Affinage

BMP15

Bone morphogenetic protein 15 · UniProt O95972

Length
392 aa
Mass
45.1 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMP15 is an oocyte-secreted TGFβ-superfamily growth factor that acts in a dosage-sensitive paracrine manner to drive ovarian follicular development beyond the primary stage, with naturally occurring sheep mutations establishing that heterozygous loss raises ovulation rate while homozygous loss causes primary ovarian failure (PMID:10888873). Its central mechanistic feature is cooperative signaling with GDF9: the two factors form heteromeric assemblies, and purified mature regions act synergistically on granulosa cells in a manner that cannot be substituted by other superfamily members (PMID:12446716, PMID:18633140, PMID:21911477). This cooperative signal proceeds through BMPRII together with ALK4/5/7-type (SMAD2/3) receptors and additionally requires ERK1/2 and SRC kinase activity, while BMP15 acting alone engages ALK3-SMAD1/5/8 signaling (PMID:18063682, PMID:21911477, PMID:21474603, PMID:24140593). Through these pathways BMP15 promotes granulosa cell proliferation, restrains premature FSH-driven differentiation by suppressing FSH receptor signaling and StAR-dependent progesterone synthesis, and is antagonized by direct follistatin binding (PMID:11741284, PMID:24140593). BMP15/GDF9 cooperation governs cumulus cell biology — driving expansion, glycolysis (with FGF8), cholesterol biosynthesis, and AMH expression via p300/H3K27ac recruitment — while BMP15 alone downregulates connexin43 and gap-junction communication (PMID:17553902, PMID:18045843, PMID:24413384, PMID:30060157). Bioactivity is gated by proprotein processing: human BMP15 is efficiently cleaved whereas mouse processing is defective owing to its proregion, and POI-associated mutations act by impairing mature protein production, receptor activation, or GDF9 synergy, often dominant-negatively (PMID:15809424, PMID:15136966, PMID:19263482, PMID:27050391, PMID:31957178). BMP15 expression is itself controlled by transcriptional regulators including GCNF, STAT3, and PITX1 (PMID:12912906, PMID:27050391, PMID:25246117). Heterozygous and homozygous BMP15 mutations cause primary ovarian insufficiency, with homozygous null variants demonstrating that human ovarian function depends on BMP15's GDF9-dependent activity (PMID:10888873, PMID:15136966, PMID:31957178).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Established that BMP15 is required for follicular development past the primary stage and acts in a dosage-sensitive fashion, defining its core reproductive function.

    Evidence Genetic mapping and phenotyping of two independent germline point mutations in sheep lines (FecXI, FecXH)

    PMID:10888873

    Open questions at the time
    • Did not resolve the receptor or signaling pathway
    • Mechanism of dosage sensitivity at the protein level not addressed
  2. 2001 High

    Identified follistatin as a direct extracellular antagonist of BMP15, showing its bioactivities are subject to negative regulation.

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

    PMID:11741284

    Open questions at the time
    • Stoichiometry and structural basis of the BMP15-follistatin complex not defined
    • In vivo relevance of antagonism untested
  3. 2002 High

    Showed BMP15 and GDF9 form non-covalent homo- and heterodimers and that co-expression alters processing, providing the molecular explanation for the Inverdale infertility mutation.

    Evidence Recombinant stable cell lines, co-immunoprecipitation, and western analysis of proprotein processing/secretion including the Inverdale mutant

    PMID:12446716

    Open questions at the time
    • Did not identify the signaling receptor complex used by the heterodimer
    • Single-lab recombinant system
  4. 2003 High

    Identified GCNF as a direct transcriptional repressor of BMP15, establishing upstream control of its expression.

    Evidence Oocyte-specific GCNF knockout mice and DR0-element promoter reporter assays

    PMID:12912906

    Open questions at the time
    • Other transcriptional regulators not addressed
    • Did not link expression dosage to follicle phenotype quantitatively
  5. 2004 High

    Genetic epistasis demonstrated BMP15 and GDF9 act synergistically in cumulus development, and that human vs mouse processing differences explain species ovulation differences.

    Evidence Gdf9+/-;Bmp15-/- double-mutant mice with cumulus/MAPK/fertilization readouts; chimeric human/mouse construct processing with furin co-expression; dominant-negative human Y235C granulosa cell assays

    PMID:15136966 PMID:15531364 PMID:15809424

    Open questions at the time
    • Precise receptor identity of the synergistic signal not yet defined
    • Y235C study limited mechanistic depth
  6. 2007 High

    Defined BMP15's metabolic role in cumulus cells, showing cooperation with FGF8 for glycolysis and with GDF9 for cholesterol biosynthesis, and mapped the synergy to BMPRII.

    Evidence Mutant mice, oocytectomy, recombinant protein rescue, FGFR/pathway inhibitors, transcript and metabolite measurements, soluble receptor ectodomain competition

    PMID:17553902 PMID:18045843 PMID:18063682

    Open questions at the time
    • Downstream transcription factors for metabolic genes not identified
    • BMPRII competition assay used a single functional readout
  7. 2008 High

    Resolved that secreted BMP15 forms include proregion-associated heteromers with GDF9 and that cooperative signaling uses BMPR2 with ALK4/5/7-type receptors.

    Evidence Recombinant co-expression, reciprocal co-IP, granulosa cell bioassay, receptor pathway inhibition, and proregion antibody neutralization

    PMID:18633140

    Open questions at the time
    • Native oocyte forms not yet characterized
    • Proregion contribution to signaling left ambiguous
  8. 2011 High

    Dissected the cooperative signaling pathway, showing synergy on granulosa cells requires SMAD2/3, ERK1/2 and SRC (not SMAD1/5/8) and is proregion-independent for mature proteins.

    Evidence Purified mature proteins, thymidine and SMAD3 reporter assays, and pathway-specific inhibitors in murine and rat granulosa cells

    PMID:21474603 PMID:21911477

    Open questions at the time
    • Species differences in NF-κB vs ERK dependence not reconciled
    • Receptor complex composition inferred pharmacologically
  9. 2014 High

    Showed BMP15 acting alone uses ALK3-SMAD1/5/8 signaling to suppress steroidogenesis (StAR/progesterone) and gap-junction communication (Cx43), distinct from its GDF9-cooperative effects.

    Evidence Human granulosa cell lines with BMP type I receptor inhibitors, ALK3 and Smad4 siRNA, and GJIC/StAR/progesterone readouts; PITX1 promoter regulation by reporter assay

    PMID:24140593 PMID:24413384 PMID:25246117

    Open questions at the time
    • Reconciliation of solo ALK3-SMAD1/5/8 vs cooperative SMAD2/3 signaling not fully integrated
    • PITX1 site only bioinformatically predicted
  10. 2017 High

    Connected upstream transcriptional control (Rac1-STAT3) to BMP15 expression and systematically classified POI mutations by mechanism, identifying GDF9 synergy as the most functionally relevant pathway.

    Evidence Fetal ovary organ culture with Rac1-STAT3 co-IP and rescue; site-directed mutagenesis of POI variants with protein production, receptor activation, and synergy assays; native ovine/bovine oocyte secretome western blots

    PMID:27050391 PMID:28359091 PMID:28733348

    Open questions at the time
    • Direct STAT3 binding to the BMP15 promoter not fully documented
    • Native oocyte forms appear monomeric, contrasting recombinant heterodimer models
  11. 2018 High

    Established BMP15/GDF9 control of AMH expression via convergent PI3K/Akt and SMAD2/3 signaling that recruits p300 for H3K27 acetylation, antagonized by FSH.

    Evidence Primary mouse and KGN human granulosa cells with pathway inhibitors, p300/H3K27ac ChIP, HDAC2 co-IP, and Fshβ-null mice; goat granulosa p38/SOX9 analysis

    PMID:29885643 PMID:30060157

    Open questions at the time
    • Species-specific use of p38/SOX9 vs PI3K/SMAD not unified
    • In vivo AMH regulation by BMP15 not directly shown
  12. 2019 High

    Showed BMP15 induces FSHR expression and estradiol output through combined SMAD1/5/8 and p38 MAPK signaling with USF1/2 promoter recruitment, adding a positive arm to FSH-responsiveness.

    Evidence HGrC1 human granulosa cells with ALK2/3 and p38 inhibitors, phospho-westerns, HAT activity, USF1/2 ChIP, and estradiol ELISA

    PMID:31079267

    Open questions at the time
    • Apparent contrast with earlier reports of FSHR suppression not reconciled
    • Single immortalized cell line
  13. 2020 High

    Demonstrated that human BMP15 loss-of-function causes POI only when homozygous, ruling out haploinsufficiency and confirming dependence on GDF9 interaction.

    Evidence Whole-exome sequencing of POI families with confocal GDF9 colocalization and SMAD reporter assays of the R329C variant; functional ovine regulatory variant (FecXN) by promoter reporter

    PMID:31957178 PMID:32636872

    Open questions at the time
    • Reconciliation with earlier heterozygous dominant-negative POI reports incomplete
    • Structural basis of GDF9 colocalization not resolved
  14. 2023 High

    Placed BMP15 in an integrated reproductive endocrine circuit, showing it controls estradiol production and vitellogenesis and prevents sex reversal via the activin-inhibin system.

    Evidence CRISPR/Cas9 bmp15/inha/inhbaa single, double and triple mutant zebrafish with hormone rescue, aromatase inhibition, and transcriptomics

    PMID:37713421

    Open questions at the time
    • Direct molecular link between Bmp15 and activin-inhibin signaling not defined
    • Mammalian relevance of the E2/Vtg axis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis and native oligomeric state of bioactive BMP15-GDF9 (cumulin) assemblies and how their receptor complex switches between solo and cooperative signaling modes remain unresolved.
  • No experimental structure of the receptor-bound heterodimer
  • Discrepancy between recombinant heterodimer and monomeric native oocyte forms unresolved
  • Quantitative receptor stoichiometry in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3
Partners
ALK3BMPR2FGF8FSTGDF9
Complex memberships
BMP15/GDF9 heterodimer (cumulin)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 BMP15 (GDF9B) is essential for ovarian follicular development beyond the primary stage; independent germline point mutations in sheep (FecXI and FecXH) establish that BMP15 acts in a dosage-sensitive manner, causing increased ovulation rate in heterozygotes and primary ovarian failure (arrest beyond primary follicle stage) in homozygotes. Genetic mapping, germline point mutation identification, sheep phenotype analysis (follicular histology, ovulation rate) Nature genetics High 10888873
2001 Follistatin directly binds BMP15 (demonstrated by surface plasmon resonance) and inhibits BMP15 bioactivities: it attenuates BMP15-stimulated granulosa cell proliferation and reverses BMP15-mediated suppression of FSH receptor mRNA expression, thereby restoring FSH-induced progesterone synthesis. Surface plasmon resonance biosensor (direct binding), primary rat granulosa cell bioassays (proliferation, FSH receptor mRNA, progesterone synthesis) Biochemical and biophysical research communications High 11741284
2002 BMP15 and GDF9 form non-covalent homodimers when expressed individually; when co-expressed they produce BMP15/GDF9 heterodimers. Co-expression markedly impairs proteolytic processing (cleavage) of both proproteins compared to singly expressed proteins. The Inverdale mutant BMP15 (InvBMP-15) forms non-covalent dimers but with significantly lower processing efficiency; when co-expressed with GDF9, processing and secretion of InvBMP-15 is abolished and GDF9 processing is also severely impaired, explaining the infertility mechanism in homozygous Inverdale ewes. Stable cell lines expressing recombinant BMP15, GDF9, or both; co-immunoprecipitation; western blot analysis of proprotein processing and secretion The Journal of biological chemistry High 12446716
2003 GCNF (germ cell nuclear factor) directly represses BMP15 (and GDF9) gene expression by binding to DR0 elements within the BMP15 and GDF9 gene promoters. Oocyte-specific GCNF knockout leads to up-regulation of BMP15 and GDF9 in oocytes at diestrus, causing aberrant double-oocyte follicles and reproductive defects. Oocyte-specific Cre/loxP GCNF knockout mice; reporter assays (GCNF binding to DR0 elements in BMP15 promoter); ovarian histology The EMBO journal High 12912906
2004 BMP15 and GDF9 act synergistically and are both required for normal cumulus cell development and function: Gdf9+/-;Bmp15-/- double-mutant mice show impaired cumulus expansion, reduced HAS2 mRNA expression, delayed LH-induced meiotic resumption correlated with reduced MAPK activation in cumulus cells, and defective fertilization and preimplantation embryogenesis. The defects in oocyte function are mediated indirectly through granulosa cells (oocyte-granulosa regulatory loop). Gdf9+/-;Bmp15-/- double-mutant mouse model; cumulus expansion assay; HAS2 mRNA expression; in vivo and in vitro oocyte maturation; MAPK activation assay; fertilization and embryo development assessment Developmental biology High 15531364
2004 Human BMP15 undergoes efficient post-translational processing to yield a mature protein, whereas mouse BMP15 mature protein production is defective in vitro. Chimeric construct analysis demonstrated that the mouse BMP15 proregion is responsible for the processing defect. Furin co-expression enables cleavage of chimeric constructs, but no mouse mature protein is secreted unless associated with the human proregion, suggesting species-specific differences in BMP15 processing underlie differences in ovulation quota. Transfected cell lines expressing chimeric human/mouse BMP15 constructs; furin co-expression; western blot analysis of mature protein secretion Proceedings of the National Academy of Sciences of the United States of America High 15809424
2004 In primary ovarian failure linked to BMP15 mutation Y235C (heterozygous, inherited from father), the mutant BMP15 protein is processed abnormally, exhibits reduced granulosa cell growth stimulation, and antagonizes wild-type BMP15 activity in granulosa cell proliferation assays, establishing a dominant-negative mechanism. Mutation identification by sequencing; functional assays on primary granulosa cells using mutant vs. wild-type BMP15; protein processing analysis American journal of human genetics Medium 15136966
2007 Oocyte-derived BMP15 and FGFs (specifically FGF8) cooperate to promote glycolysis and expression of glycolytic enzyme mRNAs (PFKP, LDHA) in cumulus cells. Neither BMP15, GDF9, nor FGF8 alone is sufficient; BMP15 + FGF8 together recapitulate the oocyte effect. GDF9 + FGF8 or BMP15 + GDF9 combinations are insufficient. FGF receptor kinase inhibition blocks the oocyte paracrine effect. Bmp15-/- and Gdf9+/-;Bmp15-/- mutant mice; oocytectomy; recombinant BMP15, GDF9, FGF8 treatment of cumulus cells; glycolysis measurement; qRT-PCR; FGF receptor inhibitor (SU5402) Development (Cambridge, England) High 17553902
2007 Oocyte-derived BMP15 and GDF9 regulate cumulus cell cholesterol biosynthesis: Bmp15-/- and Bmp15-/-;Gdf9+/- cumulus cells show downregulated transcripts for cholesterol biosynthesis enzymes (Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol, Ebp) and reduced de novo cholesterol synthesis. Oocytes require cumulus cells for cholesterol as they cannot synthesize it themselves. Co-culture with wild-type oocytes partially restores cholesterol synthesis in mutant cumulus cells. Bmp15-/- and Gdf9+/-;Bmp15-/- mutant mice; oocytectomy; de novo cholesterol synthesis measurement; transcript analysis by microarray/RT-PCR; co-culture rescue experiments Development (Cambridge, England) High 18045843
2008 Recombinant mouse BMP15 is secreted as both cleaved (mature + proregion) and uncleaved (promature) forms with non-covalent interactions between mature and proregion proteins. GDF9 mature protein co-immunoprecipitates with the BMP15 proregion, indicating a heteromeric interaction. Mouse GDF9 exists mainly as a dimer of mature protein; BMP15 in combination with GDF9 forms multimers involving the proregion. BMP15 acts cooperatively with GDF9 through BMPR2 and ACVR1B/TGFBR1/ACVR1C receptor-mediated pathways. Immunoneutralization with BMP15 proregion antibodies inhibits BMP15/GDF9 cooperative interactions. Recombinant protein co-expression; co-immunoprecipitation; western blot; rat granulosa cell [3H]-thymidine bioassay; receptor pathway inhibition; immunoneutralization with specific antibodies Biology of reproduction High 18633140
2007 The cooperative effect of GDF9 and BMP15 on granulosa cell [3H]-thymidine incorporation is mediated primarily through BMP receptor II (BMPRII): the extracellular domain of BMPRII completely blocks GDF9+BMP15-stimulated thymidine incorporation, whereas extracellular domains of other type I or type II TGFβ receptors do not. Rat granulosa cell [3H]-thymidine incorporation assay; competition with soluble extracellular domains of type I and II TGFβ/BMP receptors Endocrinology Medium 18063682
2009 Heterozygous BMP15 mutations associated with early-onset primary ovarian insufficiency (R68W, L148P, R138H) cause reduced mature protein production and significantly reduced biological activity in a luciferase reporter assay in human granulosa cells. Co-transfection of defective mutants with equal amounts of wild-type BMP15 (reproducing heterozygous state) does not fully restore wild-type activity, indicating a partial dominant-negative effect. Site-directed mutagenesis; western blot for protein secretion; novel luciferase reporter assay in human granulosa cell (GC) line; co-transfection experiments Human mutation High 19263482
2010 Estrogen (17β-estradiol) cooperates with oocyte-derived GDF9 and BMP15 to promote cumulus cell competence for expansion: oocytes or recombinant GDF9 (augmented by BMP15) are required for E2 to maintain HAS2 mRNA levels and cumulus expansion competence. One mechanism involves GDF9/BMP15 suppression of Nrip1 (nuclear receptor-interacting protein 1, an E2R inhibitor) in cumulus cells. In vitro culture of preantral granulosa cell-oocyte complexes; oocytectomy; recombinant GDF9/BMP15 treatment; HAS2 mRNA quantification; Nrip1 mRNA measurement; E2 supplementation experiments Molecular endocrinology (Baltimore, Md.) Medium 21047911
2011 Purified mature regions of GDF9 and BMP15 exhibit specific synergistic interactions on granulosa cell DNA synthesis (thymidine incorporation) and SMAD3 signaling that cannot be replaced by analogous TGFβ superfamily members. This synergistic signalling requires SMAD2/3, ERK1/2, and SRC kinase pathways (but not NF-κB), and does not depend on the presence of the proregion. Primary murine granulosa cell cultures; [3H]-thymidine incorporation; transcriptional reporter assays (SMAD3); pathway inhibitors (SB431542 for SMAD2/3, MEK inhibitor for ERK1/2, SRC kinase inhibitor); recombinant purified mature proteins Molecular human reproduction High 21911477
2011 GDF9+BMP15-stimulated [3H]-thymidine uptake in rat granulosa cells is dependent on SMAD2/3 and NF-κB pathways (ovine) or SMAD2/3 and ERK-MAPK pathways (murine), but NOT the SMAD1/5/8 pathway for either species, indicating BMP15/GDF9 cooperative signaling proceeds through ALK4/5/7-type receptors rather than classic BMP receptors. Rat granulosa cell [3H]-thymidine incorporation assay; signaling pathway inhibitors (SMAD2/3, SMAD1/5/8, NF-κB, p38-MAPK, ERK-MAPK, JNK inhibitors); western blot of molecular complexes Reproduction (Cambridge, England) Medium 21474603
2013 BMP15 (but not GDF9) down-regulates steroidogenic acute regulatory protein (StAR) mRNA and protein levels and decreases progesterone production in human granulosa cells via ALK3-mediated SMAD1/5/8 phosphorylation. Knockdown of ALK3 by siRNA reverses BMP15's effects on both SMAD1/5/8 phosphorylation and StAR expression. Immortalized (SVOG) and tumor (KGN) human granulosa cells; BMP15/GDF9 treatment; BMP type I receptor inhibitors (dorsomorphin, DMH-1); ALK3 siRNA knockdown; western blot (p-SMAD1/5/8); progesterone ELISA; StAR RT-PCR Molecular endocrinology (Baltimore, Md.) High 24140593
2014 BMP15 (but not GDF9) down-regulates connexin43 (Cx43) mRNA and protein levels and decreases gap junction intercellular communication (GJIC) activity in human granulosa cells via a Smad-dependent pathway requiring Smad4. Dorsomorphin (BMP type I receptor inhibitor) and Smad4 siRNA knockdown both reverse BMP15's suppressive effects on Cx43 and GJIC. SVOG immortalized human granulosa cells and primary human granulosa-lutein cells; BMP15/GDF9 treatment; dorsomorphin inhibition; Smad4 siRNA knockdown; Cx43 RT-PCR and western blot; GJIC activity assay Molecular human reproduction High 24413384
2016 Rac1 induces nuclear import of STAT3 through direct physical binding, and nuclear STAT3 directly activates transcription of BMP15 (as well as GDF9, Jagged1, and Nobox) in mouse oocytes during primordial follicle formation. GDF9 and BMP15 subsequently regulate Notch2 translation via mTORC1 activation in pregranulosa cells. Fetal mouse ovary organ culture; Rac1 inhibition and overexpression; in vivo inhibitor injection (multi-oocyte follicles phenotype); Rac1-STAT3 co-immunoprecipitation; transcriptional analysis of BMP15/GDF9 promoters; mTORC1 pathway analysis; rescue with exogenous GDF9/BMP15 Scientific reports Medium 27050391
2017 BMP15 mutations associated with primary ovarian insufficiency (POI) reduce biological activity through three distinct mechanisms: (1) reduced mature protein production (L148P, F194S, Y235C); (2) reduced receptor activation (~4-fold lower activity: R138H, A180T, R329H); or (3) reduced ability to synergize with GDF9 (R68W, F194S, N196K). The synergy with GDF9 is the most functionally relevant mechanism in human ovarian physiology. Site-directed mutagenesis; western blot for protein production; granulosa cell activation assays; GDF9 synergy reporter assays; sequencing of POI patients The Journal of clinical endocrinology and metabolism High 28359091
2018 GDF9 + BMP15 together (but not individually) significantly induce AMH expression in mouse and human granulosa cells via PI3K/Akt and Smad2/3 pathways that synergistically recruit coactivator p300 to the AMH promoter, promoting H3K27 acetylation. FSH inhibits this GDF9+BMP15-induced AMH expression through PKA/SF1-mediated induction of GIOT-1 transcriptional repressor, which recruits HDAC2 to deacetylate H3K27ac. Primary mouse granulosa cells and KGN human GC line; recombinant GDF9+BMP15 treatment; PI3K and Smad inhibitors; p300 ChIP; H3K27ac ChIP; FSH treatment; PKA inhibition; HDAC2 co-immunoprecipitation; Fshβ-null mice Endocrinology High 30060157
2018 BMP15 regulates AMH expression in goat granulosa cells via the p38 MAPK signaling pathway involving the SOX9 transcription factor: BMP15 treatment up-regulates AMH mRNA and protein, and p38 MAPK inhibition (pharmacological inhibitor or siRNA) decreases BMP15-induced AMH and SOX9 expression. Primary goat granulosa cells; BMP15 treatment; p38 MAPK inhibitor and siRNA; RT-PCR; ELISA for AMH Theriogenology Medium 29885643
2019 BMP15 induces FSH receptor (FSHR) expression in human granulosa cells through both Smad1/5/8 and non-Smad (p38 MAPK) pathways: BMP15 increases phosphorylation of Smad1/5/8 and p38 MAPK, increases histone acetyltransferase (HAT) activity, promotes USF1/2 transcription factor binding at the FSHR promoter, and increases CYP19A1 expression and estradiol production. LDN193189 (ALK2/3 inhibitor) suppresses all these effects. Immortalized human granulosa (HGrC1) cells; BMP15 treatment; LDN193189 and SB203580 inhibitors; western blot (p-Smad1/5/8, p-p38 MAPK, p-USF1); HAT activity assay; ChIP for USF1/2 binding; RT-PCR; estradiol ELISA Journal of assisted reproduction and genetics High 31079267
2020 BMP15 null mutations cause POI only in the homozygous state (two homozygous null variants in girls with POI and primary amenorrhea; heterozygous mothers had physiological menopause), ruling out haploinsufficiency. The mature-domain variant p.R329C impairs colocalization with GDF9 at confocal imaging and diminishes SMAD pathway activation in reporter assays, indicating that BMP15 function in the human ovary depends on its interaction (as cumulin heterodimer) with GDF9. Whole-exome/gene sequencing; western blot; immunofluorescence/confocal colocalization with GDF9; luciferase reporter assays (SMAD pathway) in COV434 follicular cell line Human mutation High 31957178
2013 BMP15 prevents cumulus cell apoptosis in porcine ovaries through upregulation of CCL2 (MCP-1) and downregulation of FBN1: siRNA knockdown of CCL2 increases apoptosis and decreases proliferation of cumulus cells treated with BMP15, while FBN1 knockdown increases proliferation and decreases apoptosis, identifying CCL2 and FBN1 as downstream effectors of BMP15 anti-apoptotic action. Porcine cumulus cells; flow cytometry (apoptosis); high-throughput sequencing (gene screening); siRNA knockdown of CCL2 and FBN1; MTT assay; qRT-PCR; western blot Cellular physiology and biochemistry Medium 23942191
2023 In zebrafish, Bmp15 acts together with the activin-inhibin system to control estradiol (E2) production from ovarian follicles, vitellogenin (Vtg) biosynthesis in the liver, and Vtg uptake by developing oocytes. Loss of bmp15 arrests follicle development at previtellogenic stage and causes female-to-male sex reversal. This arrest is partially rescued by loss of inhibin (inha), acting through increased activin (inhbaa)-driven E2 production; loss of inhbaa in the triple mutant abolishes rescue. E2 treatment rescues bmp15-/- follicle arrest. CRISPR/Cas9 bmp15, inha, inhbaa knockout zebrafish; genetic epistasis (double and triple mutants); transcriptome analysis; E2 and Vtg serum measurements; fadrozole (aromatase inhibitor) treatment; ovarian histology PLoS genetics High 37713421
2020 A single nucleotide variant upstream of the BMP15 gene (FecXN, OARX:50977717T>A) is functionally shown to decrease BMP15 promoter activity in luciferase reporter assays, establishing that regulatory (non-coding) mutations reducing BMP15 expression can increase ovulation rate (by ~0.20 lamb/lambing in heterozygotes) without causing infertility in homozygotes. GWAS with ovine 50k SNP chip; whole genome sequencing; luciferase reporter assay for BMP15 promoter activity Frontiers in genetics Medium 32636872
2017 The molecular forms of BMP15 secreted by isolated ovine and bovine oocytes are primarily cleaved and uncleaved monomeric forms of the promature protein; no dimeric or heterodimeric forms of mature BMP15 were detected by western blot under non-reducing, reducing, and reducing+cross-linking conditions. In silico modeling suggests monomeric BMP15 may interact with type II and type I cell-surface receptors to initiate synergistic actions. Isolated ovine and bovine oocytes in vitro; western blot with specific monoclonal antibodies under non-reducing/reducing/reducing+cross-linking conditions; recombinant variants (S356C cysteine mutant, human BMP15:GDF9 heterodimer) as reference standards; in silico modeling Reproduction (Cambridge, England) Medium 28733348
2014 BMP15 c.-9C>G promoter variant modifies a PITX1 transcription factor binding site; PITX1 and BMP15 co-express in human and mouse ovarian tissue, PITX1 transactivates both BMP15 promoter versions, and the -9G allele is associated with increased BMP15 transcription in luciferase reporter assays, identifying PITX1 as a transcriptional regulator of BMP15. Bioinformatics identification of PITX1 binding site; RT-PCR for co-expression in ovarian tissue; luciferase reporter assays with -9C and -9G promoter versions Reproductive biomedicine online Medium 25246117

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
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
2004 Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. American journal of human genetics 349 15136966
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
2007 Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development (Cambridge, England) 252 17553902
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 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
2002 Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9. Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. The Journal of biological chemistry 119 12446716
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
2001 Follistatin inhibits the function of the oocyte-derived factor BMP-15. Biochemical and biophysical research communications 106 11741284
2009 BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Human mutation 105 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 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
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
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
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) 70 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 61 24413384
2002 Bmp15 mutations and ovarian function. Molecular and cellular endocrinology 61 12044914
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
2007 The cooperative effect of growth and differentiation factor-9 and bone morphogenetic protein (BMP)-15 on granulosa cell function is modulated primarily through BMP receptor II. Endocrinology 51 18063682
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
2017 BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. The Journal of clinical endocrinology and metabolism 48 28359091
2013 Anti-Müllerian hormone concentration in sheep and its dependence of age and independence of BMP15 genotype: an endocrine predictor to select the best donors for embryo biotechnologies. Theriogenology 44 24268018
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 42 27050391
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
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
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
2007 BMP15 mutations in XX gonadal dysgenesis and premature ovarian failure. American journal of obstetrics and gynecology 35 17826728
2017 BMP15 and GDF9 Gene Mutations in Premature Ovarian Failure. Journal of reproduction & infertility 34 28377898
2011 A single nucleotide polymorphism in BMP15 is associated with high response to ovarian stimulation. Reproductive biomedicine online 34 21565556
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
2009 Regulation of membrane progestin receptors in the zebrafish ovary by gonadotropin, activin, TGF-beta and BMP-15. Molecular and cellular endocrinology 33 19773085
2020 Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency. Human mutation 32 31957178
2018 Genome-wide analysis of circular RNAs in bovine cumulus cells treated with BMP15 and GDF9. Scientific reports 32 29786687
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
2019 Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells. Journal of assisted reproduction and genetics 30 31079267
2015 Quantitative expression patterns of GDF9 and BMP15 genes in sheep ovarian follicles grown in vivo or cultured in vitro. Theriogenology 30 26474685
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
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
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
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
2013 Expression of receptors for BMP15 is differentially regulated in dominant and subordinate follicles during follicle deviation in cattle. Animal reproduction science 27 24388700
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
2017 BMP15 "knockout-like" effect in familial premature ovarian insufficiency with persistent ovarian reserve. Clinical genetics 25 28094433
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
2011 Active immunization against the proregions of GDF9 or BMP15 alters ovulation rate and litter size in mice. Reproduction (Cambridge, England) 23 22106408
2007 Association of genetic markers within the BMP15 gene with anovulation and infertility in women with polycystic ovary syndrome. Fertility and sterility 22 17905236
2003 [Studies of BMPR-IB and BMP15 as candidate genes for fecundity in little tailed han sheep]. Yi chuan xue bao = Acta genetica Sinica 20 14682245
2023 Rescue of bmp15 deficiency in zebrafish by mutation of inha reveals mechanisms of BMP15 regulation of folliculogenesis. PLoS genetics 18 37713421
2020 Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT. Experimental biology and medicine (Maywood, N.J.) 18 32223330
2018 BMP15 regulates AMH expression via the p38 MAPK pathway in granulosa cells from goat. Theriogenology 18 29885643
2016 Temporal expression of GDF-9 and BMP-15 mRNAs in canine ovarian follicles. Theriogenology 18 27341772
2014 BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure. Reproductive biomedicine online 18 25246117
2007 Sequence variants in exons of the BMP-15 gene in Chinese patients with premature ovarian failure. Acta obstetricia et gynecologica Scandinavica 18 17464588
2019 Association of BMP15 and GDF9 variants to premature ovarian insufficiency. Journal of assisted reproduction and genetics 17 31392662
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
2020 Genome-Wide Identification of a Regulatory Mutation in BMP15 Controlling Prolificacy in Sheep. Frontiers in genetics 16 32636872
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
2014 Molecular characterization of gdf9 and bmp15 genes in rare minnow Gobiocypris rarus and their expression upon bisphenol A exposure in adult females. Gene 15 24914497
2022 Novel bone morphogenetic protein 15 (BMP15) gene variants implicated in premature ovarian insufficiency. Reproductive biology and endocrinology : RB&E 14 35232444
2022 Identification of novel biallelic variants in BMP15 in two siblings with premature ovarian insufficiency. Journal of assisted reproduction and genetics 14 35861920
2022 Serum GDF9 and BMP15 as potential markers of ovarian function in women with and without polycystic ovary syndrome. Clinical endocrinology 14 36372988

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