Affinage

BMP15

Bone morphogenetic protein 15 · UniProt O95972

Length
392 aa
Mass
45.1 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMP15 is an oocyte-secreted TGFβ superfamily ligand that functions as a dosage-sensitive regulator of folliculogenesis, cumulus cell differentiation, and female fertility. After furin-dependent cleavage from its proprotein—whose proregion mediates noncovalent association with both its own mature domain and GDF9—BMP15 signals through ALK3/BMPRII to activate SMAD1/5/8, SMAD2/3, and non-SMAD pathways (p38 MAPK, SRC/ERK) in granulosa/cumulus cells, thereby promoting proliferation, glycolysis, cholesterol biosynthesis, FSHR and AMH expression, cumulus expansion (via EGF-like growth factor and HAS2 induction), and suppression of premature luteinization through StAR/progesterone downregulation (PMID:16818886, PMID:24140593, PMID:31079267, PMID:18045843, PMID:18063682). Its biological potency is critically amplified by synergistic heteromeric interaction with GDF9—mediated through BMPRII and SMAD2/3 signaling—and antagonized extracellularly by follistatin (PMID:21911477, PMID:11741284, PMID:18063682). Naturally occurring loss-of-function mutations cause primary ovarian insufficiency in humans and dose-dependent sterility in sheep, with pathogenic mechanisms including impaired proprotein processing, reduced mature-domain bioactivity, and disrupted BMP15–GDF9 synergy (PMID:10888873, PMID:28359091, PMID:31957178).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing BMP15 as an oocyte-essential fertility factor resolved how a single TGFβ ligand could control follicular progression in a dosage-sensitive manner, as heterozygous sheep showed increased ovulation while homozygotes had primary ovarian failure.

    Evidence Genetic mapping and sequencing of two independent sheep pedigrees with naturally occurring BMP15 point mutations (FecXI, FecXH)

    PMID:10888873

    Open questions at the time
    • Downstream signaling pathway in granulosa cells unknown at this point
    • Whether BMP15 acts alone or requires GDF9 cooperation unresolved
    • Human relevance not yet demonstrated
  2. 2001 High

    Identifying follistatin as a direct BMP15 antagonist established that extracellular sequestration regulates BMP15 bioavailability, explaining how granulosa cell proliferation and FSH responsiveness are tuned.

    Evidence Surface plasmon resonance binding and rat granulosa cell bioassays (proliferation, FSHR mRNA, progesterone)

    PMID:11741284

    Open questions at the time
    • Whether follistatin-BMP15 interaction occurs in vivo during folliculogenesis
    • Relative contribution of follistatin versus other antagonists unknown
  3. 2003 High

    Demonstrating that GCNF directly represses BMP15 transcription via DR0 promoter elements revealed how oocyte-intrinsic transcriptional regulation gates BMP15 expression, with GCNF loss leading to BMP15 overexpression and hyperfertility.

    Evidence Oocyte-specific GCNF conditional knockout, ChIP, and reporter assays in mice

    PMID:12912906

    Open questions at the time
    • Other transcription factors activating BMP15 expression not yet identified
    • Whether GCNF regulation is conserved in humans
  4. 2004 High

    Genetic epistasis between BMP15 and GDF9 demonstrated that their synergistic action—not either factor alone—drives cumulus expansion, meiotic resumption, and preimplantation competence, fundamentally reframing oocyte paracrine signaling as a cooperative system.

    Evidence Double mutant Gdf9+/−Bmp15−/− mouse analysis with Has2 mRNA, MAPK activation, cumulus expansion, and fertilization assays

    PMID:15531364

    Open questions at the time
    • Physical nature of BMP15–GDF9 interaction (heterodimer vs. separate ligands) unknown
    • Receptor complex mediating synergy not identified
  5. 2005 High

    Revealing that species-specific proregion sequences dictate furin-dependent proteolytic processing efficiency explained why mouse BMP15 is poorly processed compared to human, establishing the proregion as a critical determinant of mature protein bioavailability.

    Evidence Chimeric domain-swap constructs with furin co-expression; Western blot for mature protein production

    PMID:15809424

    Open questions at the time
    • Identity of the convertase cleaving BMP15 in vivo not confirmed
    • Whether proregion remains associated after cleavage not addressed
  6. 2006 High

    Showing that BMP15 induces cumulus expansion through EGF-like growth factor induction (and downstream COX-2, HAS2, TSG-6, pentraxin 3) defined the molecular cascade linking an oocyte signal to the extracellular matrix remodeling required for ovulation.

    Evidence Recombinant BMP15 treatment of mouse COCs with EGF receptor antagonist blocking and mRNA expression analysis

    PMID:16818886

    Open questions at the time
    • Which specific EGF-like ligand(s) are induced not fully resolved
    • Whether BMP15 alone is sufficient or requires GDF9 for full expansion in vivo
  7. 2007 High

    Defining BMP15's metabolic roles—cooperative promotion of glycolysis (with FGFs) and cholesterol biosynthesis in cumulus cells—established that oocyte paracrine factors direct cumulus cell metabolic programs to supply substrates the oocyte cannot produce itself.

    Evidence Bmp15−/− and double mutant genetics; glycolysis assays; cholesterol synthesis assays; oocytectomy and co-culture rescue

    PMID:17553902 PMID:18045843

    Open questions at the time
    • Direct transcriptional targets mediating metabolic reprogramming incompletely mapped
    • Quantitative contribution of BMP15 vs. GDF9 to each metabolic pathway unclear
  8. 2007 High

    Identifying BMPRII as the essential cooperative receptor for GDF9+BMP15 synergistic signaling on granulosa cells resolved the receptor-level mechanism of their cooperation, as BMPRII decoy uniquely abolished the synergistic proliferative response.

    Evidence Extracellular domain decoy receptor competition in rat granulosa cell thymidine incorporation assays

    PMID:18063682

    Open questions at the time
    • Type I receptor partner(s) for the cooperative complex not defined
    • Whether a BMP15–GDF9 heterodimer or separate ligands signal through BMPRII
  9. 2008 High

    Demonstrating noncovalent proregion–mature domain association and GDF9 co-immunoprecipitation with BMP15 proregion revealed that the proregion scaffolds heteromeric BMP15–GDF9 interactions critical for synergistic bioactivity.

    Evidence Co-immunoprecipitation and neutralizing antibody experiments with recombinant proteins in rat granulosa cell bioassay

    PMID:18633140

    Open questions at the time
    • Stoichiometry and structure of native BMP15–GDF9 complex undetermined
    • Later work (2017) found no stable heterodimers in native oocyte secretions, raising questions about the in vivo form
  10. 2009 High

    Functional characterization of human POI-associated BMP15 mutations (R68W, L148P, R138H) demonstrated that reduced mature protein production and diminished granulosa cell bioactivity underlie disease, directly linking specific molecular defects to ovarian insufficiency.

    Evidence Western blot for protein production and luciferase reporter bioassay in human granulosa cells with mutant and wild-type cotransfection

    PMID:19263482

    Open questions at the time
    • Whether heterozygous mutations cause disease via haploinsufficiency or dominant-negative mechanism debated
    • In vivo follicular phenotype of human carriers not directly observed
  11. 2011 High

    Reconstitution with purified mature domains showed that GDF9–BMP15 synergy operates primarily through SMAD2/3 (not SMAD1/5/8), with species-specific engagement of non-SMAD pathways (ERK/SRC in mouse, NF-κB in sheep), delineating the intracellular signaling architecture of cooperative action.

    Evidence Purified recombinant proteins; granulosa cell thymidine incorporation; SMAD3 reporter; systematic pathway inhibitor panel

    PMID:21474603 PMID:21911477

    Open questions at the time
    • Whether SMAD2/3 activation by GDF9+BMP15 uses a distinct receptor complex from individual ligands
    • Transcriptional targets downstream of cooperative SMAD2/3 activation not mapped
  12. 2013 High

    Dissecting BMP15's individual signaling in human granulosa cells showed it activates ALK3-mediated SMAD1/5/8 phosphorylation to suppress StAR/progesterone (preventing premature luteinization) and downregulate Cx43/gap junction communication, establishing BMP15's role as a brake on granulosa cell differentiation.

    Evidence ALK3 siRNA knockdown, dorsomorphin/DMH-1 inhibition, pSMAD1/5/8 Western blot, StAR mRNA, GJIC assay in human granulosa cell lines and primary cells

    PMID:24140593 PMID:24413384

    Open questions at the time
    • How BMP15-mediated SMAD1/5/8 and cooperative SMAD2/3 signaling are integrated in the same cell
    • In vivo relevance of Cx43 suppression to fertility outcomes not tested
  13. 2016 Medium

    Placing BMP15 downstream of Rac1/STAT3 during fetal follicle assembly showed that STAT3 directly activates BMP15 transcription, and BMP15/GDF9 in turn activate Notch2 via mTORC1 in pregranulosa cells, revealing a signaling cascade for primordial follicle formation.

    Evidence Fetal mouse ovary organ culture with Rac1 inhibitors/overexpression, STAT3 nuclear import assay, recombinant protein rescue

    PMID:27050391

    Open questions at the time
    • STAT3 binding site on BMP15 promoter not mapped by ChIP
    • Whether this pathway operates in human fetal ovary unknown
  14. 2017 High

    Systematic functional analysis of ten POI-associated BMP15 mutations classified three distinct pathogenic mechanisms—impaired processing, reduced bioactivity, and loss of GDF9 synergy—providing a molecular taxonomy for genotype-phenotype correlation.

    Evidence Protein production, granulosa cell reporter, and GDF9 synergy assays for each mutant

    PMID:28359091

    Open questions at the time
    • Whether these mechanisms have distinct clinical outcomes in patients
    • Structural basis of synergy-disrupting mutations not resolved
  15. 2018 High

    Demonstrating that GDF9+BMP15 together induce AMH expression via PI3K/Akt and SMAD2/3, with p300 recruitment and H3K27 acetylation at the AMH promoter, defined the epigenetic mechanism by which oocyte factors regulate this key marker of ovarian reserve.

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

    PMID:30060157

    Open questions at the time
    • Whether AMH induction feeds back to regulate BMP15 signaling
    • Contribution of BMP15 alone vs. GDF9 alone to AMH promoter remodeling not separated
  16. 2019 High

    Identifying dual SMAD1/5/8 and p38 MAPK pathways in BMP15-induced FSHR expression, with HAT-dependent chromatin remodeling and USF1/2 recruitment to the FSHR promoter, explained how BMP15 sensitizes granulosa cells to FSH and promotes estradiol production.

    Evidence LDN193189 and SB203580 inhibitors, HAT activity assay, ChIP for USF1/2 at FSHR promoter in human granulosa cells

    PMID:31079267

    Open questions at the time
    • Whether p38 and SMAD arms converge on the same promoter elements
    • In vivo validation of FSHR chromatin remodeling by BMP15 lacking
  17. 2020 High

    Family studies with homozygous BMP15 null variants showed that complete loss causes POI only in homozygotes (heterozygous mothers are fertile), while the missense R329C disrupts GDF9 colocalization and SMAD activation, clarifying that haploinsufficiency versus dominant-negative interference represents distinct genetic mechanisms.

    Evidence Family sequencing, confocal immunofluorescence for BMP15–GDF9 colocalization, luciferase reporter in COV434 cells

    PMID:31957178

    Open questions at the time
    • Whether dominant-negative mechanism requires incorporation into BMP15–GDF9 heterodimers not proven biochemically
    • Number of families studied is small
  18. 2023 High

    Zebrafish bmp15 CRISPR knockout causing previtellogenic arrest and female-to-male sex reversal—partially rescued by inhibin loss via restored activin/E2 signaling—demonstrated conserved and essential roles for BMP15 in vertebrate sex determination and vitellogenesis through the activin-inhibin axis.

    Evidence CRISPR/Cas9 triple mutant epistasis (bmp15, inha, inhbaa), serum E2/vitellogenin measurement, transcriptomics

    PMID:37713421

    Open questions at the time
    • Whether this sex-reversal mechanism applies to mammals
    • Direct transcriptional targets of BMP15 in zebrafish gonads not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The native molecular form of BMP15–GDF9 cooperative signaling (heterodimer, proregion-scaffolded complex, or separate ligands acting on a shared receptor complex) and the structural basis of their synergistic receptor engagement remain unresolved.
  • No crystal structure of BMP15 or BMP15–GDF9 complex available
  • Contradictory evidence on whether native oocyte-secreted BMP15 exists as dimers
  • Precise type I/type II receptor stoichiometry of the cooperative complex undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1474165 Reproduction 5 R-HSA-1266738 Developmental Biology 4
Partners
ALK3BMPR2FSTGCNFGDF9SMAD1SMAD3
Complex memberships
BMP15–GDF9 heteromeric complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 BMP15 (GDF9B) is an oocyte-specific member of the TGFβ superfamily essential for follicular development beyond the primary stage; naturally occurring germline point mutations in sheep (FecXI, FecXH) cause increased ovulation rate in heterozygotes and primary ovarian failure in homozygotes, establishing a dosage-sensitive role in female fertility. Genetic mapping, sequencing of naturally occurring sheep mutations, phenotypic analysis of heterozygous and homozygous carriers Nature genetics High 10888873
2001 Follistatin binds BMP-15 directly (demonstrated by surface plasmon resonance) and forms an inactive complex with it, thereby inhibiting BMP-15-stimulated granulosa cell proliferation and reversing BMP-15 suppression of FSH receptor mRNA expression and FSH-induced progesterone synthesis. Surface plasmon resonance biosensor binding assay; primary rat granulosa cell bioassays (proliferation, FSH receptor mRNA, progesterone measurement) Biochemical and biophysical research communications High 11741284
2003 GCNF (germ cell nuclear factor) directly represses BMP-15 and GDF-9 expression in oocytes by binding DR0 elements in their gene promoters; oocyte-specific GCNF knockout leads to upregulation of BMP-15 and GDF-9 at diestrus and consequent hyperfertility phenotype (double-oocyte follicles). Oocyte-specific conditional knockout (Cre/loxP), reporter assays, ChIP/molecular binding studies of GCNF to promoter DR0 elements The EMBO journal High 12912906
2004 BMP15 acts synergistically with GDF9 to regulate cumulus cell development and function; double mutant (Gdf9+/−Bmp15−/−) oocyte-cumulus complexes show impaired cumulus expansion (reduced Has2 mRNA), delayed LH-induced meiotic resumption correlated with reduced MAPK activation in cumulus cells, and defects in fertilization and preimplantation embryogenesis. Double mutant mouse genetic analysis, in vitro cumulus expansion assays, mRNA expression (Has2), MAPK activation assays, oocytectomy rescue experiments Developmental biology High 15531364
2005 Post-translational processing of BMP-15 is species-specific: human BMP-15 mature protein is readily produced, but mouse BMP-15 mature protein production is defective due to its proregion; co-expression with furin (a convertase) enables complete processing of chimeric constructs, and the proregion determines processing efficiency. Chimeric construct transfection in cells, furin co-expression, SDS-PAGE/Western blot analysis of mature protein production Proceedings of the National Academy of Sciences of the United States of America High 15809424
2006 BMP-15 induces cumulus expansion in mouse cumulus-oocyte complexes by stimulating EGF-like growth factor expression in cumulus cells and downstream signaling molecules (COX-2, HAS2, TSG-6, pentraxin 3); this activity is abrogated by an EGF receptor antagonist, and the functional mature form of BMP-15 increases markedly just before ovulation in mice. Oocyte culture assays, BMP-15 antibody neutralization, recombinant BMP-15 treatment, EGF receptor antagonist blocking, mRNA expression analysis Proceedings of the National Academy of Sciences of the United States of America High 16818886
2007 Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells; BMP15 alone is insufficient but BMP15 + FGF8 together promote glycolysis and Pfkp/Ldha mRNA expression to the same level as wild-type oocytes; this cooperation is blocked by the FGF receptor inhibitor SU5402. Bmp15−/− and Gdf9+/−Bmp15−/− double mutant mouse genetics; recombinant protein treatment; FGF receptor inhibitor; glycolysis assays; mRNA expression Development (Cambridge, England) High 17553902
2007 BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells; transcripts for cholesterol biosynthetic enzymes are downregulated in Bmp15−/− and Gdf9+/−Bmp15−/− cumulus cells and after oocytectomy; de novo cholesterol synthesis is reduced in these mutant cumulus cells, and co-culture with wild-type oocytes partially restores it. Oocytes are deficient in synthesizing cholesterol and require cumulus cell-derived cholesterol products. Mouse genetic knockouts, oocytectomy, co-culture rescue experiments, mRNA expression, de novo cholesterol synthesis assay Development (Cambridge, England) High 18045843
2007 The cooperative effect of GDF9 and BMP15 on granulosa cell proliferation (thymidine incorporation) is mediated primarily through BMP receptor II (BMPRII); the extracellular domain of BMPRII completely blocks GDF9+BMP15-stimulated thymidine incorporation, whereas other type I or type II receptor extracellular domains do not. Rat granulosa cell thymidine incorporation assay; extracellular domain decoy receptor competition assay for multiple TGFβ receptor types Endocrinology High 18063682
2008 Recombinant mouse BMP15 is secreted as cleaved mature and proregion proteins, as well as uncleaved promature protein. Noncovalent interactions exist between the BMP15 mature and proregion proteins. GDF9 mature protein co-immunoprecipitates with BMP15 proregion, indicating a heteromeric BMP15-GDF9 association. The BMP15 proregion is involved in mediating BMP15/GDF9 cooperative interactions, and immunoneutralization of the proregion disrupts these. Recombinant protein expression, co-immunoprecipitation, Western blot analysis; neutralizing antibody experiments in rat granulosa cell bioassay Biology of reproduction High 18633140
2008 Recombinant human BMP-15 mature protein exists in two forms (P16, 17 kDa): the N-terminal amino acid is pyroglutamic acid; P16 has phosphorylation at Ser6; P17 is O-glycosylated at Thr10; C-terminus is truncated in both. Proteomics/mass spectrometry characterization of recombinant human BMP-15 produced in HEK293 cells; SDS-PAGE Protein science High 18227435
2009 BMP15 mutations associated with primary ovarian insufficiency (R68W, L148P, R138H) reduce mature protein production and have significantly reduced biological activity in a human granulosa cell luciferase reporter assay; cotransfection of defective mutants with equal wild-type BMP15 cDNA (reproducing heterozygous state) does not fully recover wild-type activity, consistent with defective secretion of bioactive dimers. Western blot (mature protein production), novel luciferase-reporter bioassay in human granulosa cell line, cotransfection experiments Human mutation High 19263482
2010 BMP-15 and GDF-9 mutations in women with primary ovarian insufficiency lead to decreased mature protein production due to impaired posttranslational processing of the proprotein, resulting in significantly reduced biological activities in conditioned media bioassays. Transfection of mutant constructs in HEK293F cells, conditioned media bioassay, Western blot for mature protein Molecular and cellular endocrinology High 20547206
2010 Estrogen (17β-estradiol) and oocyte-derived GDF9 and BMP15 cooperate to promote cumulus cell development; oocyte-derived factors (GDF9, with BMP15 augmenting) suppress Nrip1 (nuclear receptor-interacting protein 1) expression in cumulus cells, thereby facilitating estrogen receptor signaling and Has2 expression/cumulus expansion. In vitro culture of preantral and antral COCs ± estradiol ± oocytectomy ± recombinant proteins; mRNA expression; functional expansion assay Molecular endocrinology (Baltimore, Md.) Medium 21047911
2011 The purified mature regions of GDF9 and BMP15 synergistically stimulate granulosa cell DNA synthesis and SMAD3 signaling. This synergistic interaction is specific (neither factor can be replaced by other TGFβ family members), depends on SMAD2/3 pathway (blocked by SB431542), and also requires ERK1/2 and SRC kinase signaling (not NF-κB). Primary murine granulosa cell culture; [³H]-thymidine incorporation; SMAD3-transcriptional reporter; pathway inhibitors (SB431542, MEK/ERK, SRC, NF-κB) Molecular human reproduction High 21911477
2011 Ovine GDF9+BMP15-stimulated granulosa cell thymidine uptake depends on SMAD2/3 and NF-κB pathways (and partially p38-MAPK), while murine GDF9+BMP15 is dependent on SMAD2/3 and ERK-MAPK, but not SMAD1/5/8 for either species. Species-specific non-SMAD pathway divergence correlates with differences in molecular complexes formed. Rat granulosa cell [³H]-thymidine incorporation with pathway-specific inhibitors; Western blot for molecular complexes Reproduction (Cambridge, England) High 21474603
2013 BMP15 suppresses progesterone production in human granulosa cells by down-regulating StAR mRNA and protein via ALK3 (BMPR type I receptor)-mediated SMAD1/5/8 phosphorylation. siRNA knockdown of ALK3 reverses BMP15-induced SMAD1/5/8 phosphorylation and StAR suppression. Immortalized human granulosa cells (SVOG, KGN); siRNA knockdown of ALK3; BMP type I receptor inhibitors (dorsomorphin, DMH-1); Western blot for pSMAD1/5/8; StAR mRNA/protein; progesterone ELISA Molecular endocrinology (Baltimore, Md.) High 24140593
2013 BMP15, but not GDF9, decreases connexin43 (Cx43) mRNA and protein levels and gap junction intercellular communication (GJIC) activity in human granulosa cells via a Smad4-dependent (Smad1/5/8-activating) pathway; BMP type I receptor inhibitor dorsomorphin and Smad4 siRNA knockdown reverse these effects. Human granulosa cell line (SVOG), primary human granulosa-lutein cells; siRNA knockdown of Smad4; dorsomorphin; Cx43 mRNA/protein; GJIC activity assay; Western blot for pSmad1/5/8 Molecular human reproduction High 24413384
2017 Multiple BMP15 mutations associated with primary ovarian insufficiency reduce (1) mature protein production (L148P, F194S, Y235C), (2) biological activity on granulosa cells (~4-fold lower for R138H, A180T, R329H), or (3) synergy with GDF9 (R68W, F194S, N196K), establishing three distinct molecular mechanisms of pathogenicity. Expression assays (protein production), granulosa cell activation reporter assays, GDF9 synergy assays with mutant BMP15 constructs The Journal of clinical endocrinology and metabolism High 28359091
2018 GDF9 and BMP15 together (but not separately) induce AMH expression in granulosa cells via the PI3K/Akt and Smad2/3 pathways, recruiting coactivator p300 to the AMH promoter and promoting H3K27 acetylation; FSH inhibits GDF9+BMP15-induced AMH expression through PKA/SF1-mediated GOTUR1 induction that recruits HDAC2 to deacetylate H3K27ac. Primary mouse granulosa cells and KGN cell line; in vivo serum AMH measurement; ChIP for H3K27ac and p300; Western blot for pSmad2/3, pAkt; pathway inhibitors; Fshβ-null mice Endocrinology High 30060157
2019 BMP15 induces FSHR expression in human granulosa cells through both Smad1/5/8 (blocked by LDN193189) and non-Smad (p38 MAPK) pathways; BMP15 increases histone acetyltransferase (HAT) activity and promotes USF1/2 binding at the FSHR promoter, leading to increased CYP19A1 expression and estradiol production. Immortalized human granulosa cells (HGrC1); LDN193189 (BMP receptor inhibitor); SB203580 (p38 inhibitor); trichostatin A; HAT activity assay; ChIP for USF1/2; FSHR and CYP19A1 mRNA; estradiol measurement Journal of assisted reproduction and genetics High 31079267
2020 Two homozygous BMP15 null variants cause primary ovarian insufficiency only in the homozygous state (mothers who are heterozygous are fertile), disproving haploinsufficiency. The missense variant p.R329C in the mature domain shows impaired colocalization with GDF9 and diminished SMAD pathway activation, indicating that heterozygous missense mutations may cause POI by interfering with cumulin (BMP15-GDF9 heterodimer) activity. Western blot, immunofluorescence/confocal colocalization with GDF9, luciferase reporter assays in COV434 follicular cell line, sequencing of family members Human mutation High 31957178
2017 Major oocyte-secreted forms of BMP15 from ovine and bovine oocytes are the cleaved and uncleaved monomeric forms of the promature proteins, with no evidence of dimeric or heterodimeric forms of mature BMP15, based on Western blotting under non-reducing, reducing, and cross-linking conditions using monoclonal antibodies that neutralize bioactivity. Isolated ovine and bovine oocyte in vitro secretion; Western blot under multiple conditions (non-reducing, reducing, reducing + cross-linking); monoclonal antibody characterization Reproduction (Cambridge, England) Medium 28733348
2013 BMP15 prevents porcine cumulus cell apoptosis through upregulation of CCL2 (MCP-1) and FBN1; siRNA knockdown of CCL2 increases cumulus cell apoptosis (eliminating BMP15 anti-apoptotic effect), while siRNA knockdown of FBN1 promotes proliferation after BMP15 treatment, establishing CCL2 and FBN1 as downstream mediators of BMP15 in cumulus cell survival. Flow cytometry for apoptosis; RNAi (siRNA) knockdown of CCL2 and FBN1; high-throughput sequencing to identify regulated genes; MTT assay; RT-qPCR; Western blot Cellular physiology and biochemistry Medium 23942191
2016 Rac1 in mouse fetal ovary promotes primordial follicle formation by inducing nuclear import of STAT3; nuclear STAT3 directly activates transcription of BMP15 (as well as Jagged1, GDF9, Nobox); BMP15 and GDF9 in turn activate Notch2 translation via mTORC1 in pregranulosa cells, regulating cyst breakdown and follicle assembly. Fetal mouse ovary organ culture; Rac1 inhibitors/overexpression; in vivo inhibitor injection; STAT3 nuclear import assay; rescue with recombinant GDF9, BMP15, Jagged1 Scientific reports Medium 27050391
2018 BMP15 regulates AMH expression in goat granulosa cells via the p38 MAPK signaling pathway; p38 MAPK inhibitor or siRNA knockdown reduces BMP15-induced AMH mRNA expression and AMH secretion; SOX9 (a transcription factor for AMH) is also regulated by BMP15 through p38 MAPK. Goat granulosa cell primary culture; p38 MAPK inhibitor and siRNA knockdown; RT-PCR for AMH and SOX9; ELISA for AMH protein Theriogenology Medium 29885643
2023 In zebrafish, bmp15 deficiency (CRISPR/Cas9 knockout) arrests follicle development at the previtellogenic stage and causes female-to-male sex reversal; this is partially rescued by loss of inhibin (inha−/−) through restoration of activin βAa (inhbaa) expression and estradiol (E2) production, demonstrating that BMP15 acts together with the activin-inhibin system to control E2 production, vitellogenin biosynthesis, and oocyte yolk accumulation. CRISPR/Cas9 knockout of bmp15, inha, inhbaa in zebrafish; histology; transcriptome analysis; serum E2 and vitellogenin measurement; E2 and aromatase inhibitor treatment PLoS genetics High 37713421

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nature genetics 712 10888873
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
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 283 15531364
2011 Integral role of GDF-9 and BMP-15 in ovarian function. Molecular reproduction and development 263 21226076
2007 Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development (Cambridge, England) 250 17553902
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
2006 Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European journal of endocrinology 202 16645022
2006 Missense mutations in the BMP15 gene are associated with ovarian failure. Human genetics 177 16508750
2006 Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. The Journal of clinical endocrinology and metabolism 160 16464940
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
2006 A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse. Proceedings of the National Academy of Sciences of the United States of America 130 16818886
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
2006 Mutations in BMPR-IB and BMP-15 genes are associated with litter size in Small Tailed Han sheep (Ovis aries). Journal of animal science 114 17040942
2001 Follistatin inhibits the function of the oocyte-derived factor BMP-15. Biochemical and biophysical research communications 106 11741284
2018 Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function. Vitamins and hormones 105 29544636
2009 BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Human mutation 104 19263482
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
2005 Posttranslational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota. Proceedings of the National Academy of Sciences of the United States of America 95 15809424
2005 Molecular biology and physiological role of the oocyte factor, BMP-15. Molecular and cellular endocrinology 92 15836954
2013 Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep. PLoS genetics 86 23637641
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
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
2013 BMP15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells. Molecular endocrinology (Baltimore, Md.) 75 24140593
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
2010 Variants of the BMP15 gene in a cohort of patients with premature ovarian failure. Human reproduction (Oxford, England) 69 20364024
2008 The proregion of mouse BMP15 regulates the cooperative interactions of BMP15 and GDF9. Biology of reproduction 68 18633140
2006 Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. Fertility and sterility 65 17027369
2008 A 17 bp deletion in the Bone Morphogenetic Protein 15 (BMP15) gene is associated to increased prolificacy in the Rasa Aragonesa sheep breed. Animal reproduction science 63 18282670
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
2002 Bmp15 mutations and ovarian function. Molecular and cellular endocrinology 60 12044914
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2009 Polymorphism of BMPR1B, BMP15 and GDF9 fecundity genes in prolific Garole sheep. Tropical animal health and production 53 20020203
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2006 Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS). Pharmacogenetics and genomics 51 16788381
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
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2013 BMP15 prevents cumulus cell apoptosis through CCL2 and FBN1 in porcine ovaries. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 42 23942191
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2015 Polymorphisms of the Ovine BMPR-IB, BMP-15 and FSHR and Their Associations with Litter Size in Two Chinese Indigenous Sheep Breeds. International journal of molecular sciences 35 25993301
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
2007 BMP15 mutations in XX gonadal dysgenesis and premature ovarian failure. American journal of obstetrics and gynecology 35 17826728
2016 Genotyping of Novel SNPs in BMPR1B, BMP15, and GDF9 Genes for Association with Prolificacy in Seven Indian Goat Breeds. Animal biotechnology 34 27135147
2015 Effect of Anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP-15) on steroidogenesis in primary-cultured human luteinizing granulosa cells through Smad5 signalling. Journal of assisted reproduction and genetics 34 26003656
2011 A single nucleotide polymorphism in BMP15 is associated with high response to ovarian stimulation. Reproductive biomedicine online 34 21565556
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 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
2009 Regulation of membrane progestin receptors in the zebrafish ovary by gonadotropin, activin, TGF-beta and BMP-15. Molecular and cellular endocrinology 33 19773085
2008 Characterization of the post-translational modification of recombinant human BMP-15 mature protein. Protein science : a publication of the Protein Society 33 18227435
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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
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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
2015 Quantitative expression patterns of GDF9 and BMP15 genes in sheep ovarian follicles grown in vivo or cultured in vitro. Theriogenology 30 26474685
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2019 Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells. Journal of assisted reproduction and genetics 29 31079267
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
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2017 FecX Bar a Novel BMP15 mutation responsible for prolificacy and female sterility in Tunisian Barbarine Sheep. BMC genetics 28 28506298
2012 BMP15 gene is activated during human amniotic fluid stem cell differentiation into oocyte-like cells. DNA and cell biology 28 22356426
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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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2013 Differential ovarian morphometry and follicular expression of BMP15, GDF9 and BMPR1B influence the prolificacy in goat. Reproduction in domestic animals = Zuchthygiene 25 23581245
2013 Accelerated growth of bovine preantral follicles in vitro after stimulation with both FSH and BMP-15 is accompanied by ultrastructural changes and increased atresia. Theriogenology 24 23582608
2019 Serum Concentrations of Oocyte-Secreted Factors BMP15 and GDF9 During IVF and in Women With Reproductive Pathologies. Endocrinology 23 31211369
2011 Active immunization against the proregions of GDF9 or BMP15 alters ovulation rate and litter size in mice. Reproduction (Cambridge, England) 23 22106408
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2007 Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome. Fertility and sterility 22 17905236
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2016 Temporal expression of GDF-9 and BMP-15 mRNAs in canine ovarian follicles. Theriogenology 18 27341772
2007 Sequence variants in exons of the BMP-15 gene in Chinese patients with premature ovarian failure. Acta obstetricia et gynecologica Scandinavica 18 17464588
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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
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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 16 23724366
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