Granulosa Cell Apoptosis Mechanisms in Ovarian Follicle Development

Granulosa cells form the somatic compartment of ovarian follicles, nurturing the oocyte and producing steroid hormones critical for reproductive function. Apoptosis of these cells drives follicular atresia, the primary fate of non-ovulatory follicles, and thereby regulates the pool of mature oocytes. A complex interplay of signalling pathways—including transforming growth factor-β (TGF-β), Wnt, PI3K/Akt and death receptor cascades—converges on mitochondria and caspases to determine cell survival or programmed death. Non-coding RNAs, notably microRNAs and long non-coding RNAs, fine-tune these signals through competing endogenous RNA interactions, transcriptional repression or mRNA stabilisation. Oxidative stress also contributes by elevating reactive oxygen species, which can trigger intrinsic apoptotic pathways. Understanding these mechanisms is crucial for addressing infertility, improving assisted reproductive technologies and enhancing fertility traits in livestock.

Research from Nature Portfolio

Recent studies have demonstrated that a long intergenic non-coding RNA designated NORFA serves as a guardian of granulosa cell integrity by sponging miR-126. This interaction relieves repression of the TGF-β receptor TGFBR2, sustaining TGF-β signalling and suppressing caspase-mediated apoptosis. A breed-specific promoter duplication enhances NORFA transcriptional activity via recruitment of transcription factor NFIX, underlining the potential for genetic modulation of fertility. In a foundational investigation, conserved miR-26b was shown to promote granulosa cell apoptosis by directly targeting the enzyme hyaluronan synthase 2 (HAS2). Loss of HAS2 attenuates the HAS2–hyaluronic acid–CD44 axis, leading to Caspase-3 activation. These insights offer potential targets for therapeutic intervention in ovarian dysfunction and for selective breeding programmes aimed at optimising litter size.

Granulosa Cell Apoptosis Mechanisms in Ovarian Follicle Development publication trend

The graph below shows the total number of articles in granulosa cell apoptosis mechanisms in ovarian follicle development across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: Programmed cell death characterised by caspase activation, DNA fragmentation and membrane blebbing.

Follicular atresia: The degeneration and resorption of ovarian follicles due to granulosa cell apoptosis.

Long non-coding RNA (lncRNA): RNA transcripts longer than 200 nucleotides that regulate gene expression without encoding proteins.

MicroRNA (miRNA): Small non-coding RNAs (~22 nucleotides) that bind complementary mRNAs to repress translation or induce degradation.

Competing endogenous RNA (ceRNA): A regulatory mechanism wherein RNAs share microRNA response elements and compete for binding, influencing each other’s expression.

Transforming growth factor-β (TGF-β) signalling: A pathway involving ligands, receptors (TGFBRs) and SMAD transcription factors that modulate cell proliferation, differentiation and apoptosis.

Oxidative stress: Cellular damage induced by an imbalance between reactive oxygen species production and antioxidant defence mechanisms.

References

1. NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death. Communications Biology (2020).
2. Conserved miR-26b enhances ovarian granulosa cell apoptosis through HAS2-HA-CD44-Caspase-3 pathway by targeting HAS2. Scientific Reports (2016).
3. A regulatory network controlling ovarian granulosa cell death. Cell Death Discovery (2023).
4. SDNOR, a Novel Antioxidative lncRNA, Is Essential for Maintaining the Normal State and Function of Porcine Follicular Granulosa Cells. Antioxidants (2023).
5. miR-423 sponged by lncRNA NORHA inhibits granulosa cell apoptosis. Journal of Animal Science and Biotechnology (2023).