Affinage

FSHR

Follicle-stimulating hormone receptor · UniProt P23945

Length
695 aa
Mass
78.2 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    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

    PMID:8661143

    Open questions at the time
    • Does not address protein structure or signaling
    • No functional consequence of exon organization tested at this stage
  2. 1998 High

    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

    PMID:9773974

    Open questions at the time
    • Does not establish in vivo necessity of the E-box
    • Other required elements left unidentified
  3. 2004 Medium

    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

    PMID:15196694

    Open questions at the time
    • Functional effect on cAMP was modest
    • Physiological relevance in gonadal cells untested
  4. 2005 Low

    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

    PMID:15769647

    Open questions at the time
    • Single neutralizing-antibody experiment with semi-quantitative readout
    • Direct mechanism of repression not defined
  5. 2006 Medium

    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

    PMID:17030088

    Open questions at the time
    • Functional signaling consequences not measured
    • Direct vs. indirect FSHR contacts not resolved
  6. 2006 Medium

    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

    PMID:17097219

    Open questions at the time
    • Limited to one transgenic line
    • Trans-acting factors at ECR4/ECR5 not identified
  7. 2012 High

    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

    PMID:23086931

    Open questions at the time
    • In vivo physiological weight of this feedback unquantified
    • Interplay with USF activators not resolved
  8. 2014 High

    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

    PMID:24670307 PMID:24970684

    Open questions at the time
    • Variant effects on receptor structure not directly resolved
    • Clinical predictive value beyond cohorts untested
  9. 2016 High

    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

    PMID:27502035

    Open questions at the time
    • Cell-type generality of the β-arrestin brake unclear
    • Mechanism of constitutive β-arrestin recruitment undefined
  10. 2017 High

    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

    PMID:29157895

    Open questions at the time
    • Single family
    • Residual non-cAMP signaling not assessed
  11. 2018 Medium

    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

    PMID:29626103 PMID:29715497

    Open questions at the time
    • Molecular basis of endothelial FSHR signaling in placenta undefined
    • Link between internalization rate and signaling magnitude not quantified
  12. 2019 High

    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

    PMID:31077743 PMID:31079267 PMID:31097679 PMID:31830376

    Open questions at the time
    • Relative in vivo contribution of each input unclear
    • Whether nitration is regulated physiologically untested
  13. 2020 High

    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

    PMID:33299978

    Open questions at the time
    • Structural basis of heteromer interface unknown
    • Regulation of FSHR:GPER ratio in vivo undefined
  14. 2021 Medium

    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

    PMID:34503515 PMID:34925235

    Open questions at the time
    • Oligomerization measured largely in HEK293
    • How TRIB3 connects to FSHR promoter or stability mechanistically unresolved
  15. 2023 Medium

    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

    PMID:36638901 PMID:37733588

    Open questions at the time
    • Direct biochemical link from FSHR to mTOR not defined
    • Single-lab pathway placement
  16. 2024 Medium

    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

    PMID:38987655

    Open questions at the time
    • Binding site on FSHR not mapped
    • In vivo exposure relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified structural/biophysical model of FSHR signaling states
  • Crosstalk hierarchy among gating mechanisms untested in physiological tissue

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1474165 Reproduction 2
Partners
14-3-3TAUAKT2APPL1APPL2ARRB1ARRB2FOXO1AGPER
Complex memberships
FSHR/GPER heteromerMTA2/HDAC1 corepressor complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Yeast two-hybrid screen, Co-immunoprecipitation, cAMP accumulation assay Molecular and cellular endocrinology Medium 15196694
2006 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. Co-immunoprecipitation, yeast two-hybrid Molecular and cellular endocrinology Medium 17030088
1996 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. Phage library screening, long PCR, genomic sequencing Genomics High 8661143
1998 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. Transient transfection of deletion and block-replacement mutants, electrophoretic mobility shift assay (EMSA), antibody supershift Molecular endocrinology High 9773974
2006 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. Transgenic mice carrying a yeast artificial chromosome (YAC) spanning 413 kb of rat Fshr locus; RT-PCR; transient transfection of ECR constructs Molecular and cellular endocrinology Medium 17097219
2012 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. ChIP, siRNA knockdown, co-immunoprecipitation, luciferase reporter assay, HDAC activity assay The Journal of biological chemistry High 23086931
2014 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. cAMP assay in primary human granulosa cells, Western blot for phospho-ERK1/2 and phospho-CREB, gene expression analysis, progesterone measurement, pharmacological ERK inhibition Molecular and cellular endocrinology High 24970684
2014 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. RT-PCR of cumulus cells from IVF patients, transfection of splice variant constructs in HEK293 cells, cAMP assay Molecular human reproduction Medium 24670307
2016 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. siRNA knockdown of β-arrestins 1 and 2, cAMP assay, progesterone measurement, cell proliferation and apoptosis assays, receptor overexpression Molecular and cellular endocrinology High 27502035
2019 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. HAT activity assay, ChIP for histone modifications and USF1/2 binding, phospho-Western blot, pharmacological inhibitors (LDN193189, SB203580), qRT-PCR, ELISA for estradiol Journal of assisted reproduction and genetics High 31079267
2020 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. BRET/co-immunoprecipitation for heteromer detection, siRNA knockdown of GPER, cAMP assay, cell viability/apoptosis assays, clinical correlation with ovarian stimulation outcomes iScience High 33299978
2021 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. Super-resolution imaging (PD-PALM) in HEK293 cells expressing FSHR, cAMP assay Frontiers in endocrinology Medium 34925235
2017 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. Sanger sequencing, Western blot, immunofluorescence, cAMP assay in transfected cells Fertility and sterility High 29157895
2019 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. Whole-genome exon sequencing, confocal microscopy for receptor localization, cAMP ELISA in transfected HEK293T cells, molecular dynamics simulations Molecular genetics & genomic medicine High 31830376
2019 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. Sanger sequencing, confocal microscopy for membrane localization, cAMP assay, Western blot for phospho-ERK1/2 in transfected cells Molecular and cellular endocrinology Medium 31077743
2019 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. Mass spectrometry for nitrated tyrosine residue identification, site-directed mutagenesis, confocal microscopy for trafficking, co-immunoprecipitation, Western blot for Akt/FoxO3a phosphorylation, apoptosis assays Aging High 31097679
2018 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. siRNA knockdown, flow cytometry for FSHR membrane levels, cAMP/PKA/CREB pathway analysis, aromatase/estradiol measurement, immunofluorescence Reproduction Medium 29626103
2023 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. High-throughput molecular pathology (transcriptional atlas of granulosa cells), genetic manipulation of HIF1, AMPK, and mTOR in vitro and in vivo Cell reports Medium 37733588
2023 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. 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 Free radical biology & medicine Medium 36638901
2018 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. 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 Molecular and cellular endocrinology High 29715497
2015 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. TALEN-mediated gene disruption in zebrafish, histological analysis, reproductive phenotyping, double mutant analysis Endocrinology High 25993524
2024 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. SVOG cell exposure, cAMP assay, PKA activity measurement, estradiol ELISA, FSHR binding assay, subcellular localization of bisphenol S Communications biology Medium 38987655
2023 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. DOR mouse model, KGN cell treatment, siRNA-FSHR knockdown, FSHR antagonist, cAMP assay, Western blot for PKA/CREB, estradiol ELISA Molecules Medium 38138611
2021 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. siRNA knockdown of TRIB3, Western blot, qPCR, immunofluorescence, p-Akt and p-GSK3β analysis, estradiol measurement in primary human GCs and KGN cells Reproductive biology and endocrinology Medium 34503515
2005 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. In vitro culture of neonatal rat ovaries, semi-quantitative RT-PCR for FSHR, bFGF neutralizing antibody treatment Frontiers in bioscience Low 15769647
2007 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. Genome-wide RNAi screen, genetic epistasis analysis in C. elegans, tissue-specific rescue assays Current biology Medium 17276913
2009 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. RNAi screen, genetic epistasis in C. elegans, infection survival assays, transcriptional reporter assays Proceedings of the National Academy of Sciences Medium 19196974
2019 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. Genetic deficiency analysis, tissue-specific rescue assays, survival assays under mitochondrial stress, SPHK-1 localization microscopy in C. elegans Genetics Medium 31801834

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 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. Endocrinology 128 25993524
2016 TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis. Cell death & disease 113 27882941
2009 The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences of the United States of America 104 19196974
1996 The structure and organization of the human follicle-stimulating hormone receptor (FSHR) gene. Genomics 97 8661143
2014 FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice. Biology of reproduction 93 25100706
2012 Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters. The Journal of clinical endocrinology and metabolism 93 22791757
2012 FSH stimulates lipid biosynthesis in chicken adipose tissue by upregulating the expression of its receptor FSHR. Journal of lipid research 92 22345708
2014 FSHR polymorphism p.N680S mediates different responses to FSH in vitro. Molecular and cellular endocrinology 91 24970684
2010 FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women. European journal of endocrinology 83 20335500
2006 APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex. Molecular and cellular endocrinology 78 17030088
2019 Upregulation of FSHR and PCNA by administration of coenzyme Q10 on cyclophosphamide-induced premature ovarian failure in a mouse model. Journal of biochemical and molecular toxicology 75 31557371
2019 Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS). Frontiers in endocrinology 73 30809190
2008 Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fecundity and molecular biology of FSHR protein and gene. Obstetrical & gynecological survey 71 19017414
2021 An overview of FSH-FSHR biology and explaining the existing conundrums. Journal of ovarian research 68 34717708
2012 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. The Journal of biological chemistry 62 23086931
2010 Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome. Molecular genetics and metabolism 62 20399696
2011 Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis. Molecular genetics and metabolism 59 21546300
2010 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. Zygote (Cambridge, England) 56 21205389
2016 β-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line. Molecular and cellular endocrinology 55 27502035
1998 Multiple promoter elements contribute to activity of the follicle-stimulating hormone receptor (FSHR) gene in testicular Sertoli cells. Molecular endocrinology (Baltimore, Md.) 51 9773974
2013 Research resource: small RNA-seq of human granulosa cells reveals miRNAs in FSHR and aromatase genes. Molecular endocrinology (Baltimore, Md.) 50 23660593
2018 MiR-31 and miR-143 affect steroid hormone synthesis and inhibit cell apoptosis in bovine granulosa cells through FSHR. Theriogenology 49 30278258
2019 Extragonadal FSHR Expression and Function-Is It Real? Frontiers in endocrinology 48 30778333
2000 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. Endocrinology 47 11089539
2020 Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival. iScience 46 33299978
2013 Association of allelic combinations of FSHR gene polymorphisms with ovarian response. Reproductive biomedicine online 46 23953588
2012 Study in 1790 Baltic men: FSHR Asn680Ser polymorphism affects total testes volume. Andrology 45 23413141
2007 The C. elegans glycopeptide hormone receptor ortholog, FSHR-1, regulates germline differentiation and survival. Current biology : CB 45 17276913
2023 Iron overload modulates follicular microenvironment via ROS/HIF-1α/FSHR signaling. Free radical biology & medicine 44 36638901
2017 A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency. Fertility and sterility 42 29157895
2019 FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans. Genetics 40 31801834
2015 Flow cytometric analysis of FSHR, BMRR1B, LHR and apoptosis in granulosa cells and ovulation rate in merino sheep. Reproduction (Cambridge, England) 38 25948249
2004 Human follitropin receptor (FSHR) interacts with the adapter protein 14-3-3tau. Molecular and cellular endocrinology 36 15196694
2021 The effect of polymorphisms in FSHR and FSHB genes on ovarian response: a prospective multicenter multinational study in Europe and Asia. Human reproduction (Oxford, England) 35 33889959
2015 Polymorphisms of the Ovine BMPR-IB, BMP-15 and FSHR and Their Associations with Litter Size in Two Chinese Indigenous Sheep Breeds. International journal of molecular sciences 35 25993301
2014 Ala307Thr and Asn680Ser polymorphisms of FSHR gene in human reproduction outcomes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 25322982
2019 Biased Signaling and Allosteric Modulation at the FSHR. Frontiers in endocrinology 34 30930853
2015 The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Protective Host Responses to Infection and Oxidative Stress. PloS one 33 26360906
2015 Functional role of the heterodimeric glycoprotein hormone, GPA2/GPB5, and its receptor, LGR1: An invertebrate perspective. General and comparative endocrinology 33 26704853
2016 Follicle-Stimulating Hormone Receptor (FSHR): A Promising Tool in Oncology? Molecular diagnosis & therapy 32 27392476
2016 Profiling of FSHR negative allosteric modulators on LH/CGR reveals biased antagonism with implications in steroidogenesis. Molecular and cellular endocrinology 31 27424143
2019 Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells. Journal of assisted reproduction and genetics 30 31079267
2019 Novel FSHR mutations in Han Chinese women with sporadic premature ovarian insufficiency. Molecular and cellular endocrinology 26 31077743
2013 Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women. Journal of assisted reproduction and genetics 26 23536150
2011 The expression of FSH receptor (FSHR) in the neonatal porcine ovary and its regulation by flutamide. Reproduction in domestic animals = Zuchthygiene 26 20642491
2019 Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients. International journal of molecular sciences 25 31212758
2014 Follicle-stimulating hormone receptor (FSHR) alternative skipping of exon 2 or 3 affects ovarian response to FSH. Molecular human reproduction 25 24670307
2014 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. Journal of ovarian research 25 25526787
2023 FSHR-mTOR-HIF1 signaling alleviates mouse follicles from AMPK-induced atresia. Cell reports 24 37733588
2021 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. Toxicology letters 23 34871762
2014 Silencing D. melanogaster lgr1 impairs transition from larval to pupal stage. General and comparative endocrinology 23 25157788
2021 Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling. Frontiers in endocrinology 22 34925235
2017 The susceptibility of FSHB -211G > T and FSHR G-29A, 919A > G, 2039A > G polymorphisms to men infertility: an association study and meta-analysis. BMC medical genetics 22 28764642
2019 Sequence variants in FSHR and CYP19A1 genes and the ovarian response to controlled ovarian stimulation. Fertility and sterility 21 31371045
2021 Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3. Journal of ovarian research 20 34717703
2020 Target prediction and validation of microRNAs expressed from FSHR and aromatase genes in human ovarian granulosa cells. Scientific reports 20 32042028
2012 The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism. Journal of assisted reproduction and genetics 20 22915343
2012 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. Theriogenology 20 23043943
2019 Novel FSHR variants causing female resistant ovary syndrome. Molecular genetics & genomic medicine 19 31830376
2018 FSHR Trans-Activation and Oligomerization. Frontiers in endocrinology 19 30619090
2021 MiR-31 targets HSD17B14 and FSHR, and miR-20b targets HSD17B14 to affect apoptosis and steroid hormone metabolism of porcine ovarian granulosa cells. Theriogenology 18 34959084
2020 Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles. Scientific reports 18 32355171
2019 Effects of FSHR polymorphisms on premature ovarian insufficiency in human beings: a meta-analysis. Reproductive biology and endocrinology : RB&E 18 31629411
2019 Characterization of gonadotropin receptors Fshr and Lhr in Japanese medaka, Oryzias latipes. General and comparative endocrinology 17 31536722
2022 A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy. JCI insight 16 36509287
2019 Identification of chicken FSHR gene promoter and the correlations between polymorphisms and egg production in Chinese native hens. Reproduction in domestic animals = Zuchthygiene 16 30702781
2017 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. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 28942449
2015 Are FSHR polymorphisms risk factors to premature ovarian insufficiency? Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 16 26291798
2013 FSHB-211 and FSHR 2039 are associated with serum levels of follicle-stimulating hormone and antimüllerian hormone in healthy girls: a longitudinal cohort study. Fertility and sterility 16 23850305
2010 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. Molecular reproduction and development 16 20422710
2020 FSHR ablation induces depression-like behaviors. Acta pharmacologica Sinica 15 32203083
2019 Tyrosine nitrations impaired intracellular trafficking of FSHR to the cell surface and FSH-induced Akt-FoxO3a signaling in human granulosa cells. Aging 15 31097679
2015 Prostate cancer imaging of FSHR antagonist modified with a hydrophilic linker. Contrast media & molecular imaging 15 26286841
2023 Paeoniflorin Alleviates Cisplatin-Induced Diminished Ovarian Reserve by Restoring the Function of Ovarian Granulosa Cells via Activating FSHR/cAMP/PKA/CREB Signaling Pathway. Molecules (Basel, Switzerland) 14 38138611
2021 Investigation of the FSHR, CYP11, and INSR Mutations and Polymorphisms in Iranian Infertile Women with Polycystic Ovary Syndrome (PCOS). Reports of biochemistry & molecular biology 14 33969141
2021 Associations of FSHR and LHCGR gene variants with ovarian reserve and clinical pregnancy rates. Reproductive biomedicine online 14 34391684
2021 Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome. International journal of molecular sciences 14 34948471
2014 Association between the expression of LHR, FSHR and CYP19 genes, cellular distribution of encoded proteins and proliferation of porcine granulosa cells in real-time. Journal of biological regulators and homeostatic agents 14 25316123
2013 Gender-specific association between FSHR and PPARG common variants and human longevity. Rejuvenation research 14 22985084
2013 Fine-mapping an association of FSHR with preterm birth in a Finnish population. PloS one 14 24205076
2011 Up-regulation of FSHR expression during gonadal sex determination in the frog Rana rugosa. General and comparative endocrinology 14 21521644
2018 The Impact of FSHR Gene Polymorphisms Ala307Thr and Asn680Ser in the Endometriosis Development. DNA and cell biology 13 29683332
2006 Distal regulatory elements are required for Fshr expression, in vivo. Molecular and cellular endocrinology 13 17097219
2022 Gonadotropin receptor polymorphisms (FSHR N680S and LHCGR N312S) are not predictive of clinical outcome and live birth in assisted reproductive technology. Fertility and sterility 12 35842313
2017 The Common Follicle-Stimulating Hormone Receptor (FSHR) Promoter Polymorphism FSHR -29G > A Affects Androgen Production in Normal Human Small Antral Follicles. Frontiers in endocrinology 12 28626448
2017 Expression and localisation of FSHR, GHR and LHR in different tissues and reproductive organs of female yaks. Folia morphologica 12 29064548
2017 Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes. Biochemical and biophysical research communications 12 29133260
2005 Stem cell factor modulates the expression of steroidogenesis related proteins and FSHR during ovarian follicular development. Frontiers in bioscience : a journal and virtual library 12 15769647
2021 TRIB3 regulates FSHR expression in human granulosa cells under high levels of free fatty acids. Reproductive biology and endocrinology : RB&E 11 34503515
2018 Role of RAB5A in FSHR-mediated signal transduction in human granulosa cells. Reproduction (Cambridge, England) 11 29626103
2018 Deletion of fetoplacental Fshr inhibits fetal vessel angiogenesis in the mouse placenta. Molecular and cellular endocrinology 11 29715497
2016 Triptorelin and cetrorelix induce immune responses and affect uterine development and expressions of genes and proteins of ESR1, LHR, and FSHR of mice. Immunopharmacology and immunotoxicology 11 27075695
2015 LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility. Journal of assisted reproduction and genetics 11 25935136
2013 Comparative messenger RNA expression of FSHβ, LHβ, FSHR, LHR, and ERβ in high and low prolific goat breeds. Animal biotechnology 11 23947667
2015 Follicle-stimulating hormone receptor (FSHR) in Chinese alligator, Alligator sinensis: molecular characterization, tissue distribution and mRNA expression changes during the female reproductive cycle. Animal reproduction science 10 25765682
2011 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. Research in veterinary science 10 21963245
2011 Gonadal and nongonadal FSHR and LHR dysfunction during lipopolysaccharide induced failure of blastocyst implantation in mouse. Journal of assisted reproduction and genetics 10 22193751
2010 Expression of follicle-stimulating hormone receptor (FSHR) mRNA in the ovary of Zi geese during developmental and egg laying stages. Folia biologica 10 20420197
2024 Bisphenol S causes excessive estrogen synthesis by activating FSHR and the downstream cAMP/PKA signaling pathway. Communications biology 9 38987655
2007 Follicle stimulating hormone receptor (FSHR) antagonist and epithelial ovarian cancer (EOC). Journal of experimental therapeutics & oncology 9 17552360

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