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Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors: modeling the function of an inactivating receptor mutation

ABSTRACT: Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cAMP-dependent signaling pathway and downstream mediators. Interestingly, the WT and A189V mutant receptors activated distinct pathways in a G-protein-coupled receptor signaling assay. FSH stimulation of WT FSHR-expressing cells induced phosphorylation of PI3Kp85a/g, MAPKAPK2 and proteins involved in calcium-dependent signaling, among others, while in the A189V mutant cells FSH induced phosphorylation of e.g., P90RSK, ERK3, and focal adhesion kinase. Lastly, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses, to investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184352 | GEO | 2022/05/01

REPOSITORIES: GEO

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Modeling FSHR function with hPSCs

Project description:Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. We expressed MAC-tagged FSH receptor (FSHR) in HEK293 cells followed by affinity purification mass spectrometry analyses, to investigate interactome of FSHR at resting state and upon FSH stimulation. In total, 19 specific high-confidence interactors for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility.

2021-12-17 | MSV000088577 | MassIVE

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Genome-wide analysis of gonadotropin-dependent gene expression and crosstalk of the regulatory pathways in the female ovaries

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Impact of G protein versus beta-arrestin-dependent signal transduction at the FSH receptor (affy_fsh_human)

Project description:affy_fsh_human - affy_fsh_human - - G protein-coupled receptors (GPCR) are centrally involved in most physiological processes and are a major drug targets. They transduce extracellular signals inside the cells through at least two different mechanisms: i) the classical coupling to heterotrimeric G proteins and ii) a newly discovered beta-arrestin-dependent pathway. The fundamental issue of the respective impacts that these two transduction mechanisms exert on gene regulation has not been clearly addressed to date. To tackle this question, we have developed two mutants of the follicle stimulating hormone (FSH) receptors which do not couple to G proteins upon FSH activation but continue to recruit beta-arrestins and signal through them.-In the present study, we compare the wild-type FSH receptor to either the R466A or the T469F mutants. These two mutations are localized in the second intra cellular loop of the FSH receptor and prevent G protein coupling to the active FSH receptor. Each receptor was permanently expressed in HEK-293 cells at comparable levels. Cells were treated or not for 6 hours with 3 nM FSH. Keywords: treated vs untreated comparison,wt vs mutant comparison 18 arrays - Human GenomeU133A 2.0

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Impact of G protein versus beta-arrestin-dependent signal transduction at the FSH receptor (affy_fsh_human)

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Expression data from cumulus cells from C57Bl/6 and Ptger2 (EP2) KO mice

Project description:To understand the role of prostaglandin (PG) receptor EP2 (Ptger2) signaling in ovulation and fertilization, we investigated time-dependent expression profiles in wild-type (WT) and Ptger2-/- cumuli before and after ovulation by using microarrays. We used Affymetrix U74A ver2 microarrays to investigate gonadotropin-induced gene expression profiles in WT and EP2KO cumulus cells before and after ovulation. Immature mice were primed with pregnant mare serum gonadotropin (PMSG) as an FSH-like stimulation. The cumulus-oocyte complexes (COCs) were isolated from mice 48 h after PMSG injection (H0) and from PMSG-primed mice exposed to human chorionic gonadotropin (hCG) as an LH-like stimulation for 3, 9 or 14 h (H3, H9 or H14, respectively).

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Genome-wide analysis of FSH and LH dependent gene expression and the crosstalk between these two pathways in mice testes

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Project description:PKA activation by FSH is essential to transduce FSH-mediated effects on granulosa cell proliferation, differentiation and steroidogenesis. However, It is unknown whether activation of PKA is sufficient to account for the entire program of granulosa cell responses to FSH. We addressed this question by conducting a comprehensive comparative analysis of signaling pathways and gene expression profiles of granulosa cells stimulated with FSH or expressing a constitutively active PKA mutant, PKA-CQR.

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Laser Capture Microdissection isolation of preovulatory granulosa cells from WT and bERKO ovaries

Project description:Determining the spatial and temporal expression of genes involved in the ovulatory pathway is critical for the understanding of the role of each estrogen receptor in the modulation of folliculogenesis and ovulation. Estrogen receptor (ER) β is highly expressed in ovarian granulosa cells and mice lacking ERβ (βERKO) are subfertile due to inefficient ovulation. Previous work has focused on isolated granulosa cells or cultured follicles and while informative, provides confounding results due to the heterogeneous cell types present including granulosa, theca and oocytes and exposure to in vitro conditions. Herein, we isolated preovulatory granulosa cells from WT and ERβ-null mice using laser capture microdissection to examine the genomic transcriptional response downstream of PMSG (mimicking FSH) and PMSG/hCG (mimicking LH) stimulation. This allows for a direct comparison of in vivo granulosa cells at the same stage of development from both WT and ERβ-null ovaries. ERβ-null granulosa cells showed altered expression of genes known to be regulated by FSH (Akap12 and Runx2) as well as not previously reported (Arnt2 and Pou5f1) in WT granulosa cells. Our analysis also identified 304 genes not previously associated with ERβ in granulosa cells. LH responsive genes including Abcb1b and Fam110c show reduced expression in ERβ-null granulosa cells; however novel genes including Rassf2 and Megf10 were also identified as being downstream of LH signaling in granulosa cells. Collectively, our data suggests that granulosa cells from ERβ-null ovaries may not be appropriately differentiated and are unable to respond properly to gonadotropin stimulation We used microarray to compare the gene expression profiles of wiltype (WT) and Erb-null (bERKO) preovulatory granulosa cells as they respond to either PMSG or PMSG+hCG treatments.

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