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Comparative analysis of PI3K-AKT and MEK-ERK1/2 signaling-driven molecular changes in granulosa cells

Vijay Simha Baddela, Marten Michaelis, Xuelian Tao

    Reproduction (Cambridge, England)
    |December 12, 2024
    PubMed

    Insights

    The PI3K-AKT and MEK-ERK pathways regulate steroidogenesis and metabolism in granulosa cells. Both pathways are crucial for estradiol and progesterone production, as well as cellular energy processes.

    Area of Science:

    • Reproductive Biology
    • Molecular Endocrinology
    • Cellular Metabolism

    Background:

    • The PI3K-AKT and MEK-ERK1/2 signaling pathways are critical for granulosa cell (GC) function, influencing proliferation, viability, and differentiation.
    • Follicle-stimulating hormone (FSH) and IGF1 activate these pathways in GCs via their respective receptors.
    • Both pathways play essential roles in regulating the metabolic activity of GCs, including glycolysis and mitochondrial function.

    Purpose of the Study:

    • To comparatively analyze the transcriptome changes induced by the AKT and ERK (ERK1/2) pathways in GCs.
    • To elucidate the distinct and overlapping gene regulatory roles of AKT and ERK in GC steroidogenesis and metabolism.
    • To identify novel candidate genes regulated by these pathways in GCs.

    Main Methods:

    • GCs were isolated from antral follicles and treated with FSH and IGF1.
    • Inhibitors were used to investigate the specific roles of AKT and ERK pathways.
    • Transcriptome analysis (RNA sequencing) was performed to identify differentially expressed genes.
    • Bioinformatics analysis was employed to interpret pathway impacts.
    • Validation experiments included radioimmunoassays and mRNA/protein analysis of key genes (CYP19A1, STAR).

    Main Results:

    • AKT pathway regulated 1436 genes, while ERK pathway regulated 654 genes in GCs.
    • 94 genes were commonly downregulated, 11 commonly upregulated, and 110 oppositely regulated by AKT and ERK inhibition.
    • AKT inhibition impacted FSH, ESRRG, and HIF1 pathways; ERK inhibition affected CG, FOS, TGFβ, EGR1, and LH pathways.
    • Estradiol production was induced by AKT and inhibited by ERK, confirmed by gene and protein analysis.
    • Both pathways are essential for GC glucose uptake, lactate production, and mitochondrial activity.

    Conclusions:

    • The PI3K-AKT and MEK-ERK pathways differentially regulate steroidogenesis and cellular metabolism in granulosa cells.
    • These pathways coordinate key reproductive processes and metabolic functions, impacting estradiol and progesterone production.
    • The findings provide a valuable resource for future research into novel genes and therapeutic targets in reproductive endocrinology and cell biology.
    Keywords:
    MEK-ERK1/2PI3K-AKTgranulosa cellsmetabolismovarysex steroids

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