Activating-transcription factor 3 stimulates follicle-stimulating hormone β transcription in vitro, but is dispensable for FSH production in murine gonadotropes in vivo
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220809 | GEO | 2023/06/28
REPOSITORIES: GEO
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Project description:Mammalian reproduction is dependent on the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, which are secreted by pituitary gonadotrope cells. The zinc-finger transcription factor, GATA2, was previously implicated in FSH production in male mice, although its mechanisms of action and role in females were not determined. To address these gaps in knowledge, we generated and analyzed gonadotrope-specific Gata2 knockout mice using the Cre-lox system. While conditional knockout (cKO) males exhibited ~50% reductions in serum FSH levels and pituitary FSHβ subunit (Fshb) expression relative to controls, FSH production was apparently normal in cKO females. RNA-seq analysis of purified gonadotropes from control and cKO males revealed a profound decrease in expression of gremlin (Grem1), a bone morphogenetic protein (BMP) antagonist. Grem1 was expressed in gonadotropes, but not other cell lineages, in the adult male mouse pituitary. Gata2, Grem1, and Fshb mRNA levels were significantly higher in pituitaries of wild-type males relative to females but decreased in males treated with estradiol and increased following ovariectomy in control but not cKO females. Recombinant gremlin stimulated Fshb expression in pituitary cultures from wild-type mice. Collectively, the data suggest that GATA2 promotes Grem1 expression in gonadotropes and that the gremlin protein potentiates FSH production. The mechanisms of gremlin action have not yet been established but may involve attenuation of BMP binding to activin type II receptors in gonadotropes, potentiating induction of Fshb transcription by activins or related ligands.
2022-07-14 | GSE190064 | GEO
Project description:Mammalian reproduction is dependent on the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, which are secreted by pituitary gonadotrope cells. The zinc-finger transcription factor, GATA2, was previously implicated in FSH production in male mice, although its mechanisms of action and role in females were not determined. To address these gaps in knowledge, we generated and analyzed gonadotrope-specific Gata2 knockout mice using the Cre-lox system. While conditional knockout (cKO) males exhibited ~50% reductions in serum FSH levels and pituitary FSHβ subunit (Fshb) expression relative to controls, FSH production was apparently normal in cKO females. RNA-seq analysis of purified gonadotropes from control and cKO males revealed a profound decrease in expression of gremlin (Grem1), a bone morphogenetic protein (BMP) antagonist. Grem1 was expressed in gonadotropes, but not other cell lineages, in the adult male mouse pituitary. Gata2, Grem1, and Fshb mRNA levels were significantly higher in pituitaries of wild-type males relative to females but decreased in males treated with estradiol and increased following ovariectomy in control but not cKO females. Recombinant gremlin stimulated Fshb expression in pituitary cultures from wild-type mice. Collectively, the data suggest that GATA2 promotes Grem1 expression in gonadotropes and that the gremlin protein potentiates FSH production. The mechanisms of gremlin action have not yet been established but may involve attenuation of BMP binding to activin type II receptors in gonadotropes, potentiating induction of Fshb transcription by activins or related ligands.
2022-07-14 | GSE190060 | GEO
Project description:Mammalian reproduction is dependent on the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, which are secreted by pituitary gonadotrope cells. The zinc-finger transcription factor, GATA2, was previously implicated in FSH production in male mice, although its mechanisms of action and role in females were not determined. To address these gaps in knowledge, we generated and analyzed gonadotrope-specific Gata2 knockout mice using the Cre-lox system. While conditional knockout (cKO) males exhibited ~50% reductions in serum FSH levels and pituitary FSHβ subunit (Fshb) expression relative to controls, FSH production was apparently normal in cKO females. RNA-seq analysis of purified gonadotropes from control and cKO males revealed a profound decrease in expression of gremlin (Grem1), a bone morphogenetic protein (BMP) antagonist. Grem1 was expressed in gonadotropes, but not other cell lineages, in the adult male mouse pituitary. Gata2, Grem1, and Fshb mRNA levels were significantly higher in pituitaries of wild-type males relative to females but decreased in males treated with estradiol and increased following ovariectomy in control but not cKO females. Recombinant gremlin stimulated Fshb expression in pituitary cultures from wild-type mice. Collectively, the data suggest that GATA2 promotes Grem1 expression in gonadotropes and that the gremlin protein potentiates FSH production. The mechanisms of gremlin action have not yet been established but may involve attenuation of BMP binding to activin type II receptors in gonadotropes, potentiating induction of Fshb transcription by activins or related ligands.
2022-07-14 | GSE189915 | GEO
Project description:The Foxo transcription factors regulate multiple cellular functions. Foxo1 and Foxo3 are highly expressed in granulosa cells of ovarian follicles. Selective depletion of the Foxo1 and Foxo3 genes in granulosa cells revealed a novel ovarian-pituitary endocrine feedback loop characterized by: 1) undetectable levels of serum FSH but not LH, 2) reduced expression of the pituitary Fshb gene and its transcriptional regulators and 3) ovarian production of a factor(s) that suppresses pituitary cell Fshb. Equally notable and independent of FSH, depletion of Foxo1/3 altered the expression of specific genes associated with follicle growth versus apoptosis by disrupting critical regulatory interactions of Foxo1/3 with the activin and BMP2 pathways, respectively. As a consequence, granulosa cell proliferation and apoptosis were decreased. These data provide the first evidence that Foxo1/3 divergently regulate follicle growth or death by interacting with the activin and BMP pathways in granulosa cells and by modulating pituitary FSH production. A direct comparison of ovarian granulosa cells from wild type d25, Foxo1/3 dKO d25 and Foxo1/3 dKO 2 month mice.
2013-02-16 | E-GEOD-35593 | biostudies-arrayexpress
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE86119 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE85869 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE86129 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE86127 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE86126 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE86125 | GEO