Similar Datasets
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:FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremlin expression
| PRJNA785651 | ENA
Project description:Impairments in pituitary FSH synthesis or action cause infertility. However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis. Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH β-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice developed overtly normally but were subfertile in adulthood. Testis size and spermatogenesis were significantly impaired in cKO males. cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls. In contrast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation. Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production. Basal and activin-stimulated Fshb expression was similarly impaired in Foxl2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo.
| S-EPMC3589670 | biostudies-literature
Project description:FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremlin expression [snATAC-Seq]
| PRJNA785652 | ENA
Project description:FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremlin expression [snRNA-Seq]
| PRJNA785648 | ENA
Project description:FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremline expression
| PRJNA785001 | ENA
Project description:Mammalian reproduction depends 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; however, its mechanisms of action and role in females were not determined. To directly address GATA2 function in gonadotropes, we generated and analyzed gonadotrope-specific Gata2 KO mice using the Cre-lox system. We found that while conditional KO (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. In addition, 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. We show Grem1 was expressed in gonadotropes, but not other cell lineages, in the adult male mouse pituitary. Furthermore, Gata2, Grem1, and Fshb mRNA levels were significantly higher in the pituitaries of WT males relative to females but decreased in males treated with estradiol and increased following ovariectomy in control but not cKO females. Finally, we found that recombinant gremlin stimulated Fshb expression in pituitary cultures from WT 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, facilitating induction of Fshb transcription by activins or related ligands.
| S-EPMC9251782 | biostudies-literature
Project description:Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon ? treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.
| S-EPMC3617632 | biostudies-other