V216M, T238A reducing prodomain-mediated latency; R146C reducing secretion and SMAD2 activation) established genotype–phenotype relationships for GDF9 in human reproductive disorders.

    Evidence Site-directed mutagenesis, HEK293T expression, granulosa cell bioassay, Smad2 phosphorylation, structural modeling

    PMID:23851219 PMID:24438375

    Open questions at the time
    • No in vivo rescue experiments in animal models
    • Penetrance modifiers for heterozygous carriers not identified
  12. 2013 High

    Elucidation that GDF9 drives follistatin transcription through Smad3 and FOXL2 binding elements, with the FOXL2-C134W granulosa cell tumor mutation abolishing this response, linked GDF9 signaling to both normal follicular physiology and ovarian tumorigenesis.

    Evidence Luciferase reporters with SBE/FBE mutagenesis, FOXL2 knockdown/overexpression in primary granulosa cells and COV434 line

    PMID:23523567 PMID:23567549

    Open questions at the time
    • ChIP for endogenous FOXL2 at the follistatin locus not performed
    • In vivo validation of FOXL2-C134W effect on GDF9 target genes lacking
  13. 2016 High

    Positioning GDF9 downstream of Rac1–STAT3 and upstream of mTORC1–Notch2 in pregranulosa cells established the signaling hierarchy governing primordial follicle assembly.

    Evidence Fetal mouse ovary organ culture with Rac1 inhibition/overexpression, STAT3 nuclear import, ChIP, recombinant GDF9/BMP15 rescue

    PMID:27050391

    Open questions at the time
    • Whether STAT3 binds the GDF9 promoter directly in vivo not shown by ChIP in oocytes
    • Human relevance not tested
  14. 2018 Medium

    Discovery that GDF9/BMP15 suppress cumulus cell apoptosis through negative regulation of miR-375 (which targets BMPR2) added a post-transcriptional regulatory layer to the GDF9 signaling network and defined a BMPR2–ALK4/5/7–ALK6 receptor complex for the heterodimer.

    Evidence miR-375 mimic/inhibitor transfection, BMPR2 siRNA, apoptosis flow cytometry, p-Smad Western blot in bovine cumulus cells

    PMID:29587293

    Open questions at the time
    • miR-375 regulation in human granulosa cells not confirmed
    • Direct miR-375 promoter binding by GDF9-activated TFs not shown
    • Single-lab finding
  15. 2018 High

    GDF9 and BMP15 together stimulate AMH expression through PI3K/Akt and Smad2/3 convergence on p300-mediated H3K27 acetylation at the AMH promoter, with FSH antagonizing this via HDAC2 recruitment, establishing a chromatin-level switch for AMH regulation.

    Evidence ChIP for H3K27ac and p300 in primary granulosa cells and KGN cells, Fshβ-null mouse model, pathway inhibitors

    PMID:30060157

    Open questions at the time
    • Whether PI3K/Akt and Smad2/3 converge on p300 through direct interaction or separate mechanisms not resolved
    • Relevance to clinical AMH levels in women not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of GDF9 prodomain-mediated latency and its release mechanism in vivo, whether GDF9 and BMP15 signal as a true covalent heterodimer or as cooperative monomers on receptor complexes, and the complete receptor stoichiometry and activation mechanism at the target cell surface.
  • No crystal or cryo-EM structure of GDF9 alone or in complex with receptors
  • In vivo mechanism of prodomain dissociation/latency release unknown
  • GDF9:BMP15 oligomeric state debated between co-IP and Western blot studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1474165 Reproduction 4
Partners
ALK5BMP15BMPR2FOXL2GCNFNOBOXSMAD3STAT3
Complex memberships
GDF9:BMP15 heteromeric complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GDF9 was identified as a new member of the TGF-β superfamily, predicted to encode a secreted protein with a signal sequence, a tetrabasic proteolytic processing site, and a C-terminal region homologous to TGF-β family members. Uniquely, GDF9 (and GDF3) lack the conserved cysteine residue believed to form the inter-subunit disulfide linkage present in all other family members, suggesting novel subunit interactions. cDNA cloning, sequence analysis, Northern blot The Journal of biological chemistry High 8429021
1999 Recombinant GDF9 (bacteria-derived GST fusion) stimulates growth of preantral follicles isolated from immature rats in an additive manner with FSH, and stimulates inhibin-α content in neonatal ovary explants. GDF9 is an N-glycosylated secreted protein. Amino-terminal tagged GDF9 was not bioactive, indicating the tag disrupts function. Recombinant protein production, preantral follicle culture assay, inhibin-α measurement, immunoblot, immunohistochemistry Endocrinology High 10067849
2000 In vivo treatment with recombinant GDF9 in immature rats increased ovarian weight and the number of primary and small preantral follicles, decreased primordial follicles, and increased the theca cell marker CYP17 (by immunoblot). This is distinct from FSH, which acts on more advanced follicles, indicating GDF9 specifically promotes primordial-to-primary follicle transition and theca cell development. In vivo recombinant protein injection, histomorphometry, immunoblot for CYP17 Endocrinology High 11014238
2003 The transcriptional repressor GCNF directly binds DR0 elements in the GDF9 (and BMP15) gene promoters and represses their transcriptional activity. Oocyte-specific knockout of GCNF in mice leads to upregulation of GDF9 and BMP15 in oocytes and results in abnormal double-oocyte follicles and hypofertility, demonstrating GCNF as a direct transcriptional regulator of GDF9. Oocyte-specific Cre/loxP knockout mouse, promoter reporter assay, molecular binding studies (GCNF binding to DR0 elements), ovarian histology The EMBO journal High 12912906
2006 NOBOX directly binds NOBOX binding elements (NBEs: TAATTG, TAGTTG, TAATTA) in the Gdf9 promoter (at positions -786, -967, -1259) with high affinity, augments transcriptional activity of a Gdf9 promoter-luciferase reporter, and co-precipitates with Gdf9 promoter sequences in chromatin immunoprecipitation assays. CAST (cyclic amplification of sequence targets), promoter-luciferase reporter assay, chromatin immunoprecipitation (ChIP), EMSA-type DNA binding The Journal of biological chemistry High 16997917
2007 GDF9 and BMP15 together (but not individually) control cholesterol biosynthesis in cumulus cells by promoting expression of enzymes of the cholesterol biosynthetic pathway (Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol, Ebp). Oocytes are deficient in de novo cholesterol synthesis and depend on cumulus cells for cholesterol, and GDF9/BMP15-driven cumulus cell cholesterol synthesis compensates for this oocyte deficiency. Bmp15-/- and Bmp15-/-Gdf9+/- double mutant mouse analysis, oocytectomy, wild-type oocyte co-culture rescue, transcript profiling, de novo cholesterol synthesis measurement Development (Cambridge, England) High 18045843
2007 GDF9 increases theca cell proliferation (DNA synthesis by [3H]-thymidine incorporation) and decreases progesterone and androstenedione production in small-follicle (3-6 mm) bovine theca cells in the presence of LH and IGF1. GDF9 activates SMAD2/3-mediated CAGA promoter activity in transfected theca cells (signaling via ALK5), and decreases LHR and CYP11A1 mRNA levels. Large-follicle theca cells are unresponsive, correlating with lower ALK5 expression. [3H]-thymidine incorporation, steroid production assay, SMAD reporter assay, RT-PCR, immunostaining Biology of reproduction High 17959852
2008 Mouse GDF9 exists mostly as a mature protein dimer. Recombinant mouse GDF9 and BMP15 are secreted as cleaved mature and proregion proteins; GDF9 mature protein co-immunoprecipitates with the BMP15 proregion, demonstrating a heteromeric BMP15/GDF9 association. BMP15 proregion neutralization inhibited cooperative BMP15/GDF9 activity in granulosa cell bioassay. Mouse BMP15 acts cooperatively with GDF9 through BMPR2 and ACVR1B/TGFBR1/ACVR1C receptor-mediated pathways. Cooperative interactions are species specific and multimeric, involving the proregion. Co-immunoprecipitation, Western blot, granulosa cell [3H]-thymidine incorporation bioassay, immunoneutralization with proregion antibodies Biology of reproduction High 18633140
2010 GDF9 and BMP15 together (but not individually) stimulate AMH/Amh expression in granulosa cells through PI3K/Akt and Smad2/3 pathways, which synergistically recruit coactivator p300 to the AMH promoter region promoting H3K27 acetylation. FSH antagonizes this effect via PKA/SF1-induced GIOT-1 expression, which recruits HDAC2 to deacetylate H3K27ac and suppress AMH expression. Primary mouse granulosa cells and KGN cell line, recombinant GDF9+BMP15 treatment, chromatin immunoprecipitation (H3K27ac, p300), Fshβ-null mouse model, pathway inhibitor assays Endocrinology High 30060157
2010 GDF9 and BMP15 (GDF9+BMP15)-stimulated [3H]-thymidine uptake in rat granulosa cells signals through the SMAD2/3 pathway (completely blocked by SB431542) but not through SMAD1/5/8. Ovine GDF9+BMP15 additionally requires NF-κB and partially p38-MAPK; murine GDF9+BMP15 additionally requires ERK1/2 MAPK. Species differences in non-SMAD pathway usage correlate with differences in molecular complexes formed. [3H]-thymidine incorporation bioassay with specific pathway inhibitors, Western blot analysis of molecular complexes Reproduction (Cambridge, England) High 21474603
2010 Estrogen (17β-estradiol) and oocyte-derived GDF9 coordinately promote cumulus cell development and competence for expansion. Oocytes or recombinant GDF9 (but not FGF8) suppress Nrip1 (nuclear receptor-interacting protein 1, a potential estrogen receptor inhibitor) expression in cumulus cells, providing a molecular mechanism for oocyte-estrogen crosstalk in follicular development. In vitro preantral granulosa cell-oocyte complex culture, oocytectomy, recombinant GDF9 and BMP15 supplementation, transcript analysis (Has2, Nrip1) Molecular endocrinology (Baltimore, Md.) High 21047911
2011 Purified mature regions of GDF9 and BMP15 synergistically interact on murine granulosa cells to stimulate DNA synthesis and SMAD3 signaling. This synergy is specific (neither factor can be replaced by analogous TGF-β family members), does not require the pro-region, and is blocked by SB431542 (SMAD2/3 inhibitor), MAPK/ERK inhibition, or SRC kinase inhibition, but not by NF-κB inhibition. Primary murine granulosa cell [3H]-thymidine incorporation, SMAD3 transcriptional reporter assay, specific pathway inhibitors, recombinant mature domain proteins Molecular human reproduction High 21911477
2012 Human GDF9 is secreted in a latent (inactive) form, whereas murine GDF9 is active. A single residue in the mature domain, Gly391 (which forms part of the type I receptor binding site), confers latency to human GDF9. Substituting Arg at position 391 (as in mouse/rat) activates human GDF9 to similar potency as murine GDF9 in both adrenocortical cell and granulosa cell proliferation assays (EC50 ~52-55 ng/ml). Prodomain interactions differentially regulate GDF9 activity across species. Site-directed mutagenesis, adrenocortical cell luciferase assay, murine granulosa cell proliferation assay, species sequence comparison Endocrinology High 22234469
2013 GDF9 stimulates follistatin transcription in granulosa cells via Smad3 and requires FOXL2 binding elements in the follistatin gene. In primary granulosa cells, FOXL2 negatively regulates GDF9-stimulated follistatin transcription. FOXL2C134W (the granulosa cell tumor mutation) completely abolishes GDF9-induced follistatin transcription via enhanced inhibition dependent on Smad3 interaction with the Smad binding element. Primary granulosa cell culture, recombinant GDF9 treatment, luciferase reporter with SBE and FBE mutations, FOXL2 knockdown/overexpression Molecular and cellular endocrinology High 23567549
2013 FOXL2 (wild-type) expression is necessary for GDF9 stimulation of follistatin transcription in COV434 granulosa cell tumor cells (which lack endogenous FOXL2). FOXL2C134W, in the presence of Smad3, negates GDF9-stimulated follistatin transcription; mutation of the Smad binding element restores normal FOXL2 activity to FOXL2C134W. The FOXL2 binding element is essential for GDF9 activity. Luciferase reporter assay with SBE and FBE mutations, COV434 cell line, FOXL2 overexpression Molecular and cellular endocrinology High 23523567
2013 Human GDF9 mutations P103S and P374L (found in mothers of dizygotic twins) completely abrogate GDF9 protein expression, predicting a 50% reduction in GDF9 levels in heterozygous carriers. Three prodomain mutations associated with premature ovarian failure (S186Y, V216M, T238A) activate hGDF9 by reducing prodomain affinity for the mature domain, allowing easier receptor access. These mechanistic findings link altered GDF9 synthesis/activity to common ovarian pathologies. Site-directed mutagenesis, HEK293T cell expression, in vitro granulosa cell proliferation bioassay, homology modeling The Journal of clinical endocrinology and metabolism High 24438375
2013 The GDF9 mutation p.R146C (found in women with diminished ovarian reserve) significantly reduces GDF9 mature protein secretion in cultured cells, reduces GDF9's ability to stimulate granulosa cell proliferation, and reduces Smad2 pathway activation. Structural modeling predicts this mutation disrupts an α-helix in GDF9. This establishes p.R146C as a loss-of-function mutation affecting GDF9 processing and signaling. Cell expression studies, granulosa cell proliferation assay, Smad2 phosphorylation assay, protein structure modeling Human reproduction (Oxford, England) High 23851219
2016 The small GTPase Rac1 promotes primordial follicle formation in mouse ovary by inducing nuclear import of STAT3 through physical binding. Nuclear STAT3 directly activates transcription of GDF9, BMP15, Jagged1 and Nobox. GDF9 and BMP15 then activate mTORC1 signaling in pregranulosa cells to promote Notch2 translation; overexpression of GDF9 and BMP15 reverses the effect of Rac1 disruption on primordial follicle formation via Notch2 signaling. Fetal mouse ovary organ culture, Rac1 inhibition/overexpression, STAT3 nuclear import assay, Rac1-STAT3 physical interaction, transcriptional reporter/ChIP, rescue with recombinant GDF9 and BMP15, mTORC1/Notch2 pathway analysis Scientific reports High 27050391
2017 Multiple BMP15 mutations associated with primary ovarian insufficiency reduce mature protein production, reduce activity on granulosa cells, or specifically reduce synergy with GDF9 in a granulosa cell bioassay. Three variants (R68W, F194S, N196K) have significantly reduced ability to synergize with GDF9, identifying GDF9-BMP15 synergistic interaction as functionally critical in the human ovary. Site-directed mutagenesis, HEK293T expression, granulosa cell bioassay, synergy assessment with recombinant GDF9 The Journal of clinical endocrinology and metabolism High 28359091
2017 Major oocyte-secreted molecular forms of ovine and bovine BMP15 and GDF9 are the cleaved and uncleaved monomeric forms of the pro-mature proteins, with no evidence for dimeric or heterodimeric forms under non-reducing, reducing, or reducing+cross-linking conditions by Western blot. In silico modeling suggests monomeric BMP15 and GDF9 can interact with type II and type I cell-surface receptors to initiate synergistic actions. Western blot with monoclonal antibodies under multiple conditions (non-reducing, reducing, cross-linking), recombinant variants including cysteine mutant BMP15 and human BMP15:GDF9 heterodimer (cumulin), in silico structural modeling Reproduction (Cambridge, England) Medium 28733348
2018 GDF9 and BMP15 suppress bovine cumulus cell apoptosis and promote proliferation. GDF9/BMP15 negatively regulate miR-375 expression, which in turn targets BMPR2. High miR-375 increases ALK4 expression and decreases p-Smad2/3 and p-Smad1/5/8. BMP15 and GDF9 activate both Smad2/3 and Smad1/5/8 phosphorylation in cumulus cells; the BMP15/GDF9 heterodimer signals through a BMPR2-ALK4/5/7-ALK6 receptor complex. miR-375 mimic/inhibitor transfection, BMPR2 siRNA, flow cytometry (apoptosis), CCK-8 (proliferation), Western blot for p-Smad2/3 and p-Smad1/5/8, RT-qPCR Cellular physiology and biochemistry Medium 29587293
2021 GDF9 (50 ng/ml) reduces follicular apoptosis and promotes granulosa cell proliferation in sheep ovarian tissue culture through the PI3K/Akt/FOXO3a pathway: GDF9 increases phospho-Akt immunostaining and promotes nuclear exclusion of FOXO3a, and these effects are blocked by PI3K inhibitor LY294002. Ovine ovarian cortex organ culture, PI3K inhibitor (LY294002), p-Akt and p-FOXO3a immunostaining, apoptosis and proliferation assays Reproductive sciences (Thousand Oaks, Calif.) Medium 33409876
2010 Impaired posttranslational processing of GDF9 proprotein mutants (S186Y and V216M identified in POI women) results in reduced mature GDF9 protein production and reduced biological activity of conditioned media from transfected HEK293F cells, establishing that proregion mutations affect GDF9 function by disrupting mature protein production. HEK293F cell transfection, conditioned media bioassay on granulosa cells, Western blot for mature GDF9 protein Molecular and cellular endocrinology Medium 20547206
2011 In vivo immunization of mice against the GDF9 proregion (full-length proregion) resulted in more corpora lutea but significantly smaller litter sizes compared with controls. Immunization against BMP15 N-terminus proregion peptide reduced corpora lutea and litter size. These in vivo data indicate that the secreted proregions of GDF9 and BMP15 have physiologically important roles in regulating ovulation rate and fertility. Active immunization, corpus lutea counting, litter size measurement Reproduction (Cambridge, England) Medium 22106408

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development (Cambridge, England) 302 18045843
2011 Integral role of GDF-9 and BMP-15 in ovarian function. Molecular reproduction and development 263 21226076
1999 Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology 261 10067849
1999 Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. The Journal of clinical endocrinology and metabolism 244 10443672
1993 GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. The Journal of biological chemistry 232 8429021
2006 Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European journal of endocrinology 202 16645022
2000 In vivo treatment with GDF-9 stimulates primordial and primary follicle progression and theca cell marker CYP17 in ovaries of immature rats. Endocrinology 167 11014238
2018 GDF-9 and BMP-15 direct the follicle symphony. Journal of assisted reproduction and genetics 145 30039232
2010 The role of oocyte-secreted factors GDF9 and BMP15 in follicular development and oogenesis. Reproduction in domestic animals = Zuchthygiene 134 21198974
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
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
2018 Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function. Vitamins and hormones 105 29544636
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 102 15515056
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
2013 A missense mutation in growth differentiation factor 9 (GDF9) is strongly associated with litter size in sheep. BMC genetics 91 23280002
2005 The art and artifact of GDF9 activity: cumulus expansion and the cumulus expansion-enabling factor. Biology of reproduction 86 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 82 21496799
2018 Oocyte-Derived Factors (GDF9 and BMP15) and FSH Regulate AMH Expression Via Modulation of H3K27AC in Granulosa Cells. Endocrinology 79 30060157
2003 GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility. The EMBO journal 79 12912906
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 Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. Fertility and sterility 65 17027369
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 60 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 55 15607004
2010 Expression of GDF-9, BMP-15 and their receptors in mammalian ovary follicles. Journal of molecular histology 53 20857181
2009 Polymorphism of BMPR1B, BMP15 and GDF9 fecundity genes in prolific Garole sheep. Tropical animal health and production 53 20020203
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) 49 23851219
2017 BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. The Journal of clinical endocrinology and metabolism 47 28359091
2019 The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency. Human fertility (Cambridge, England) 43 31607184
2016 Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice. Scientific reports 41 27050391
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 Growth differentiation factor 9 (Gdf9) was localized in the female as well as male germ cells in a protogynous hermaphroditic teleost fish, ricefield eel Monopterus albus. General and comparative endocrinology 37 22732078
2008 The promoter of the oocyte-specific gene, Gdf9, is active in population of cultured mouse embryonic stem cells with an oocyte-like phenotype. Methods (San Diego, Calif.) 36 18593614
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
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 35 19480014
2016 Genotyping of Novel SNPs in BMPR1B, BMP15, and GDF9 Genes for Association with Prolificacy in Seven Indian Goat Breeds. Animal biotechnology 34 27135147
2018 GDF9 and BMP15 induce development of antrum-like structures by bovine granulosa cells without oocytes. The Journal of reproduction and development 33 30033985
2017 BMP15 and GDF9 Gene Mutations in Premature Ovarian Failure. Journal of reproduction & infertility 33 28377898
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
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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 32 28214889
2010 Polymorphisms of caprine GDF9 gene and their association with litter size in Jining Grey goats. Molecular biology reports 32 21181498
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 31 32659273
2006 Promotion of ovarian follicular development by injecting vascular endothelial growth factor (VEGF) and growth differentiation factor 9 (GDF-9) genes. The Journal of reproduction and development 31 16538032
2017 Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clinical genetics 30 29044499
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
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
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2021 miR-23b-3p inhibits chicken granulosa cell proliferation and steroid hormone synthesis via targeting GDF9. Theriogenology 29 34687940
2018 Efficient generation of goats with defined point mutation (I397V) in GDF9 through CRISPR/Cas9. Reproduction, fertility, and development 29 28692815
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
2005 Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary. Reproductive toxicology (Elmsford, N.Y.) 29 16105726
2004 Molecular cloning of porcine growth differentiation factor 9 (GDF-9) cDNA and its role in early folliculogenesis: direct ovarian injection of GDF-9 gene fragments promotes early folliculogenesis. Reproduction (Cambridge, England) 29 15509699
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2014 Aberrant GDF9 expression and activation are associated with common human ovarian disorders. The Journal of clinical endocrinology and metabolism 28 24438375
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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
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2001 Molecular cloning of a cDNA encoding a bovine growth differentiation factor-9 (GDF-9) and expression of GDF-9 in bovine ovarian oocytes and in vitro-produced embryos. Cloning 25 11918837
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2013 Importance of the GDF9 signaling pathway on cumulus cell expansion and oocyte competency in sheep. Theriogenology 24 23764009
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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
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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
2024 The Roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in Folliculogenesis and In Vitro Fertilization. Journal of clinical medicine 22 38999341
2017 Maximum-likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility. Ecology and evolution 22 29177034
2014 Direct evidence on the contribution of a missense mutation in GDF9 to variation in ovulation rate of Finnsheep. PloS one 22 24751660
2013 Essential but differential role of FOXL2wt and FOXL2C134W in GDF-9 stimulation of follistatin transcription in co-operation with Smad3 in the human granulosa cell line COV434. Molecular and cellular endocrinology 22 23523567
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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
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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.) 17 33409876
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2016 Differential expression of GDF-9 and BMP- 15 during follicular development in canine ovaries evaluated by flow cytometry. Animal reproduction science 17 26876149
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