Transcriptome of the NR5A1 expressing pituitary gonadotropes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216466 | GEO | 2022/10/28
REPOSITORIES: GEO
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Project description:NR5A1 is expressed in the pituitary gonadotropes and regulates their functional differentiation. We have previously identified a pituitary-specific enhancer region located in the 6th intron of the Nr5a1 gene. In this study, deletion of the pituitary enhancer by genome editing abolished the expression of NR5A1 in the pituitary gland, confirming the functional importance of the enhancer. Transcriptomic changes in the enhancer-deleted mouse pituitary were revealed in both males and females.
2022-10-28 | GSE216468 | 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 | 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 | GSE189915 | 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:The inhibins control reproduction by suppressing follicle-stimulating hormone synthesis by pituitary gonadotrope cells. The recently discovered inhibin B co-receptor mediating this inhibition, TGFBR3L, is selectively and highly expressed in gonadotropes in both mice and humans. We sought to characterize mechanisms controlling cell-specific Tgfbr3l/TGFBR3L transcription. We identified two steroidogenic factor 1 (SF-1) cis-elements in the proximal Tgfbr3l promoter in mice. Using single-nucleus ATAC-seq we find that gonadotrope-specific SF-1 (Nr5a1) knockout mice, which exhibit hypogonadotropic hypogonadism, display, contrary to controls, closed chromatin in the promoter region of theTgfbr3l gene in gonadotropes. These, and other, data collectively indicate that SF-1 directly regulates Tgfbr3l/TGFBR3L transcription, contributing to gonadotrope-specific expression of the gene.
2023-03-13 | GSE198907 | GEO
Project description:The pituitary tumors (PA) arise in adenohypophyseal cells and are the second most common tumor in central nervous system. Reflective of their monoclonal cell of origin these tumors could be classified according to the hormone that they produce. The mutational and copy number variation burden in these tumors are scarce, indicating other molecular events are involved in pituitary tumorigenesis. Here we show throughout transcriptome and methylome analysis that there are three readily distinctive molecular signatures. The first group is comprised by the gonadotropes, null cell and silent corticotroph PA, the second group comprised by ACTH PA and the group cluster together the TSH-, PRL- and GH- PA. These groups showed CACNA2D4, EPHA4 and SLIT1 gene up-regulation, respectively. Pathway enrichment analysis support the previous observations. The calcium signaling pathway is characteristic for gonadotropes null cell and silent corticotroph, the Renin-Angiotensin system for the ACTH PA and the Fatty acid metabolisms for the TSH-, PRL-, GH- cluster. The analysis of scRNA-seq from non-tumoral pituitary tissue revealed that these three groups originate since the pituitary development/embryogenesis. The immune cell infiltration landscape revealed that PA could be potentially infiltrated by NK and mast cells. Taken together these results correlate with the expression of the NR5A1, TBX19 and POU1F1 transcription factors, which drive pituitary embryogenesis and theoretically tumorigenesis and potentially indicates three divergent cell precursors cells. We used microarrays to detail the molecular alteration in PA compared to non-tumoral gland.
2020-11-16 | GSE147786 | GEO
Project description:Anterior pituitary cells are highly active with regards to protein synthesis and secretion, processes which depend heavily on mitochondrial ATP production and functional endoplasmic reticula. It is well known that obesity adds an allostatic overload to tissues, requiring them to adapt to inflammation and oxidative stress. Therefore, we hypothesized that the pituitary is highly vulnerable to the stress of high fat diet-induced weight gain. In this study, we utilized a 10-15 week high fat diet (HFD, 60%) plus a thermoneutral housing paradigm, testing both male and female FVB.129P mice. We quantified serum hormones and cytokines, characterized the metabolic phenotype, and defined changes in the pituitary transcriptome using single-cell RNA-seq. Weight gain was significant by 3 weeks in HFD mice, and by 10 weeks all HFD groups had gained 20 g. HFD females (15 weeks) had increased energy expenditure and decreased activity. All HFD groups showed increases in serum leptin, Il-6, resistin, MCP-1, and TNFα. HFD males had increased insulin; both HFD males and females had increased TSH, and HFD females had decreased serum prolactin and growth hormone (GH) pulse amplitude. Pituitary scRNA-seq revealed modest or no changes in pituitary cell gene expression in the different cell types from HFD males after 10 or 15 weeks or HFD females after 10 weeks. However, females exposed to a HFD for 15 weeks showed significant numbers of differentially expressed genes in lactotropes and stem cells. Pathway analyses identified a reduction in pathways that supported protein translation, ribosome biogenesis, and oxidative phosphorylation, indicating mitochondrial dysfunction. Collectively, these studies reveal that pituitary cells from males are more resilient to the oxidative stress of obesity than females and identify the most vulnerable pituitary cell populations in females.
2024-01-04 | GSE244595 | GEO
Project description:The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene expression program in the cysts. We confirmed expression of FOXA1, FOXJ1 and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes, and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
2020-04-22 | GSE149019 | GEO
Project description:The goals of this study is to enrich the population of ovine gonadotropes via adenovirus-mediated targeting and flow cytometry to compare NGS-derived transcriptome profiling (RNA-seq) of a gonadotrope-enriched cell population to the combined transcriptome of all anterior pituitary cells and apply enrichment method to query the transcriptome of sorted ovine pituitary cells in response to treatment with 10 nM estradiol (E2) for six hours. Methods: mRNA profiles of sheep anterior pituitary cells were generated by deep sequencing, in sextuplicates, using Illumina HiSeq. The sequence reads that passed quality filters were analyzed at the transcript level with GSNAP, followed by featureCounts and then followed by edgeR. qRT–PCR validation was performed using SYBR Green assays. Results: About 124 million sequence reads per sample were mapped to the sheep genome (Oar v.3.1) which identified 17,082 transcripts in the pituitaries. RNA-seq data confirmed overrepresentation of genes known to be expressed in pituitary in sorted samples; 11 of genes (5 gonadotrope-specific and 6 non gonadotrope-specific) were validated with qRT–PCR. RNA-seq data had a linear relationship with qRT–PCR. Approximately 7.2% of the transcripts showed differential expression between the sorted (gonadotropes) and unsorted (all anterior pituitary cells) pituitary cells, with a fold change ≥3 and FDR <0.05. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized genes that may contribute to gonadotrope function. 232 genes were detected as upregulated in the sorted GFP-positive cells treated with E2 (gonadotropes) and 31 were downregulated following E2 treatment with a fold change ≥1.5 and FDR <0.1. Conclusions: Our study represents the first detailed analysis of the gonadotrope transcriptome, with 6 biologic replicates, generated by RNA-seq technology. The data analysis workflows reported here should provide a framework for comparative investigations of gonadotrope expression profiles. This method was applied to determine differentially expressed genes in the sorted population of pituitary cells (gonadotropes) in response to 10 nM E2.
2019-10-22 | GSE121685 | GEO
Project description:The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes polypeptide hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence or differentiate into specific cell types, especially thyrotropes, are not well understood. We utilized single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify transcription factors in pituitary stem and endocrine populations, with a focus on thyrotrope subpopulations. We first identified common gene regulatory networks activated in proliferating stem and proliferating endocrine cells. We ascertained Shox2 and Sox14 as candidate regulators of pars distalis and pars tuberalis thyrotropes, respectively, and subsequently found reduced hormone expression in Sox14-knockout pars tuberalis thyrotropes. We further discovered dual-identity cells expressing both POU1F1 and NR5A1 and demonstrated that approximately one-third of pars distalis thyrotropes are descended from NR5A1-expressing cells, typically considered gonadotrope progenitors. We have therefore used single-cell transcriptomics to identify novel developmental mechanisms regulating the specification and hormone expression in thyrotrope subpopulations.
2022-09-02 | GSE205418 | GEO