Epg5 deficiency leads to primary ovarian insufficiency due to WT1 accumulation in mouse granulosa cells

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is an ovarian defect in humans characterized by the premature depletion of ovarian follicles before the age of 40. However, the mechanisms underlying POI remain largely unknown. Here, we show that knockout of Epg5 (ectopic P-granules autophagy protein 5 homolog (C. elegans)) results in subfertility in female mice, which exhibit a POI-like phenotype. Single-cell RNA sequencing analysis revealed that the knockout of Epg5 affected the differentiation of granulosa cells (GCs). Further investigation demonstrated that knockout of Epg5 blocks macroautophagic/autophagic flux, resulting in the accumulation of WT1 (WT1 transcription factor), an essential transcription factor for GCs, suggesting WT1 needs to be selectively degraded by the autophagy pathway. We found that the insufficient degradation of WT1 in the antral follicular stage contributes to reduced expression of steroidogenesis-related genes, thereby disrupting GC differentiation. Collectively, our studies show that EPG5 promotes WT1 degradation in GCs, indicating that the dysregulation of Epg5 in GCs can trigger POI pathogenesis.

Automated summary

This study found that knockout of the Epg5 gene in mice results in reduced fertility and a phenotype similar to POI. Further investigation revealed that Epg5 knockout blocks the autophagy pathway, leading to the accumulation of WT1 and disruption of granulosa cell differentiation, which may contribute to POI pathogenesis.