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.