Fosl2 Regulates FSH‐Dependent Follicle Maturation Through Feedback Amplification of FSH/FSHR Signaling

Follicle stimulating hormone (FSH)‐dependent follicle maturation constitutes the cornerstone of female reproductive cyclicity and fertility, with FSH/FSHR signaling recognized as the regulator. While amplification of this signaling is essential for FSH‐dependent follicle maturation, the molecular drivers remain less well‐understood. Through integrated single‐cell and spatial transcriptomic analyses, we identified Fosl2 as an FSH‐responsive transcription factor exhibiting a dynamic temporal expression pattern that closely mirrored that of the Fshr . In vitro Fosl2 knockdown resulted in notable reductions in granulosa cell proliferation, induced apoptosis, and disrupted FSH‐dependent follicle maturation. In vivo studies using conditional Fosl2 knockout demonstrated a complete halt in FSH‐dependent follicle maturation and resultant infertility. Mechanistic exploration unveiled that FSH/FSHR initiates Fosl2 transcription via the cAMP‐PKA‐CREB cascade, while FOSL2 protein, in turn, acts as a direct transcriptional activator of the Fshr gene itself, as well as estrogen‐synthesis genes ( Cyp11a1 and Cyp19a1 ), thereby establishing a positive feedback loop for FSH/FSHR signaling. Cross‐species validation demonstrated evolutionary conservation of this loop, with Fosl2 knockdown impairing FSH/FSHR signaling in sheep and human. Our findings identify a Fosl2 ‐centered feedback loop essential for amplifying FSH/FSHR, underscoring Fosl2 ’s critical role in reproduction.