Granulosa Cell Biology and Insulin-Like Growth Factor Signaling

Granulosa cells form the somatic compartment of the ovarian follicle, providing essential support to the oocyte through nutrient delivery, paracrine factors and steroid hormone synthesis. Their proliferation, differentiation and survival are orchestrated by the interplay of gonadotrophins—principally follicle-stimulating hormone (FSH)—and the insulin-like growth factor (IGF) system. IGF-I and IGF-II, produced locally by granulosa cells, engage the IGF-I receptor to activate key intracellular cascades such as the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, which converge on transcriptional programmes governing steroidogenesis, cell cycle progression and anti-apoptotic mechanisms. The bioavailability of IGFs is tightly regulated by a family of IGF binding proteins (IGFBPs) and their specific proteases, whose dynamic modulation of IGF capture and release underpins follicle selection and dominance. Cross-talk between FSH-driven cyclic AMP-protein kinase A (PKA) signalling and IGF-induced pathways further refines granulosa cell responses, ensuring coordinated follicular growth, oocyte maturation and successful ovulation. Dysregulation of these networks has profound implications for fertility disorders and ovarian pathologies.

Research from Nature Portfolio

Recent studies have demonstrated that PKA activation alone, through expression of a constitutively active PKA mutant, recapitulates the vast majority of FSH-dependent signalling events and gene expression programmes in granulosa cells. Under these conditions, phosphorylation of CREB, β-catenin, AKT, ERK1/2 and additional effector kinases mirrors that induced by FSH, driving transcripts involved in steroid biosynthesis and follicular differentiation. Notably, a subset of genes linked to ovulation is more robustly induced by persistent PKA signalling, highlighting its sufficiency as a master upstream kinase. These findings underscore the central role of PKA in integrating hormonal and growth-factor cues to direct granulosa cell fate and offer a modular framework for interrogating the molecular choreography of follicular maturation.

Granulosa Cell Biology and Insulin-Like Growth Factor Signaling publication trend

The graph below shows the total number of articles in granulosa cell biology and insulin-like growth factor signaling across all publications each year (not limited to Nature Index journals).

Technical terms

Granulosa cell: Somatic ovarian cell that surrounds and supports the oocyte during follicle development.
Insulin-like growth factor (IGF): Peptide growth factors (IGF-I, IGF-II) that promote cell proliferation, differentiation and survival.
IGF binding protein (IGFBP): Family of proteins that bind IGFs, modulating their concentration and receptor access.
Protein Kinase A (PKA): cAMP-dependent serine/threonine kinase that mediates FSH signalling in granulosa cells.
Phosphatidylinositol 3-kinase (PI3K): Lipid kinase that initiates the AKT signalling cascade downstream of growth factor receptors.
Insulin receptor substrate 1 (IRS1): Adaptor protein that links IGF-I receptor activation to downstream PI3K signalling.

References

1. Insulin-Like Growth Factor Binding Proteins and IGFBP Proteases: A Dynamic System Regulating the Ovarian Folliculogenesis. Frontiers in Endocrinology (2018).
2. Protein Kinase A: A Master Kinase of Granulosa Cell Differentiation. Scientific Reports (2016).
3. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway*. Journal of Biological Chemistry (2016).
4. The Insulin‐Like Growth Factor System. Journal of Diabetes Research (2003).