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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. Abbreviations:  3-MA, 3-methyladenine; CHX, cycloheximide; CQ, chloroquine; EPG5, ectopic P-granules autophagy protein 5 homolog ( C. elegans ); GC, granulosa cell; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MII, metaphase II; POI, primary ovarian insufficiency; PB1, polar body 1; SQSTM1/p62, sequestosome 1; WT1, WT1 transcription factor

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