Identification of Ywhab as a Candidate Downstream Target of Figla During Ovarian Reserve Establishment.

Early follicular development and primordial follicle formation are essential for ovarian reserve establishment, and disruption of this process may contribute to fertility disorders such as premature ovarian insufficiency (POI). Figla is an oocyte-specific transcription factor required for primordial follicle formation, but its candidate downstream genes and associated pathways remain incompletely understood. This study aimed to investigate the role of Figla in early follicular development and to explore its potential downstream regulatory events. A Figla knockout mouse model was generated to evaluate the effects of Figla deficiency on ovarian development and primordial follicle formation. ChIP-seq, motif analysis, and promoter activity assays were performed to identify FIGLA-associated chromatin regions and candidate genes. In addition, Figla overexpression and Ywhab knockdown experiments were conducted in a granulosa cell line, together with ovarian tissue Western blot analysis, to assess changes in growth activity, migration, ERK phosphorylation, and apoptosis-related markers. Figla was highly expressed in late embryonic and early postnatal ovaries, and its deletion primarily disrupted perinatal primordial follicle assembly, accompanied by progressive oocyte loss. ChIP-seq, motif, and promoter analyses supported Ywhab as a candidate gene potentially regulated by Figla. In KGN cells, Figla overexpression increased Ywhab expression and coincided with greater growth activity, migration, ERK phosphorylation, and changes in BAD/BCL-2/BAX-related markers. These cellular and signaling changes were attenuated by Ywhab knockdown. Additional ovarian tissue analysis showed reduced p-ERK/ERK and increased p-BAD/BAD ratios in Figla(-/-) ovaries. These findings support Ywhab as a candidate downstream gene potentially regulated by Figla and suggest a possible link between Figla-associated transcriptional regulation and cellular processes relevant to early follicular development. Further validation is needed before extending these findings to ovarian reserve establishment more broadly or to POI-related reproductive disorders.