{"gene":"FSHR","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2004,"finding":"The adapter protein 14-3-3tau interacts with the intracellular loops of FSHR in a FSH (follitropin)-dependent manner, identified by yeast two-hybrid screening with the first and second intracellular loops of FSHR as bait, confirmed by co-immunoprecipitation in HEK293 cells stably expressing FSHR. Over-expression of 14-3-3tau modestly decreased FSH-induced cAMP accumulation.","method":"Yeast two-hybrid screen, Co-immunoprecipitation, cAMP accumulation assay","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP confirmed, yeast two-hybrid primary screen, single lab with two orthogonal methods","pmids":["15196694"],"is_preprint":false},{"year":2006,"finding":"FSHR interacts with APPL1, APPL2, Akt2, and FOXO1a as part of distinct scaffolding networks. APPL1 and APPL2 associate with each other via the N-terminal BAR domain of APPL1. APPL1, but not APPL2, associates with Akt2. FOXO1a does not associate with either APPL1 or APPL2, indicating distinct interaction interfaces with FSHR.","method":"Co-immunoprecipitation, yeast two-hybrid","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple Co-IPs identifying distinct interaction partners, single lab","pmids":["17030088"],"is_preprint":false},{"year":1996,"finding":"The human FSHR gene spans ~54 kb and consists of 10 exons and 9 introns. The extracellular domain is encoded by 9 exons; the C-terminal extracellular domain, transmembrane domain, and intracellular domain are all encoded by the large exon 10 (1234 bp). The gene encodes 695 amino acids.","method":"Phage library screening, long PCR, genomic sequencing","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic sequencing and structural characterization, replicated with rat FSHR gene structure","pmids":["8661143"],"is_preprint":false},{"year":1998,"finding":"Multiple promoter elements control FSHR gene activity in Sertoli cells. An E-box element (CACGTG) has the single greatest impact on promoter function. Upstream stimulatory factor 1 (USF1) and USF2 were identified as primary components binding the E-box by EMSA. Additional elements both 5' and 3' of transcriptional start sites are required for full promoter activity.","method":"Transient transfection of deletion and block-replacement mutants, electrophoretic mobility shift assay (EMSA), antibody supershift","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of promoter elements combined with EMSA and multiple cell-type comparisons in a single rigorous study","pmids":["9773974"],"is_preprint":false},{"year":2006,"finding":"Distal regulatory elements outside a 413 kb region of the rat Fshr locus are required for appropriate spatiotemporal Fshr expression in Sertoli and granulosa cells in vivo. Six evolutionarily conserved regions (ECRs) absent from the transgene were identified by comparative genomics; two (ECR4 and ECR5) showed differential transcriptional activity in expressing vs. non-expressing cells.","method":"Transgenic mice carrying a yeast artificial chromosome (YAC) spanning 413 kb of rat Fshr locus; RT-PCR; transient transfection of ECR constructs","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo transgenic approach with functional follow-up, but limited to one transgenic line","pmids":["17097219"],"is_preprint":false},{"year":2012,"finding":"Metastasis-associated protein 2 (MTA2), induced by FSH (indirectly) or testosterone (directly) in Sertoli cells, acts as a corepressor of FSHR transcription by recruiting HDAC1 to the FSHR promoter, thereby downregulating FSHR expression as a negative feedback mechanism. This FSH/androgen receptor/MTA2 cascade requires functional androgen receptor and desensitizes FSH response in Sertoli cells.","method":"ChIP, siRNA knockdown, co-immunoprecipitation, luciferase reporter assay, HDAC activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP demonstrating MTA2 recruitment to FSHR promoter, combined with siRNA functional rescue and HDAC activity assay, multiple orthogonal methods","pmids":["23086931"],"is_preprint":false},{"year":2014,"finding":"The FSHR p.N680S polymorphism mediates different kinetics of intracellular signaling. The N homozygous genotype achieves cAMP plateau at 45 min versus 90 min for S homozygous cells. Reflecting cAMP kinetics, phospho-ERK1/2, phospho-CREB activation, AREG and STARD1 gene expression, and progesterone production differ quantitatively between N and S cells. ERK pathway blockade with U0126 abolishes the genotype-mediated differences.","method":"cAMP assay in primary human granulosa cells, Western blot for phospho-ERK1/2 and phospho-CREB, gene expression analysis, progesterone measurement, pharmacological ERK inhibition","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal functional assays in primary human cells, including pharmacological pathway dissection, single lab","pmids":["24970684"],"is_preprint":false},{"year":2014,"finding":"Alternative skipping of FSHR exon 2, exon 3, or both (exons 2+3) produces splice variants that fail to initiate cAMP signaling in response to FSH despite high FSH doses when transfected into HEK293 cells, unlike full-length FSHR. These exon-skipping variants were found exclusively in low ovarian responders.","method":"RT-PCR of cumulus cells from IVF patients, transfection of splice variant constructs in HEK293 cells, cAMP assay","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in HEK293 cells with cAMP assay, supported by patient sample analysis, single lab","pmids":["24670307"],"is_preprint":false},{"year":2016,"finding":"In human granulosa-like hGL5 cells, FSHR and LHCGR cannot activate the canonical cAMP/PKA pathway due to constitutive coupling to β-arrestins 1 and 2, which silence cAMP signaling. siRNA knockdown of β-arrestin 1 and 2 unlocks cAMP/PKA signaling, leading to progesterone synthesis and apoptosis. FSH treatment, but not LH, accelerates cAMP/PKA-mediated apoptosis after β-arrestin silencing, an effect reproducible by FSHR overexpression but not LHCGR overexpression.","method":"siRNA knockdown of β-arrestins 1 and 2, cAMP assay, progesterone measurement, cell proliferation and apoptosis assays, receptor overexpression","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (siRNA, OE, cAMP, steroidogenesis, apoptosis assays) in a single rigorous study demonstrating β-arrestin gating of FSHR-cAMP pathway","pmids":["27502035"],"is_preprint":false},{"year":2019,"finding":"BMP15 induces FSHR expression in human granulosa cells through Smad (Smad 1/5/8 phosphorylation) and non-Smad (p38 MAPK/USF1 phosphorylation) pathways. BMP15 increases histone acetyltransferase (HAT) activity and promotes USF1/2 binding at the FSHR promoter region with associated histone modifications. LDN193189 (BMP receptor inhibitor) suppresses BMP15-induced FSHR expression, HAT activity, and p38/USF1 phosphorylation.","method":"HAT activity assay, ChIP for histone modifications and USF1/2 binding, phospho-Western blot, pharmacological inhibitors (LDN193189, SB203580), qRT-PCR, ELISA for estradiol","journal":"Journal of assisted reproduction and genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus multiple pharmacological and biochemical assays demonstrating the Smad/p38/USF1 mechanism, single lab with multiple orthogonal methods","pmids":["31079267"],"is_preprint":false},{"year":2020,"finding":"FSHR forms heteromeric complexes with the G-protein-coupled estrogen receptor GPER in human granulosa cells. FSHR/GPER heteromers reprogram FSH signaling from cAMP/death signals to proliferative/anti-apoptotic signals delivered via the Gβγ dimer. High FSHR:GPER ratio favors Gαs/cAMP coupling and pro-apoptotic signaling, while GPER knockdown or impairment of heteromer formation enhances FSH-dependent cell death and steroidogenesis.","method":"BRET/co-immunoprecipitation for heteromer detection, siRNA knockdown of GPER, cAMP assay, cell viability/apoptosis assays, clinical correlation with ovarian stimulation outcomes","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — BRET-based heteromer detection, siRNA functional rescue, signaling pathway assays in primary human granulosa cells, single lab with multiple orthogonal methods","pmids":["33299978"],"is_preprint":false},{"year":2021,"finding":"Differential FSH glycosylation modulates FSHR oligomerization. High concentrations of hypo-glycosylated FSH21/18 and equine FSH rapidly dissociate FSHR oligomers into monomers, whereas fully-glycosylated FSH24 shows slower kinetics. Dissociation of FSHR oligomers correlates with higher cAMP production. A β-arrestin biased FSHR agonist (truncated eLHβ + deglycosylated eLHα) increases FSHR homomerization. Low FSH concentrations promote FSHR oligomer association.","method":"Super-resolution imaging (PD-PALM) in HEK293 cells expressing FSHR, cAMP assay","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel super-resolution imaging method for receptor oligomerization, correlated with cAMP functional readout, single lab","pmids":["34925235"],"is_preprint":false},{"year":2017,"finding":"A novel homozygous nonsense mutation p.R59X (c.175C>T) in FSHR exon 2 causes loss of full-length FSHR protein expression and completely abolishes FSH-induced cAMP signaling in vitro, causing primary ovarian insufficiency with follicular arrest at early antral stage.","method":"Sanger sequencing, Western blot, immunofluorescence, cAMP assay in transfected cells","journal":"Fertility and sterility","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional assay (cAMP) and protein expression analysis directly linking mutation to signaling abolishment, combined with in vivo patient phenotype","pmids":["29157895"],"is_preprint":false},{"year":2019,"finding":"Two novel heterozygous FSHR mutations (p.Ile61Asn and p.Pro688Thr) cause resistant ovarian syndrome. p.Ile61Asn lacks cell surface localization and completely abolishes FSH-induced cAMP response. p.Pro688Thr retains cell surface localization but causes decreased FSH-induced cAMP production. Molecular dynamics simulations confirmed significant structural changes.","method":"Whole-genome exon sequencing, confocal microscopy for receptor localization, cAMP ELISA in transfected HEK293T cells, molecular dynamics simulations","journal":"Molecular genetics & genomic medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — differential effects on localization vs. cAMP signaling characterized by multiple orthogonal methods for two distinct mutations, single lab","pmids":["31830376"],"is_preprint":false},{"year":2019,"finding":"Novel FSHR mutation p.L597I shows decreased membrane localization compared with wild-type FSHR and reduces FSH-induced cAMP production and ERK1/2 phosphorylation. Mutation p.M265V does not affect membrane localization or FSH-induced cAMP/ERK signaling.","method":"Sanger sequencing, confocal microscopy for membrane localization, cAMP assay, Western blot for phospho-ERK1/2 in transfected cells","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays distinguishing two mutations mechanistically, single lab","pmids":["31077743"],"is_preprint":false},{"year":2019,"finding":"Peroxynitrite causes tyrosine nitration of FSHR at four residues, sequestering FSHR in the cytoplasm and leading to proteasome-mediated degradation. Site-directed mutagenesis identified Y626 as pivotal for intracellular trafficking of FSHR to the cell surface. Nitration of FSHR (via Y626) impairs FSH-induced Akt-FoxO3a signaling, mimicking the effects of the FSHR-Y626A mutant on cell survival.","method":"Mass spectrometry for nitrated tyrosine residue identification, site-directed mutagenesis, confocal microscopy for trafficking, co-immunoprecipitation, Western blot for Akt/FoxO3a phosphorylation, apoptosis assays","journal":"Aging","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of nitration sites, combined with mutagenesis and functional signaling assays, multiple orthogonal methods in single rigorous study","pmids":["31097679"],"is_preprint":false},{"year":2018,"finding":"RAB5A regulates FSH-mediated translocation of FSHR from the membrane to the cytoplasm (receptor internalization) and the subsequent FSH-FSHR signaling. RAB5A negatively regulates aromatase expression and estradiol synthesis in human granulosa cells via the cAMP/PKA/CREB pathway, and this regulation is associated with two transcription factors USF1 and USF2.","method":"siRNA knockdown, flow cytometry for FSHR membrane levels, cAMP/PKA/CREB pathway analysis, aromatase/estradiol measurement, immunofluorescence","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA-based functional studies with receptor trafficking and downstream signaling readouts, single lab","pmids":["29626103"],"is_preprint":false},{"year":2023,"finding":"FSHR activates the mTOR-HIF1 signaling axis in ovarian granulosa cells as a major downstream effector of FSH. HIF1 activation is essential for follicle growth. Energy shortage leads to AMPK activation driving follicular atresia, while FSHR-mTOR-HIF1 signaling enables follicles to escape atresia under energy stress.","method":"High-throughput molecular pathology (transcriptional atlas of granulosa cells), genetic manipulation of HIF1, AMPK, and mTOR in vitro and in vivo","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional genetic studies with pathway placement, single lab, transcriptional atlas approach with functional follow-up","pmids":["37733588"],"is_preprint":false},{"year":2023,"finding":"Iron overload activates the ROS/HIF-1α pathway to disrupt HIF-1α/FSHR/CYP19A1 signaling in granulosa cells, leading to decreased estrogen synthesis, granulosa cell apoptosis, and oocyte maldevelopment. Iron-induced ROS amplify mitochondrial damage and cytochrome C release leading to apoptosis.","method":"Cell line and chronic iron overload mouse model, ROS measurement, cytochrome C release assay, HIF-1α and FSHR/CYP19A1 expression analysis, in vitro fertilization assessment","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrated cell and animal model studies with mechanistic pathway analysis, single lab","pmids":["36638901"],"is_preprint":false},{"year":2018,"finding":"Deletion of fetoplacental Fshr in mice significantly reduces placental labyrinth area and fetal vessel angiogenesis within Fshr-null labyrinths at mid-gestation compared to wild-type placentas, demonstrating that signaling through endothelial FSHR is required for normal fetal placental vascular angiogenesis.","method":"Fshr null mouse genetic model; quantitative morphometric analysis of placental labyrinths; in vivo genetic approach comparing Fshr wt vs null fetuses in identical dam genotype background","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo genetic model with matched controls and quantitative morphometric analysis, directly links endothelial FSHR to angiogenesis","pmids":["29715497"],"is_preprint":false},{"year":2015,"finding":"Genetic deletion of zebrafish fshr using TALEN causes complete failure of follicle activation in females (all follicles arrested at primary growth stage), followed by sex reversal to fertile males. In fshr-deficient males, initiation of spermatogenesis in juveniles is retarded but adult spermatogenesis is normal. Double mutation of fshr and lhcgr results in infertile males. Neither fshr nor lhcgr deficiency phenocopies deficiency of their cognate ligands FSH or LH.","method":"TALEN-mediated gene disruption in zebrafish, histological analysis, reproductive phenotyping, double mutant analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise gene-targeted loss-of-function in zebrafish with specific cellular and reproductive phenotypes, double-mutant epistasis analysis","pmids":["25993524"],"is_preprint":false},{"year":2024,"finding":"Bisphenol S accumulates on the cell membrane and directly binds FSHR, activating the downstream cAMP/PKA signaling pathway and enhancing testosterone-to-17β-estradiol conversion (aromatase activity) in human ovarian granulosa cells at environmentally relevant concentrations.","method":"SVOG cell exposure, cAMP assay, PKA activity measurement, estradiol ELISA, FSHR binding assay, subcellular localization of bisphenol S","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and downstream signaling assays in human granulosa cells, single lab with multiple biochemical readouts","pmids":["38987655"],"is_preprint":false},{"year":2023,"finding":"Paeoniflorin activates the FSHR/cAMP/PKA/CREB signaling pathway in granulosa cells to restore aromatase expression and estradiol synthesis in diminished ovarian reserve. siRNA-mediated FSHR knockdown and FSHR antagonist treatment abolish the beneficial effects of paeoniflorin on estradiol synthesis and aromatase expression.","method":"DOR mouse model, KGN cell treatment, siRNA-FSHR knockdown, FSHR antagonist, cAMP assay, Western blot for PKA/CREB, estradiol ELISA","journal":"Molecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placed by siRNA and pharmacological inhibition with multiple downstream readouts, single lab","pmids":["38138611"],"is_preprint":false},{"year":2021,"finding":"TRIB3 (Tribbles pseudokinase 3) mediates downregulation of FSHR expression in human granulosa cells exposed to high free fatty acids via the Akt/GSK3β signaling pathway. TRIB3 knockdown reverses the FFA-induced decline in FSHR expression and estradiol production, with increased p-Akt; inhibition of Akt (Ser473) after TRIB3 knockdown elevates p-GSK3β and FSHR expression while reducing estradiol.","method":"siRNA knockdown of TRIB3, Western blot, qPCR, immunofluorescence, p-Akt and p-GSK3β analysis, estradiol measurement in primary human GCs and KGN cells","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA-based mechanistic study with pharmacological confirmation in human cells, single lab","pmids":["34503515"],"is_preprint":false},{"year":2005,"finding":"Stem cell factor (SCF) inhibits FSHR mRNA expression in neonatal rat ovarian granulosa cells, and this inhibitory effect is mediated by basic fibroblast growth factor (bFGF) produced in oocytes; inactivation of bFGF by neutralizing antibody reverses SCF's inhibition of FSHR.","method":"In vitro culture of neonatal rat ovaries, semi-quantitative RT-PCR for FSHR, bFGF neutralizing antibody treatment","journal":"Frontiers in bioscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single neutralizing antibody experiment, semi-quantitative RT-PCR, single lab","pmids":["15769647"],"is_preprint":false},{"year":2007,"finding":"C. elegans FSHR-1 (ortholog of mammalian glycoprotein hormone receptors) controls germline differentiation and survival through a canonical signaling pathway involving Gαs and adenyl cyclase. FSHR-1 acts nonautonomously via the soma to control germline processes, acting in parallel to the sex-determination pathway. Loss of fshr-1 combined with loss of PUF family members fbf-1/fbf-2 causes germline masculinization and failure to maintain germline stem cell niche.","method":"Genome-wide RNAi screen, genetic epistasis analysis in C. elegans, tissue-specific rescue assays","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis analysis placing FSHR-1 in Gαs/adenylyl cyclase pathway, tissue-specific rescue, C. elegans ortholog","pmids":["17276913"],"is_preprint":false},{"year":2009,"finding":"C. elegans FSHR-1 (a conserved GPCR) is required for innate immune response to Gram-negative and Gram-positive bacterial pathogens. FSHR-1 acts in the intestine (primary pathogen exposure site), signals in parallel to the p38 MAPK pathway, and converges to regulate transcriptional induction of an overlapping but non-identical set of antimicrobial effectors.","method":"RNAi screen, genetic epistasis in C. elegans, infection survival assays, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis placing FSHR-1 parallel to p38 MAPK, tissue-specific functional evidence, C. elegans ortholog","pmids":["19196974"],"is_preprint":false},{"year":2019,"finding":"C. elegans FSHR-1 promotes activation of the mitochondrial unfolded protein response (UPRmt) by functioning in neurons to activate UPRmt cell-nonautonomously, acting upstream of SPHK-1/sphingosine kinase in the intestine. FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine.","method":"Genetic deficiency analysis, tissue-specific rescue assays, survival assays under mitochondrial stress, SPHK-1 localization microscopy in C. elegans","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific rescue establishing cell non-autonomous neuronal function, genetic epistasis with SPHK-1, C. elegans ortholog","pmids":["31801834"],"is_preprint":false}],"current_model":"FSHR is a G protein-coupled receptor expressed on granulosa and Sertoli cells that, upon FSH binding, couples primarily to Gαs to activate adenylyl cyclase and produce cAMP, which drives PKA/CREB-mediated transcription for steroidogenesis and folliculogenesis; its signaling is regulated by β-arrestin-dependent silencing of cAMP, receptor oligomerization state (influenced by FSH glycosylation), interactions with scaffolding partners (14-3-3tau, APPL1/2, Akt2, FOXO1a), heteromeric complex formation with GPER that reprograms death signals to proliferative signals via Gβγ, downstream activation of mTOR-HIF1 for follicle survival, transcriptional control via USF1/USF2-E-box and BMP15-Smad/p38 pathways, negative feedback via MTA2/HDAC1-mediated promoter repression, and post-translational regulation via peroxynitrite-mediated tyrosine nitration at Y626 that impairs membrane trafficking and Akt-FoxO3a signaling; in the placenta, endothelial FSHR drives fetal vascular angiogenesis."},"narrative":{"mechanistic_narrative":"FSHR is a G protein-coupled receptor that, upon binding follicle-stimulating hormone, transduces signals controlling folliculogenesis and granulosa/Sertoli cell function, with loss-of-function mutations causing primary ovarian insufficiency [PMID:29157895, PMID:25993524]. Its gene structure places the C-terminal extracellular domain, transmembrane, and intracellular domains within a single large exon 10, while the bulk of the ligand-binding extracellular domain is encoded by upstream exons [PMID:8661143]. The canonical output is Gαs-driven cAMP/PKA/CREB signaling that promotes steroidogenesis and aromatase-dependent estradiol synthesis, a pathway pharmacologically and genetically dissectable in granulosa cells [PMID:24970684, PMID:38138611]. This cAMP arm is gated rather than constitutive: constitutive coupling to β-arrestins 1 and 2 silences cAMP signaling, and relieving this brake unlocks PKA-driven progesterone synthesis and apoptosis [PMID:27502035]. Signaling outcome is further set by receptor quaternary state—FSH glycosylation controls dissociation of FSHR oligomers into monomers, correlating with higher cAMP output [PMID:34925235]—and by heteromerization with the estrogen receptor GPER, which reprograms FSH signaling from cAMP/pro-apoptotic toward Gβγ-mediated proliferative/anti-apoptotic signals depending on the FSHR:GPER ratio [PMID:33299978]. Downstream, FSHR engages scaffolds including 14-3-3tau and an APPL1/APPL2/Akt2/FOXO1a network, and drives the mTOR-HIF1 axis required for follicle growth and escape from atresia [PMID:15196694, PMID:17030088, PMID:37733588]. FSHR transcription is controlled by a USF1/USF2-bound E-box and distal conserved elements, induced by BMP15 via Smad and p38/USF1 pathways with histone acetylation, and repressed as negative feedback by an androgen-driven MTA2/HDAC1 corepressor complex [PMID:9773974, PMID:31079267, PMID:23086931]. Receptor surface levels and signaling are additionally tuned post-translationally by RAB5A-dependent internalization and by peroxynitrite-mediated tyrosine nitration at Y626, which sequesters FSHR in the cytoplasm and impairs Akt-FoxO3a signaling [PMID:29626103, PMID:31097679]. Beyond gonads, endothelial FSHR is required for fetal placental vascular angiogenesis [PMID:29715497].","teleology":[{"year":1996,"claim":"Establishing the human FSHR gene architecture defined how the receptor's ligand-binding and signal-transducing domains are encoded, framing later mutation and splice-variant analyses.","evidence":"Phage library screening, long PCR, and genomic sequencing of the human locus","pmids":["8661143"],"confidence":"High","gaps":["Does not address protein structure or signaling","No functional consequence of exon organization tested at this stage"]},{"year":1998,"claim":"Mapping FSHR promoter elements answered how cell-type-restricted FSHR transcription is achieved, identifying an E-box and its USF1/USF2 binders as dominant.","evidence":"Promoter deletion/block-replacement mutagenesis with EMSA and antibody supershift in Sertoli cells","pmids":["9773974"],"confidence":"High","gaps":["Does not establish in vivo necessity of the E-box","Other required elements left unidentified"]},{"year":2004,"claim":"Identification of 14-3-3tau as an FSH-dependent intracellular-loop partner introduced the idea that adapter proteins shape FSHR cAMP output.","evidence":"Yeast two-hybrid with FSHR intracellular loops, reciprocal co-IP, and cAMP assay in HEK293","pmids":["15196694"],"confidence":"Medium","gaps":["Functional effect on cAMP was modest","Physiological relevance in gonadal cells untested"]},{"year":2005,"claim":"SCF/bFGF signaling was placed upstream as a paracrine repressor of FSHR mRNA, hinting at oocyte-to-granulosa control of receptor abundance.","evidence":"Neonatal rat ovary culture with bFGF neutralizing antibody and semi-quantitative RT-PCR","pmids":["15769647"],"confidence":"Low","gaps":["Single neutralizing-antibody experiment with semi-quantitative readout","Direct mechanism of repression not defined"]},{"year":2006,"claim":"Co-IP/yeast two-hybrid mapping of an APPL1/APPL2/Akt2/FOXO1a network showed FSHR organizes distinct scaffolding interfaces, linking the receptor to Akt/FOXO survival machinery.","evidence":"Co-immunoprecipitation and yeast two-hybrid interaction mapping","pmids":["17030088"],"confidence":"Medium","gaps":["Functional signaling consequences not measured","Direct vs. indirect FSHR contacts not resolved"]},{"year":2006,"claim":"Transgenic dissection of the rat Fshr locus demonstrated that distal conserved elements outside a 413 kb region are required for correct spatiotemporal expression.","evidence":"YAC transgenic mice, RT-PCR, and ECR reporter transfections","pmids":["17097219"],"confidence":"Medium","gaps":["Limited to one transgenic line","Trans-acting factors at ECR4/ECR5 not identified"]},{"year":2012,"claim":"Discovery of an androgen-driven MTA2/HDAC1 corepressor at the FSHR promoter explained how FSH response is desensitized through negative feedback.","evidence":"ChIP, siRNA, co-IP, luciferase reporter, and HDAC activity assays in Sertoli cells","pmids":["23086931"],"confidence":"High","gaps":["In vivo physiological weight of this feedback unquantified","Interplay with USF activators not resolved"]},{"year":2014,"claim":"The N680S polymorphism and exon-2/3 skipping variants linked receptor sequence/structure to signaling kinetics and ovarian responsiveness, connecting genotype to cAMP/ERK/CREB output.","evidence":"cAMP/phospho-ERK/CREB assays in primary granulosa cells; splice-variant reconstitution in HEK293 with patient sampling","pmids":["24970684","24670307"],"confidence":"High","gaps":["Variant effects on receptor structure not directly resolved","Clinical predictive value beyond cohorts untested"]},{"year":2016,"claim":"Showing that constitutive β-arrestin coupling silences FSHR cAMP signaling reframed the receptor as a gated rather than constitutively active cAMP generator.","evidence":"β-arrestin 1/2 siRNA knockdown with cAMP, progesterone, proliferation/apoptosis assays and receptor overexpression","pmids":["27502035"],"confidence":"High","gaps":["Cell-type generality of the β-arrestin brake unclear","Mechanism of constitutive β-arrestin recruitment undefined"]},{"year":2017,"claim":"A homozygous p.R59X nonsense mutation directly tied loss of full-length FSHR and abolished cAMP signaling to primary ovarian insufficiency with follicular arrest.","evidence":"Sanger sequencing, Western blot, immunofluorescence, and cAMP assay in transfected cells plus patient phenotype","pmids":["29157895"],"confidence":"High","gaps":["Single family","Residual non-cAMP signaling not assessed"]},{"year":2018,"claim":"RAB5A-dependent internalization and an endothelial requirement for fetal placental angiogenesis expanded FSHR biology to receptor trafficking control and a non-gonadal vascular role.","evidence":"siRNA/flow cytometry trafficking assays in granulosa cells; Fshr-null mouse placental morphometry","pmids":["29626103","29715497"],"confidence":"Medium","gaps":["Molecular basis of endothelial FSHR signaling in placenta undefined","Link between internalization rate and signaling magnitude not quantified"]},{"year":2019,"claim":"Multiple 2019 studies resolved how post-translational and transcriptional inputs tune FSHR: BMP15/Smad/p38-USF1 induction, peroxynitrite Y626 nitration impairing trafficking/Akt-FoxO3a, and trafficking-vs-signaling-distinct disease mutations.","evidence":"ChIP/HAT assays, mass spectrometry plus site-directed mutagenesis, confocal localization, and cAMP/ERK assays across granulosa and HEK293 systems","pmids":["31079267","31097679","31830376","31077743"],"confidence":"High","gaps":["Relative in vivo contribution of each input unclear","Whether nitration is regulated physiologically untested"]},{"year":2020,"claim":"BRET detection of FSHR/GPER heteromers showed that receptor partnering reprograms FSH signaling between pro-apoptotic cAMP and Gβγ-driven proliferative outputs based on stoichiometry.","evidence":"BRET/co-IP heteromer detection, GPER siRNA, cAMP and viability assays in primary granulosa cells with clinical correlation","pmids":["33299978"],"confidence":"High","gaps":["Structural basis of heteromer interface unknown","Regulation of FSHR:GPER ratio in vivo undefined"]},{"year":2021,"claim":"Super-resolution imaging tied FSH glycosylation to FSHR oligomer dissociation and cAMP output, and TRIB3 was shown to downregulate FSHR via Akt/GSK3β under lipotoxic stress.","evidence":"PD-PALM imaging with cAMP assays in HEK293; TRIB3 siRNA with p-Akt/p-GSK3β and estradiol readouts in human granulosa cells","pmids":["34925235","34503515"],"confidence":"Medium","gaps":["Oligomerization measured largely in HEK293","How TRIB3 connects to FSHR promoter or stability mechanistically unresolved"]},{"year":2023,"claim":"FSHR was placed upstream of an mTOR-HIF1 axis enabling follicles to escape atresia, with iron-overload ROS disrupting the HIF-1α/FSHR/CYP19A1 circuit, integrating FSHR into metabolic stress responses.","evidence":"Granulosa transcriptional atlas with genetic manipulation of HIF1/AMPK/mTOR; iron-overload mouse and cell models with ROS and apoptosis assays","pmids":["37733588","36638901"],"confidence":"Medium","gaps":["Direct biochemical link from FSHR to mTOR not defined","Single-lab pathway placement"]},{"year":2024,"claim":"Demonstration that bisphenol S binds FSHR and activates cAMP/PKA identified the receptor as a direct target for environmental endocrine disruption of aromatase activity.","evidence":"FSHR binding, cAMP/PKA, and estradiol assays in human granulosa cells","pmids":["38987655"],"confidence":"Medium","gaps":["Binding site on FSHR not mapped","In vivo exposure relevance not established"]},{"year":null,"claim":"How the multiple regulatory layers—β-arrestin gating, oligomer state, GPER heteromerization, scaffolds, and post-translational nitration—are integrated to set a single FSHR signaling outcome in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural/biophysical model of FSHR signaling states","Crosstalk hierarchy among gating mechanisms untested in physiological tissue"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,8,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,14,15,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,10]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[12,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,9]}],"complexes":["FSHR/GPER heteromer","MTA2/HDAC1 corepressor complex"],"partners":["GPER","14-3-3TAU","APPL1","APPL2","AKT2","FOXO1A","ARRB1","ARRB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23945","full_name":"Follicle-stimulating hormone receptor","aliases":["Follitropin receptor"],"length_aa":695,"mass_kda":78.2,"function":"G protein-coupled receptor for follitropin, the follicle-stimulating hormone (PubMed:11847099, PubMed:24058690, PubMed:24692546). Through cAMP production activates the downstream PI3K-AKT and ERK1/ERK2 signaling pathways (PubMed:24058690)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P23945/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FSHR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FSHR","total_profiled":1310},"omim":[{"mim_id":"620006","title":"RAD54-LIKE 2; RAD54L2","url":"https://www.omim.org/entry/620006"},{"mim_id":"612842","title":"RASD FAMILY, MEMBER 2; RASD2","url":"https://www.omim.org/entry/612842"},{"mim_id":"611926","title":"IMMUNODEFICIENCY, OVARIAN DYSGENESIS, AND PULMONARY FIBROSIS","url":"https://www.omim.org/entry/611926"},{"mim_id":"609652","title":"GLYCOPROTEIN HORMONE, BETA-5; GPHB5","url":"https://www.omim.org/entry/609652"},{"mim_id":"609651","title":"GLYCOPROTEIN HORMONE, ALPHA-2; GPHA2","url":"https://www.omim.org/entry/609651"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"ovary","ntpm":2.6},{"tissue":"testis","ntpm":2.1}],"url":"https://www.proteinatlas.org/search/FSHR"},"hgnc":{"alias_symbol":["FSHRO","LGR1"],"prev_symbol":["ODG1"]},"alphafold":{"accession":"P23945","domains":[{"cath_id":"3.80.10.10","chopping":"19-121","consensus_level":"medium","plddt":94.3073,"start":19,"end":121},{"cath_id":"3.80.10.10","chopping":"147-284_344-351","consensus_level":"medium","plddt":93.3988,"start":147,"end":351},{"cath_id":"1.20.1070.10","chopping":"364-560_572-620","consensus_level":"high","plddt":87.6529,"start":364,"end":620},{"cath_id":"-","chopping":"630-660","consensus_level":"medium","plddt":74.0787,"start":630,"end":660}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23945","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23945-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23945-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FSHR","jax_strain_url":"https://www.jax.org/strain/search?query=FSHR"},"sequence":{"accession":"P23945","fasta_url":"https://rest.uniprot.org/uniprotkb/P23945.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23945/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23945"}},"corpus_meta":[{"pmid":"25993524","id":"PMC_25993524","title":"Disruption of Zebrafish Follicle-Stimulating Hormone Receptor (fshr) But Not Luteinizing Hormone Receptor (lhcgr) Gene by TALEN Leads to Failed Follicle Activation in Females Followed by Sexual Reversal to Males.","date":"2015","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25993524","citation_count":128,"is_preprint":false},{"pmid":"27882941","id":"PMC_27882941","title":"TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27882941","citation_count":113,"is_preprint":false},{"pmid":"19196974","id":"PMC_19196974","title":"The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19196974","citation_count":104,"is_preprint":false},{"pmid":"8661143","id":"PMC_8661143","title":"The structure and organization of the human follicle-stimulating hormone receptor (FSHR) gene.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8661143","citation_count":97,"is_preprint":false},{"pmid":"22791757","id":"PMC_22791757","title":"Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters.","date":"2012","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22791757","citation_count":93,"is_preprint":false},{"pmid":"25100706","id":"PMC_25100706","title":"FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/25100706","citation_count":93,"is_preprint":false},{"pmid":"22345708","id":"PMC_22345708","title":"FSH stimulates lipid biosynthesis in chicken adipose tissue by upregulating the expression of its receptor FSHR.","date":"2012","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/22345708","citation_count":92,"is_preprint":false},{"pmid":"24970684","id":"PMC_24970684","title":"FSHR polymorphism p.N680S mediates different responses to FSH in vitro.","date":"2014","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24970684","citation_count":91,"is_preprint":false},{"pmid":"20335500","id":"PMC_20335500","title":"FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women.","date":"2010","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20335500","citation_count":83,"is_preprint":false},{"pmid":"17030088","id":"PMC_17030088","title":"APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex.","date":"2006","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17030088","citation_count":78,"is_preprint":false},{"pmid":"31557371","id":"PMC_31557371","title":"Upregulation of FSHR and PCNA by administration of coenzyme Q10 on cyclophosphamide-induced premature ovarian failure in a mouse model.","date":"2019","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31557371","citation_count":75,"is_preprint":false},{"pmid":"30809190","id":"PMC_30809190","title":"Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS).","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30809190","citation_count":73,"is_preprint":false},{"pmid":"19017414","id":"PMC_19017414","title":"Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fecundity and molecular biology of FSHR protein and gene.","date":"2008","source":"Obstetrical & gynecological survey","url":"https://pubmed.ncbi.nlm.nih.gov/19017414","citation_count":71,"is_preprint":false},{"pmid":"34717708","id":"PMC_34717708","title":"An overview of FSH-FSHR biology and explaining the existing conundrums.","date":"2021","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/34717708","citation_count":68,"is_preprint":false},{"pmid":"20399696","id":"PMC_20399696","title":"Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome.","date":"2010","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20399696","citation_count":62,"is_preprint":false},{"pmid":"23086931","id":"PMC_23086931","title":"Sertoli cell-specific expression of metastasis-associated protein 2 (MTA2) is required for transcriptional regulation of the follicle-stimulating hormone receptor (FSHR) gene during spermatogenesis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23086931","citation_count":62,"is_preprint":false},{"pmid":"21546300","id":"PMC_21546300","title":"Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis.","date":"2011","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21546300","citation_count":59,"is_preprint":false},{"pmid":"21205389","id":"PMC_21205389","title":"Expression of follicle-stimulating hormone receptor (FSHR) in goat ovarian follicles and the impact of sequential culture medium on in vitro development of caprine preantral follicles.","date":"2010","source":"Zygote (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21205389","citation_count":56,"is_preprint":false},{"pmid":"27502035","id":"PMC_27502035","title":"β-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line.","date":"2016","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27502035","citation_count":55,"is_preprint":false},{"pmid":"9773974","id":"PMC_9773974","title":"Multiple promoter elements contribute to activity of the follicle-stimulating hormone receptor (FSHR) gene in testicular Sertoli cells.","date":"1998","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9773974","citation_count":51,"is_preprint":false},{"pmid":"23660593","id":"PMC_23660593","title":"Research resource: small RNA-seq of human granulosa cells reveals miRNAs in FSHR and aromatase genes.","date":"2013","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23660593","citation_count":50,"is_preprint":false},{"pmid":"30278258","id":"PMC_30278258","title":"MiR-31 and miR-143 affect steroid hormone synthesis and inhibit cell apoptosis in bovine granulosa cells through FSHR.","date":"2018","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/30278258","citation_count":49,"is_preprint":false},{"pmid":"30778333","id":"PMC_30778333","title":"Extragonadal FSHR Expression and Function-Is It Real?","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30778333","citation_count":48,"is_preprint":false},{"pmid":"11089539","id":"PMC_11089539","title":"Characterization of two fly LGR (leucine-rich repeat-containing, G protein-coupled receptor) proteins homologous to vertebrate glycoprotein hormone receptors: constitutive activation of wild-type fly LGR1 but not LGR2 in transfected mammalian cells.","date":"2000","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11089539","citation_count":47,"is_preprint":false},{"pmid":"33299978","id":"PMC_33299978","title":"Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/33299978","citation_count":46,"is_preprint":false},{"pmid":"23953588","id":"PMC_23953588","title":"Association of allelic combinations of FSHR gene polymorphisms with ovarian response.","date":"2013","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/23953588","citation_count":46,"is_preprint":false},{"pmid":"23413141","id":"PMC_23413141","title":"Study in 1790 Baltic men: FSHR Asn680Ser polymorphism affects total testes volume.","date":"2012","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/23413141","citation_count":45,"is_preprint":false},{"pmid":"17276913","id":"PMC_17276913","title":"The C. elegans glycopeptide hormone receptor ortholog, FSHR-1, regulates germline differentiation and survival.","date":"2007","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/17276913","citation_count":45,"is_preprint":false},{"pmid":"36638901","id":"PMC_36638901","title":"Iron overload modulates follicular microenvironment via ROS/HIF-1α/FSHR signaling.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36638901","citation_count":44,"is_preprint":false},{"pmid":"29157895","id":"PMC_29157895","title":"A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency.","date":"2017","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/29157895","citation_count":42,"is_preprint":false},{"pmid":"31801834","id":"PMC_31801834","title":"FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans.","date":"2019","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31801834","citation_count":40,"is_preprint":false},{"pmid":"25948249","id":"PMC_25948249","title":"Flow cytometric analysis of FSHR, BMRR1B, LHR and apoptosis in granulosa cells and ovulation rate in merino sheep.","date":"2015","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25948249","citation_count":38,"is_preprint":false},{"pmid":"15196694","id":"PMC_15196694","title":"Human follitropin receptor (FSHR) interacts with the adapter protein 14-3-3tau.","date":"2004","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15196694","citation_count":36,"is_preprint":false},{"pmid":"25322982","id":"PMC_25322982","title":"Ala307Thr and Asn680Ser polymorphisms of FSHR gene in human reproduction outcomes.","date":"2014","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25322982","citation_count":35,"is_preprint":false},{"pmid":"33889959","id":"PMC_33889959","title":"The effect of polymorphisms in FSHR and FSHB genes on ovarian response: a prospective multicenter multinational study in Europe and Asia.","date":"2021","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33889959","citation_count":35,"is_preprint":false},{"pmid":"25993301","id":"PMC_25993301","title":"Polymorphisms of the Ovine BMPR-IB, BMP-15 and FSHR and Their Associations with Litter Size in Two Chinese Indigenous Sheep Breeds.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25993301","citation_count":35,"is_preprint":false},{"pmid":"30930853","id":"PMC_30930853","title":"Biased Signaling and Allosteric Modulation at the FSHR.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30930853","citation_count":34,"is_preprint":false},{"pmid":"26704853","id":"PMC_26704853","title":"Functional role of the heterodimeric glycoprotein hormone, GPA2/GPB5, and its receptor, LGR1: An invertebrate perspective.","date":"2015","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26704853","citation_count":33,"is_preprint":false},{"pmid":"26360906","id":"PMC_26360906","title":"The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Protective Host Responses to Infection and Oxidative Stress.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26360906","citation_count":33,"is_preprint":false},{"pmid":"27392476","id":"PMC_27392476","title":"Follicle-Stimulating Hormone Receptor (FSHR): A Promising Tool in Oncology?","date":"2016","source":"Molecular diagnosis & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27392476","citation_count":32,"is_preprint":false},{"pmid":"27424143","id":"PMC_27424143","title":"Profiling of FSHR negative allosteric modulators on LH/CGR reveals biased antagonism with implications in steroidogenesis.","date":"2016","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27424143","citation_count":31,"is_preprint":false},{"pmid":"31079267","id":"PMC_31079267","title":"Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells.","date":"2019","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31079267","citation_count":30,"is_preprint":false},{"pmid":"31077743","id":"PMC_31077743","title":"Novel FSHR mutations in Han Chinese women with sporadic premature ovarian insufficiency.","date":"2019","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31077743","citation_count":26,"is_preprint":false},{"pmid":"20642491","id":"PMC_20642491","title":"The expression of FSH receptor (FSHR) in the neonatal porcine ovary and its regulation by flutamide.","date":"2011","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/20642491","citation_count":26,"is_preprint":false},{"pmid":"23536150","id":"PMC_23536150","title":"Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women.","date":"2013","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23536150","citation_count":26,"is_preprint":false},{"pmid":"25526787","id":"PMC_25526787","title":"Evaluating influence of the genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis.","date":"2014","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/25526787","citation_count":25,"is_preprint":false},{"pmid":"24670307","id":"PMC_24670307","title":"Follicle-stimulating hormone receptor (FSHR) alternative skipping of exon 2 or 3 affects ovarian response to FSH.","date":"2014","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24670307","citation_count":25,"is_preprint":false},{"pmid":"31212758","id":"PMC_31212758","title":"Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31212758","citation_count":25,"is_preprint":false},{"pmid":"37733588","id":"PMC_37733588","title":"FSHR-mTOR-HIF1 signaling alleviates mouse follicles from AMPK-induced atresia.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37733588","citation_count":24,"is_preprint":false},{"pmid":"25157788","id":"PMC_25157788","title":"Silencing D. melanogaster lgr1 impairs transition from larval to pupal stage.","date":"2014","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25157788","citation_count":23,"is_preprint":false},{"pmid":"34871762","id":"PMC_34871762","title":"Copper exposure disrupts ovarian steroidogenesis in human ovarian granulosa cells via the FSHR/CYP19A1 pathway and alters methylation patterns on the SF-1 gene promoter.","date":"2021","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34871762","citation_count":23,"is_preprint":false},{"pmid":"34925235","id":"PMC_34925235","title":"Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling.","date":"2021","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34925235","citation_count":22,"is_preprint":false},{"pmid":"28764642","id":"PMC_28764642","title":"The susceptibility of FSHB -211G > T and FSHR G-29A, 919A > G, 2039A > G polymorphisms to men infertility: an association study and meta-analysis.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28764642","citation_count":22,"is_preprint":false},{"pmid":"31371045","id":"PMC_31371045","title":"Sequence variants in FSHR and CYP19A1 genes and the ovarian response to controlled ovarian stimulation.","date":"2019","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/31371045","citation_count":21,"is_preprint":false},{"pmid":"34717703","id":"PMC_34717703","title":"Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3.","date":"2021","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/34717703","citation_count":20,"is_preprint":false},{"pmid":"32042028","id":"PMC_32042028","title":"Target prediction and validation of microRNAs expressed from FSHR and aromatase genes in human ovarian granulosa cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32042028","citation_count":20,"is_preprint":false},{"pmid":"23043943","id":"PMC_23043943","title":"Elevated level of 17β-estradiol is associated with overexpression of FSHR, CYP19A1, and CTNNB1 genes in porcine ovarian follicles after prenatal and neonatal flutamide exposure.","date":"2012","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/23043943","citation_count":20,"is_preprint":false},{"pmid":"22915343","id":"PMC_22915343","title":"The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism.","date":"2012","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22915343","citation_count":20,"is_preprint":false},{"pmid":"30619090","id":"PMC_30619090","title":"FSHR Trans-Activation and Oligomerization.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30619090","citation_count":19,"is_preprint":false},{"pmid":"31830376","id":"PMC_31830376","title":"Novel FSHR variants causing female resistant ovary syndrome.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31830376","citation_count":19,"is_preprint":false},{"pmid":"34959084","id":"PMC_34959084","title":"MiR-31 targets HSD17B14 and FSHR, and miR-20b targets HSD17B14 to affect apoptosis and steroid hormone metabolism of porcine ovarian granulosa cells.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34959084","citation_count":18,"is_preprint":false},{"pmid":"31629411","id":"PMC_31629411","title":"Effects of FSHR polymorphisms on premature ovarian insufficiency in human beings: a meta-analysis.","date":"2019","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/31629411","citation_count":18,"is_preprint":false},{"pmid":"32355171","id":"PMC_32355171","title":"Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32355171","citation_count":18,"is_preprint":false},{"pmid":"31536722","id":"PMC_31536722","title":"Characterization of gonadotropin receptors Fshr and Lhr in Japanese medaka, Oryzias latipes.","date":"2019","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31536722","citation_count":17,"is_preprint":false},{"pmid":"36509287","id":"PMC_36509287","title":"A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36509287","citation_count":16,"is_preprint":false},{"pmid":"30702781","id":"PMC_30702781","title":"Identification of chicken FSHR gene promoter and the correlations between polymorphisms and egg production in Chinese native hens.","date":"2019","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/30702781","citation_count":16,"is_preprint":false},{"pmid":"20422710","id":"PMC_20422710","title":"Molecular cloning and expression analysis of Fshr and Lhr in relation to Fshb and Lhb subunits during the period of temperature-dependent sex determination in pejerrey Odontesthes bonariensis.","date":"2010","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/20422710","citation_count":16,"is_preprint":false},{"pmid":"23850305","id":"PMC_23850305","title":"FSHB-211 and FSHR 2039 are associated with serum levels of follicle-stimulating hormone and antimüllerian hormone in healthy girls: a longitudinal cohort study.","date":"2013","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/23850305","citation_count":16,"is_preprint":false},{"pmid":"26291798","id":"PMC_26291798","title":"Are FSHR polymorphisms risk factors to premature ovarian insufficiency?","date":"2015","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26291798","citation_count":16,"is_preprint":false},{"pmid":"28942449","id":"PMC_28942449","title":"FSHR and LHR Expression and Signaling as Well as Maturation and Apoptosis of Cumulus-Oocyte Complexes Following Treatment with FSH Receptor Binding Inhibitor in Sheep.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28942449","citation_count":16,"is_preprint":false},{"pmid":"32203083","id":"PMC_32203083","title":"FSHR ablation induces depression-like behaviors.","date":"2020","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/32203083","citation_count":15,"is_preprint":false},{"pmid":"31097679","id":"PMC_31097679","title":"Tyrosine nitrations impaired intracellular trafficking of FSHR to the cell surface and FSH-induced Akt-FoxO3a signaling in human granulosa cells.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31097679","citation_count":15,"is_preprint":false},{"pmid":"26286841","id":"PMC_26286841","title":"Prostate cancer imaging of FSHR antagonist modified with a hydrophilic linker.","date":"2015","source":"Contrast media & molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/26286841","citation_count":15,"is_preprint":false},{"pmid":"34391684","id":"PMC_34391684","title":"Associations of FSHR and LHCGR gene variants with ovarian reserve and clinical pregnancy rates.","date":"2021","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/34391684","citation_count":14,"is_preprint":false},{"pmid":"34948471","id":"PMC_34948471","title":"Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948471","citation_count":14,"is_preprint":false},{"pmid":"33969141","id":"PMC_33969141","title":"Investigation of the FSHR, CYP11, and INSR Mutations and Polymorphisms in Iranian Infertile Women with Polycystic Ovary Syndrome (PCOS).","date":"2021","source":"Reports of biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33969141","citation_count":14,"is_preprint":false},{"pmid":"22985084","id":"PMC_22985084","title":"Gender-specific association between FSHR and PPARG common variants and human longevity.","date":"2013","source":"Rejuvenation research","url":"https://pubmed.ncbi.nlm.nih.gov/22985084","citation_count":14,"is_preprint":false},{"pmid":"21521644","id":"PMC_21521644","title":"Up-regulation of FSHR expression during gonadal sex determination in the frog Rana rugosa.","date":"2011","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21521644","citation_count":14,"is_preprint":false},{"pmid":"24205076","id":"PMC_24205076","title":"Fine-mapping an association of FSHR with preterm birth in a Finnish population.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24205076","citation_count":14,"is_preprint":false},{"pmid":"38138611","id":"PMC_38138611","title":"Paeoniflorin Alleviates Cisplatin-Induced Diminished Ovarian Reserve by Restoring the Function of Ovarian Granulosa Cells via Activating FSHR/cAMP/PKA/CREB Signaling Pathway.","date":"2023","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38138611","citation_count":14,"is_preprint":false},{"pmid":"25316123","id":"PMC_25316123","title":"Association between the expression of LHR, FSHR and CYP19 genes, cellular distribution of encoded proteins and proliferation of porcine granulosa cells in real-time.","date":"2014","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/25316123","citation_count":14,"is_preprint":false},{"pmid":"29683332","id":"PMC_29683332","title":"The Impact of FSHR Gene Polymorphisms Ala307Thr and Asn680Ser in the Endometriosis Development.","date":"2018","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29683332","citation_count":13,"is_preprint":false},{"pmid":"17097219","id":"PMC_17097219","title":"Distal regulatory elements are required for Fshr expression, in vivo.","date":"2006","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17097219","citation_count":13,"is_preprint":false},{"pmid":"29133260","id":"PMC_29133260","title":"Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29133260","citation_count":12,"is_preprint":false},{"pmid":"35842313","id":"PMC_35842313","title":"Gonadotropin receptor polymorphisms (FSHR N680S and LHCGR N312S) are not predictive of clinical outcome and live birth in assisted reproductive technology.","date":"2022","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/35842313","citation_count":12,"is_preprint":false},{"pmid":"29064548","id":"PMC_29064548","title":"Expression and localisation of FSHR, GHR and LHR in different tissues and reproductive organs of female yaks.","date":"2017","source":"Folia morphologica","url":"https://pubmed.ncbi.nlm.nih.gov/29064548","citation_count":12,"is_preprint":false},{"pmid":"15769647","id":"PMC_15769647","title":"Stem cell factor modulates the expression of steroidogenesis related proteins and FSHR during ovarian follicular development.","date":"2005","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/15769647","citation_count":12,"is_preprint":false},{"pmid":"28626448","id":"PMC_28626448","title":"The Common Follicle-Stimulating Hormone Receptor (FSHR) Promoter Polymorphism FSHR -29G > A Affects Androgen Production in Normal Human Small Antral Follicles.","date":"2017","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28626448","citation_count":12,"is_preprint":false},{"pmid":"34503515","id":"PMC_34503515","title":"TRIB3 regulates FSHR expression in human granulosa cells under high levels of free fatty acids.","date":"2021","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/34503515","citation_count":11,"is_preprint":false},{"pmid":"29626103","id":"PMC_29626103","title":"Role of RAB5A in FSHR-mediated signal transduction in human granulosa cells.","date":"2018","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29626103","citation_count":11,"is_preprint":false},{"pmid":"27075695","id":"PMC_27075695","title":"Triptorelin and cetrorelix induce immune responses and affect uterine development and expressions of genes and proteins of ESR1, LHR, and FSHR of mice.","date":"2016","source":"Immunopharmacology and immunotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/27075695","citation_count":11,"is_preprint":false},{"pmid":"23947667","id":"PMC_23947667","title":"Comparative messenger RNA expression of FSHβ, LHβ, FSHR, LHR, and ERβ in high and low prolific goat breeds.","date":"2013","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23947667","citation_count":11,"is_preprint":false},{"pmid":"25935136","id":"PMC_25935136","title":"LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility.","date":"2015","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25935136","citation_count":11,"is_preprint":false},{"pmid":"29715497","id":"PMC_29715497","title":"Deletion of fetoplacental Fshr inhibits fetal vessel angiogenesis in the mouse placenta.","date":"2018","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29715497","citation_count":11,"is_preprint":false},{"pmid":"20420197","id":"PMC_20420197","title":"Expression of follicle-stimulating hormone receptor (FSHR) mRNA in the ovary of Zi geese during developmental and egg laying stages.","date":"2010","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/20420197","citation_count":10,"is_preprint":false},{"pmid":"25765682","id":"PMC_25765682","title":"Follicle-stimulating hormone receptor (FSHR) in Chinese alligator, Alligator sinensis: molecular characterization, tissue distribution and mRNA expression changes during the female reproductive cycle.","date":"2015","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/25765682","citation_count":10,"is_preprint":false},{"pmid":"22193751","id":"PMC_22193751","title":"Gonadal and nongonadal FSHR and LHR dysfunction during lipopolysaccharide induced failure of blastocyst implantation in mouse.","date":"2011","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22193751","citation_count":10,"is_preprint":false},{"pmid":"21963245","id":"PMC_21963245","title":"The effect of IGF-1 and FSH on the in vitro development of caprine secondary follicles and on the IGF-1, IGFR-I and FSHR mRNA levels.","date":"2011","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/21963245","citation_count":10,"is_preprint":false},{"pmid":"17552360","id":"PMC_17552360","title":"Follicle stimulating hormone receptor (FSHR) antagonist and epithelial ovarian cancer (EOC).","date":"2007","source":"Journal of experimental therapeutics & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17552360","citation_count":9,"is_preprint":false},{"pmid":"38987655","id":"PMC_38987655","title":"Bisphenol S causes excessive estrogen synthesis by activating FSHR and the downstream cAMP/PKA signaling pathway.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38987655","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55788,"output_tokens":7444,"usd":0.139512,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16824,"output_tokens":4997,"usd":0.104523,"stage2_stop_reason":"end_turn"},"total_usd":0.244035,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"The adapter protein 14-3-3tau interacts with the intracellular loops of FSHR in a FSH (follitropin)-dependent manner, identified by yeast two-hybrid screening with the first and second intracellular loops of FSHR as bait, confirmed by co-immunoprecipitation in HEK293 cells stably expressing FSHR. Over-expression of 14-3-3tau modestly decreased FSH-induced cAMP accumulation.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation, cAMP accumulation assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP confirmed, yeast two-hybrid primary screen, single lab with two orthogonal methods\",\n      \"pmids\": [\"15196694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FSHR interacts with APPL1, APPL2, Akt2, and FOXO1a as part of distinct scaffolding networks. APPL1 and APPL2 associate with each other via the N-terminal BAR domain of APPL1. APPL1, but not APPL2, associates with Akt2. FOXO1a does not associate with either APPL1 or APPL2, indicating distinct interaction interfaces with FSHR.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple Co-IPs identifying distinct interaction partners, single lab\",\n      \"pmids\": [\"17030088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human FSHR gene spans ~54 kb and consists of 10 exons and 9 introns. The extracellular domain is encoded by 9 exons; the C-terminal extracellular domain, transmembrane domain, and intracellular domain are all encoded by the large exon 10 (1234 bp). The gene encodes 695 amino acids.\",\n      \"method\": \"Phage library screening, long PCR, genomic sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic sequencing and structural characterization, replicated with rat FSHR gene structure\",\n      \"pmids\": [\"8661143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Multiple promoter elements control FSHR gene activity in Sertoli cells. An E-box element (CACGTG) has the single greatest impact on promoter function. Upstream stimulatory factor 1 (USF1) and USF2 were identified as primary components binding the E-box by EMSA. Additional elements both 5' and 3' of transcriptional start sites are required for full promoter activity.\",\n      \"method\": \"Transient transfection of deletion and block-replacement mutants, electrophoretic mobility shift assay (EMSA), antibody supershift\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of promoter elements combined with EMSA and multiple cell-type comparisons in a single rigorous study\",\n      \"pmids\": [\"9773974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Distal regulatory elements outside a 413 kb region of the rat Fshr locus are required for appropriate spatiotemporal Fshr expression in Sertoli and granulosa cells in vivo. Six evolutionarily conserved regions (ECRs) absent from the transgene were identified by comparative genomics; two (ECR4 and ECR5) showed differential transcriptional activity in expressing vs. non-expressing cells.\",\n      \"method\": \"Transgenic mice carrying a yeast artificial chromosome (YAC) spanning 413 kb of rat Fshr locus; RT-PCR; transient transfection of ECR constructs\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo transgenic approach with functional follow-up, but limited to one transgenic line\",\n      \"pmids\": [\"17097219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Metastasis-associated protein 2 (MTA2), induced by FSH (indirectly) or testosterone (directly) in Sertoli cells, acts as a corepressor of FSHR transcription by recruiting HDAC1 to the FSHR promoter, thereby downregulating FSHR expression as a negative feedback mechanism. This FSH/androgen receptor/MTA2 cascade requires functional androgen receptor and desensitizes FSH response in Sertoli cells.\",\n      \"method\": \"ChIP, siRNA knockdown, co-immunoprecipitation, luciferase reporter assay, HDAC activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP demonstrating MTA2 recruitment to FSHR promoter, combined with siRNA functional rescue and HDAC activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"23086931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The FSHR p.N680S polymorphism mediates different kinetics of intracellular signaling. The N homozygous genotype achieves cAMP plateau at 45 min versus 90 min for S homozygous cells. Reflecting cAMP kinetics, phospho-ERK1/2, phospho-CREB activation, AREG and STARD1 gene expression, and progesterone production differ quantitatively between N and S cells. ERK pathway blockade with U0126 abolishes the genotype-mediated differences.\",\n      \"method\": \"cAMP assay in primary human granulosa cells, Western blot for phospho-ERK1/2 and phospho-CREB, gene expression analysis, progesterone measurement, pharmacological ERK inhibition\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal functional assays in primary human cells, including pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"24970684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Alternative skipping of FSHR exon 2, exon 3, or both (exons 2+3) produces splice variants that fail to initiate cAMP signaling in response to FSH despite high FSH doses when transfected into HEK293 cells, unlike full-length FSHR. These exon-skipping variants were found exclusively in low ovarian responders.\",\n      \"method\": \"RT-PCR of cumulus cells from IVF patients, transfection of splice variant constructs in HEK293 cells, cAMP assay\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in HEK293 cells with cAMP assay, supported by patient sample analysis, single lab\",\n      \"pmids\": [\"24670307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In human granulosa-like hGL5 cells, FSHR and LHCGR cannot activate the canonical cAMP/PKA pathway due to constitutive coupling to β-arrestins 1 and 2, which silence cAMP signaling. siRNA knockdown of β-arrestin 1 and 2 unlocks cAMP/PKA signaling, leading to progesterone synthesis and apoptosis. FSH treatment, but not LH, accelerates cAMP/PKA-mediated apoptosis after β-arrestin silencing, an effect reproducible by FSHR overexpression but not LHCGR overexpression.\",\n      \"method\": \"siRNA knockdown of β-arrestins 1 and 2, cAMP assay, progesterone measurement, cell proliferation and apoptosis assays, receptor overexpression\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (siRNA, OE, cAMP, steroidogenesis, apoptosis assays) in a single rigorous study demonstrating β-arrestin gating of FSHR-cAMP pathway\",\n      \"pmids\": [\"27502035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BMP15 induces FSHR expression in human granulosa cells through Smad (Smad 1/5/8 phosphorylation) and non-Smad (p38 MAPK/USF1 phosphorylation) pathways. BMP15 increases histone acetyltransferase (HAT) activity and promotes USF1/2 binding at the FSHR promoter region with associated histone modifications. LDN193189 (BMP receptor inhibitor) suppresses BMP15-induced FSHR expression, HAT activity, and p38/USF1 phosphorylation.\",\n      \"method\": \"HAT activity assay, ChIP for histone modifications and USF1/2 binding, phospho-Western blot, pharmacological inhibitors (LDN193189, SB203580), qRT-PCR, ELISA for estradiol\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus multiple pharmacological and biochemical assays demonstrating the Smad/p38/USF1 mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31079267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FSHR forms heteromeric complexes with the G-protein-coupled estrogen receptor GPER in human granulosa cells. FSHR/GPER heteromers reprogram FSH signaling from cAMP/death signals to proliferative/anti-apoptotic signals delivered via the Gβγ dimer. High FSHR:GPER ratio favors Gαs/cAMP coupling and pro-apoptotic signaling, while GPER knockdown or impairment of heteromer formation enhances FSH-dependent cell death and steroidogenesis.\",\n      \"method\": \"BRET/co-immunoprecipitation for heteromer detection, siRNA knockdown of GPER, cAMP assay, cell viability/apoptosis assays, clinical correlation with ovarian stimulation outcomes\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRET-based heteromer detection, siRNA functional rescue, signaling pathway assays in primary human granulosa cells, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33299978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Differential FSH glycosylation modulates FSHR oligomerization. High concentrations of hypo-glycosylated FSH21/18 and equine FSH rapidly dissociate FSHR oligomers into monomers, whereas fully-glycosylated FSH24 shows slower kinetics. Dissociation of FSHR oligomers correlates with higher cAMP production. A β-arrestin biased FSHR agonist (truncated eLHβ + deglycosylated eLHα) increases FSHR homomerization. Low FSH concentrations promote FSHR oligomer association.\",\n      \"method\": \"Super-resolution imaging (PD-PALM) in HEK293 cells expressing FSHR, cAMP assay\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel super-resolution imaging method for receptor oligomerization, correlated with cAMP functional readout, single lab\",\n      \"pmids\": [\"34925235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel homozygous nonsense mutation p.R59X (c.175C>T) in FSHR exon 2 causes loss of full-length FSHR protein expression and completely abolishes FSH-induced cAMP signaling in vitro, causing primary ovarian insufficiency with follicular arrest at early antral stage.\",\n      \"method\": \"Sanger sequencing, Western blot, immunofluorescence, cAMP assay in transfected cells\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional assay (cAMP) and protein expression analysis directly linking mutation to signaling abolishment, combined with in vivo patient phenotype\",\n      \"pmids\": [\"29157895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two novel heterozygous FSHR mutations (p.Ile61Asn and p.Pro688Thr) cause resistant ovarian syndrome. p.Ile61Asn lacks cell surface localization and completely abolishes FSH-induced cAMP response. p.Pro688Thr retains cell surface localization but causes decreased FSH-induced cAMP production. Molecular dynamics simulations confirmed significant structural changes.\",\n      \"method\": \"Whole-genome exon sequencing, confocal microscopy for receptor localization, cAMP ELISA in transfected HEK293T cells, molecular dynamics simulations\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — differential effects on localization vs. cAMP signaling characterized by multiple orthogonal methods for two distinct mutations, single lab\",\n      \"pmids\": [\"31830376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Novel FSHR mutation p.L597I shows decreased membrane localization compared with wild-type FSHR and reduces FSH-induced cAMP production and ERK1/2 phosphorylation. Mutation p.M265V does not affect membrane localization or FSH-induced cAMP/ERK signaling.\",\n      \"method\": \"Sanger sequencing, confocal microscopy for membrane localization, cAMP assay, Western blot for phospho-ERK1/2 in transfected cells\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays distinguishing two mutations mechanistically, single lab\",\n      \"pmids\": [\"31077743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Peroxynitrite causes tyrosine nitration of FSHR at four residues, sequestering FSHR in the cytoplasm and leading to proteasome-mediated degradation. Site-directed mutagenesis identified Y626 as pivotal for intracellular trafficking of FSHR to the cell surface. Nitration of FSHR (via Y626) impairs FSH-induced Akt-FoxO3a signaling, mimicking the effects of the FSHR-Y626A mutant on cell survival.\",\n      \"method\": \"Mass spectrometry for nitrated tyrosine residue identification, site-directed mutagenesis, confocal microscopy for trafficking, co-immunoprecipitation, Western blot for Akt/FoxO3a phosphorylation, apoptosis assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of nitration sites, combined with mutagenesis and functional signaling assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31097679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAB5A regulates FSH-mediated translocation of FSHR from the membrane to the cytoplasm (receptor internalization) and the subsequent FSH-FSHR signaling. RAB5A negatively regulates aromatase expression and estradiol synthesis in human granulosa cells via the cAMP/PKA/CREB pathway, and this regulation is associated with two transcription factors USF1 and USF2.\",\n      \"method\": \"siRNA knockdown, flow cytometry for FSHR membrane levels, cAMP/PKA/CREB pathway analysis, aromatase/estradiol measurement, immunofluorescence\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA-based functional studies with receptor trafficking and downstream signaling readouts, single lab\",\n      \"pmids\": [\"29626103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FSHR activates the mTOR-HIF1 signaling axis in ovarian granulosa cells as a major downstream effector of FSH. HIF1 activation is essential for follicle growth. Energy shortage leads to AMPK activation driving follicular atresia, while FSHR-mTOR-HIF1 signaling enables follicles to escape atresia under energy stress.\",\n      \"method\": \"High-throughput molecular pathology (transcriptional atlas of granulosa cells), genetic manipulation of HIF1, AMPK, and mTOR in vitro and in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional genetic studies with pathway placement, single lab, transcriptional atlas approach with functional follow-up\",\n      \"pmids\": [\"37733588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Iron overload activates the ROS/HIF-1α pathway to disrupt HIF-1α/FSHR/CYP19A1 signaling in granulosa cells, leading to decreased estrogen synthesis, granulosa cell apoptosis, and oocyte maldevelopment. Iron-induced ROS amplify mitochondrial damage and cytochrome C release leading to apoptosis.\",\n      \"method\": \"Cell line and chronic iron overload mouse model, ROS measurement, cytochrome C release assay, HIF-1α and FSHR/CYP19A1 expression analysis, in vitro fertilization assessment\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrated cell and animal model studies with mechanistic pathway analysis, single lab\",\n      \"pmids\": [\"36638901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of fetoplacental Fshr in mice significantly reduces placental labyrinth area and fetal vessel angiogenesis within Fshr-null labyrinths at mid-gestation compared to wild-type placentas, demonstrating that signaling through endothelial FSHR is required for normal fetal placental vascular angiogenesis.\",\n      \"method\": \"Fshr null mouse genetic model; quantitative morphometric analysis of placental labyrinths; in vivo genetic approach comparing Fshr wt vs null fetuses in identical dam genotype background\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo genetic model with matched controls and quantitative morphometric analysis, directly links endothelial FSHR to angiogenesis\",\n      \"pmids\": [\"29715497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genetic deletion of zebrafish fshr using TALEN causes complete failure of follicle activation in females (all follicles arrested at primary growth stage), followed by sex reversal to fertile males. In fshr-deficient males, initiation of spermatogenesis in juveniles is retarded but adult spermatogenesis is normal. Double mutation of fshr and lhcgr results in infertile males. Neither fshr nor lhcgr deficiency phenocopies deficiency of their cognate ligands FSH or LH.\",\n      \"method\": \"TALEN-mediated gene disruption in zebrafish, histological analysis, reproductive phenotyping, double mutant analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise gene-targeted loss-of-function in zebrafish with specific cellular and reproductive phenotypes, double-mutant epistasis analysis\",\n      \"pmids\": [\"25993524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bisphenol S accumulates on the cell membrane and directly binds FSHR, activating the downstream cAMP/PKA signaling pathway and enhancing testosterone-to-17β-estradiol conversion (aromatase activity) in human ovarian granulosa cells at environmentally relevant concentrations.\",\n      \"method\": \"SVOG cell exposure, cAMP assay, PKA activity measurement, estradiol ELISA, FSHR binding assay, subcellular localization of bisphenol S\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and downstream signaling assays in human granulosa cells, single lab with multiple biochemical readouts\",\n      \"pmids\": [\"38987655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Paeoniflorin activates the FSHR/cAMP/PKA/CREB signaling pathway in granulosa cells to restore aromatase expression and estradiol synthesis in diminished ovarian reserve. siRNA-mediated FSHR knockdown and FSHR antagonist treatment abolish the beneficial effects of paeoniflorin on estradiol synthesis and aromatase expression.\",\n      \"method\": \"DOR mouse model, KGN cell treatment, siRNA-FSHR knockdown, FSHR antagonist, cAMP assay, Western blot for PKA/CREB, estradiol ELISA\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placed by siRNA and pharmacological inhibition with multiple downstream readouts, single lab\",\n      \"pmids\": [\"38138611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIB3 (Tribbles pseudokinase 3) mediates downregulation of FSHR expression in human granulosa cells exposed to high free fatty acids via the Akt/GSK3β signaling pathway. TRIB3 knockdown reverses the FFA-induced decline in FSHR expression and estradiol production, with increased p-Akt; inhibition of Akt (Ser473) after TRIB3 knockdown elevates p-GSK3β and FSHR expression while reducing estradiol.\",\n      \"method\": \"siRNA knockdown of TRIB3, Western blot, qPCR, immunofluorescence, p-Akt and p-GSK3β analysis, estradiol measurement in primary human GCs and KGN cells\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA-based mechanistic study with pharmacological confirmation in human cells, single lab\",\n      \"pmids\": [\"34503515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Stem cell factor (SCF) inhibits FSHR mRNA expression in neonatal rat ovarian granulosa cells, and this inhibitory effect is mediated by basic fibroblast growth factor (bFGF) produced in oocytes; inactivation of bFGF by neutralizing antibody reverses SCF's inhibition of FSHR.\",\n      \"method\": \"In vitro culture of neonatal rat ovaries, semi-quantitative RT-PCR for FSHR, bFGF neutralizing antibody treatment\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single neutralizing antibody experiment, semi-quantitative RT-PCR, single lab\",\n      \"pmids\": [\"15769647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans FSHR-1 (ortholog of mammalian glycoprotein hormone receptors) controls germline differentiation and survival through a canonical signaling pathway involving Gαs and adenyl cyclase. FSHR-1 acts nonautonomously via the soma to control germline processes, acting in parallel to the sex-determination pathway. Loss of fshr-1 combined with loss of PUF family members fbf-1/fbf-2 causes germline masculinization and failure to maintain germline stem cell niche.\",\n      \"method\": \"Genome-wide RNAi screen, genetic epistasis analysis in C. elegans, tissue-specific rescue assays\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis placing FSHR-1 in Gαs/adenylyl cyclase pathway, tissue-specific rescue, C. elegans ortholog\",\n      \"pmids\": [\"17276913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans FSHR-1 (a conserved GPCR) is required for innate immune response to Gram-negative and Gram-positive bacterial pathogens. FSHR-1 acts in the intestine (primary pathogen exposure site), signals in parallel to the p38 MAPK pathway, and converges to regulate transcriptional induction of an overlapping but non-identical set of antimicrobial effectors.\",\n      \"method\": \"RNAi screen, genetic epistasis in C. elegans, infection survival assays, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis placing FSHR-1 parallel to p38 MAPK, tissue-specific functional evidence, C. elegans ortholog\",\n      \"pmids\": [\"19196974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans FSHR-1 promotes activation of the mitochondrial unfolded protein response (UPRmt) by functioning in neurons to activate UPRmt cell-nonautonomously, acting upstream of SPHK-1/sphingosine kinase in the intestine. FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine.\",\n      \"method\": \"Genetic deficiency analysis, tissue-specific rescue assays, survival assays under mitochondrial stress, SPHK-1 localization microscopy in C. elegans\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific rescue establishing cell non-autonomous neuronal function, genetic epistasis with SPHK-1, C. elegans ortholog\",\n      \"pmids\": [\"31801834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FSHR is a G protein-coupled receptor expressed on granulosa and Sertoli cells that, upon FSH binding, couples primarily to Gαs to activate adenylyl cyclase and produce cAMP, which drives PKA/CREB-mediated transcription for steroidogenesis and folliculogenesis; its signaling is regulated by β-arrestin-dependent silencing of cAMP, receptor oligomerization state (influenced by FSH glycosylation), interactions with scaffolding partners (14-3-3tau, APPL1/2, Akt2, FOXO1a), heteromeric complex formation with GPER that reprograms death signals to proliferative signals via Gβγ, downstream activation of mTOR-HIF1 for follicle survival, transcriptional control via USF1/USF2-E-box and BMP15-Smad/p38 pathways, negative feedback via MTA2/HDAC1-mediated promoter repression, and post-translational regulation via peroxynitrite-mediated tyrosine nitration at Y626 that impairs membrane trafficking and Akt-FoxO3a signaling; in the placenta, endothelial FSHR drives fetal vascular angiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FSHR is a G protein-coupled receptor that, upon binding follicle-stimulating hormone, transduces signals controlling folliculogenesis and granulosa/Sertoli cell function, with loss-of-function mutations causing primary ovarian insufficiency [#12, #20]. Its gene structure places the C-terminal extracellular domain, transmembrane, and intracellular domains within a single large exon 10, while the bulk of the ligand-binding extracellular domain is encoded by upstream exons [#2]. The canonical output is Gαs-driven cAMP/PKA/CREB signaling that promotes steroidogenesis and aromatase-dependent estradiol synthesis, a pathway pharmacologically and genetically dissectable in granulosa cells [#6, #22]. This cAMP arm is gated rather than constitutive: constitutive coupling to β-arrestins 1 and 2 silences cAMP signaling, and relieving this brake unlocks PKA-driven progesterone synthesis and apoptosis [#8]. Signaling outcome is further set by receptor quaternary state—FSH glycosylation controls dissociation of FSHR oligomers into monomers, correlating with higher cAMP output [#11]—and by heteromerization with the estrogen receptor GPER, which reprograms FSH signaling from cAMP/pro-apoptotic toward Gβγ-mediated proliferative/anti-apoptotic signals depending on the FSHR:GPER ratio [#10]. Downstream, FSHR engages scaffolds including 14-3-3tau and an APPL1/APPL2/Akt2/FOXO1a network, and drives the mTOR-HIF1 axis required for follicle growth and escape from atresia [#0, #1, #17]. FSHR transcription is controlled by a USF1/USF2-bound E-box and distal conserved elements, induced by BMP15 via Smad and p38/USF1 pathways with histone acetylation, and repressed as negative feedback by an androgen-driven MTA2/HDAC1 corepressor complex [#3, #9, #5]. Receptor surface levels and signaling are additionally tuned post-translationally by RAB5A-dependent internalization and by peroxynitrite-mediated tyrosine nitration at Y626, which sequesters FSHR in the cytoplasm and impairs Akt-FoxO3a signaling [#16, #15]. Beyond gonads, endothelial FSHR is required for fetal placental vascular angiogenesis [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the human FSHR gene architecture defined how the receptor's ligand-binding and signal-transducing domains are encoded, framing later mutation and splice-variant analyses.\",\n      \"evidence\": \"Phage library screening, long PCR, and genomic sequencing of the human locus\",\n      \"pmids\": [\"8661143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein structure or signaling\", \"No functional consequence of exon organization tested at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping FSHR promoter elements answered how cell-type-restricted FSHR transcription is achieved, identifying an E-box and its USF1/USF2 binders as dominant.\",\n      \"evidence\": \"Promoter deletion/block-replacement mutagenesis with EMSA and antibody supershift in Sertoli cells\",\n      \"pmids\": [\"9773974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo necessity of the E-box\", \"Other required elements left unidentified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of 14-3-3tau as an FSH-dependent intracellular-loop partner introduced the idea that adapter proteins shape FSHR cAMP output.\",\n      \"evidence\": \"Yeast two-hybrid with FSHR intracellular loops, reciprocal co-IP, and cAMP assay in HEK293\",\n      \"pmids\": [\"15196694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect on cAMP was modest\", \"Physiological relevance in gonadal cells untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SCF/bFGF signaling was placed upstream as a paracrine repressor of FSHR mRNA, hinting at oocyte-to-granulosa control of receptor abundance.\",\n      \"evidence\": \"Neonatal rat ovary culture with bFGF neutralizing antibody and semi-quantitative RT-PCR\",\n      \"pmids\": [\"15769647\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single neutralizing-antibody experiment with semi-quantitative readout\", \"Direct mechanism of repression not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Co-IP/yeast two-hybrid mapping of an APPL1/APPL2/Akt2/FOXO1a network showed FSHR organizes distinct scaffolding interfaces, linking the receptor to Akt/FOXO survival machinery.\",\n      \"evidence\": \"Co-immunoprecipitation and yeast two-hybrid interaction mapping\",\n      \"pmids\": [\"17030088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional signaling consequences not measured\", \"Direct vs. indirect FSHR contacts not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Transgenic dissection of the rat Fshr locus demonstrated that distal conserved elements outside a 413 kb region are required for correct spatiotemporal expression.\",\n      \"evidence\": \"YAC transgenic mice, RT-PCR, and ECR reporter transfections\",\n      \"pmids\": [\"17097219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to one transgenic line\", \"Trans-acting factors at ECR4/ECR5 not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of an androgen-driven MTA2/HDAC1 corepressor at the FSHR promoter explained how FSH response is desensitized through negative feedback.\",\n      \"evidence\": \"ChIP, siRNA, co-IP, luciferase reporter, and HDAC activity assays in Sertoli cells\",\n      \"pmids\": [\"23086931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological weight of this feedback unquantified\", \"Interplay with USF activators not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The N680S polymorphism and exon-2/3 skipping variants linked receptor sequence/structure to signaling kinetics and ovarian responsiveness, connecting genotype to cAMP/ERK/CREB output.\",\n      \"evidence\": \"cAMP/phospho-ERK/CREB assays in primary granulosa cells; splice-variant reconstitution in HEK293 with patient sampling\",\n      \"pmids\": [\"24970684\", \"24670307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variant effects on receptor structure not directly resolved\", \"Clinical predictive value beyond cohorts untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that constitutive β-arrestin coupling silences FSHR cAMP signaling reframed the receptor as a gated rather than constitutively active cAMP generator.\",\n      \"evidence\": \"β-arrestin 1/2 siRNA knockdown with cAMP, progesterone, proliferation/apoptosis assays and receptor overexpression\",\n      \"pmids\": [\"27502035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type generality of the β-arrestin brake unclear\", \"Mechanism of constitutive β-arrestin recruitment undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A homozygous p.R59X nonsense mutation directly tied loss of full-length FSHR and abolished cAMP signaling to primary ovarian insufficiency with follicular arrest.\",\n      \"evidence\": \"Sanger sequencing, Western blot, immunofluorescence, and cAMP assay in transfected cells plus patient phenotype\",\n      \"pmids\": [\"29157895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single family\", \"Residual non-cAMP signaling not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"RAB5A-dependent internalization and an endothelial requirement for fetal placental angiogenesis expanded FSHR biology to receptor trafficking control and a non-gonadal vascular role.\",\n      \"evidence\": \"siRNA/flow cytometry trafficking assays in granulosa cells; Fshr-null mouse placental morphometry\",\n      \"pmids\": [\"29626103\", \"29715497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of endothelial FSHR signaling in placenta undefined\", \"Link between internalization rate and signaling magnitude not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple 2019 studies resolved how post-translational and transcriptional inputs tune FSHR: BMP15/Smad/p38-USF1 induction, peroxynitrite Y626 nitration impairing trafficking/Akt-FoxO3a, and trafficking-vs-signaling-distinct disease mutations.\",\n      \"evidence\": \"ChIP/HAT assays, mass spectrometry plus site-directed mutagenesis, confocal localization, and cAMP/ERK assays across granulosa and HEK293 systems\",\n      \"pmids\": [\"31079267\", \"31097679\", \"31830376\", \"31077743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of each input unclear\", \"Whether nitration is regulated physiologically untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"BRET detection of FSHR/GPER heteromers showed that receptor partnering reprograms FSH signaling between pro-apoptotic cAMP and Gβγ-driven proliferative outputs based on stoichiometry.\",\n      \"evidence\": \"BRET/co-IP heteromer detection, GPER siRNA, cAMP and viability assays in primary granulosa cells with clinical correlation\",\n      \"pmids\": [\"33299978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of heteromer interface unknown\", \"Regulation of FSHR:GPER ratio in vivo undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Super-resolution imaging tied FSH glycosylation to FSHR oligomer dissociation and cAMP output, and TRIB3 was shown to downregulate FSHR via Akt/GSK3β under lipotoxic stress.\",\n      \"evidence\": \"PD-PALM imaging with cAMP assays in HEK293; TRIB3 siRNA with p-Akt/p-GSK3β and estradiol readouts in human granulosa cells\",\n      \"pmids\": [\"34925235\", \"34503515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomerization measured largely in HEK293\", \"How TRIB3 connects to FSHR promoter or stability mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FSHR was placed upstream of an mTOR-HIF1 axis enabling follicles to escape atresia, with iron-overload ROS disrupting the HIF-1α/FSHR/CYP19A1 circuit, integrating FSHR into metabolic stress responses.\",\n      \"evidence\": \"Granulosa transcriptional atlas with genetic manipulation of HIF1/AMPK/mTOR; iron-overload mouse and cell models with ROS and apoptosis assays\",\n      \"pmids\": [\"37733588\", \"36638901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link from FSHR to mTOR not defined\", \"Single-lab pathway placement\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that bisphenol S binds FSHR and activates cAMP/PKA identified the receptor as a direct target for environmental endocrine disruption of aromatase activity.\",\n      \"evidence\": \"FSHR binding, cAMP/PKA, and estradiol assays in human granulosa cells\",\n      \"pmids\": [\"38987655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on FSHR not mapped\", \"In vivo exposure relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers—β-arrestin gating, oligomer state, GPER heteromerization, scaffolds, and post-translational nitration—are integrated to set a single FSHR signaling outcome in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural/biophysical model of FSHR signaling states\", \"Crosstalk hierarchy among gating mechanisms untested in physiological tissue\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 8, 12]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [8, 10, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 14, 15, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 10]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [12, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 9]}\n    ],\n    \"complexes\": [\n      \"FSHR/GPER heteromer\",\n      \"MTA2/HDAC1 corepressor complex\"\n    ],\n    \"partners\": [\n      \"GPER\",\n      \"14-3-3tau\",\n      \"APPL1\",\n      \"APPL2\",\n      \"Akt2\",\n      \"FOXO1a\",\n      \"ARRB1\",\n      \"ARRB2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}