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bioRxiv · 10.1101/2025.03.11.642212

FOSL2 Directly Regulates FSHR and CYP11A1 Transcription: An Essential Transcription Factor for Gonadotropin-Dependent Folliculogenesis

Shi, H.·Chen, C.·Ran, Z.·Liao, J.·Wu, Z.·Wang, X.·Zhao, Y.·Ke, W.·Tan, B.·Liu, Y.·Ren, W.·Li, X.·He, C.
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Abstract

The meticulous orchestration of gonadotropin-dependent folliculogenesis constitutes the cornerstone of female reproductive cyclicity and fertility, with FSH/FSHR signaling recognized as the master regulator. Achieving the necessary amplification of this signaling is essential for successful GTH-dependent folliculogenesis, yet the mechanisms remain inadequately defined. Our study utilizes single-cell and spatial transcriptomics to identify FOSL2 as an FSH-inducible transcription factor, exhibiting precise spatiotemporal co-expression with FSHR. FOSL2 knockdown in vitro resulted in notable reductions in granulosa cell proliferation, induced apoptosis, and disrupted gonadotropin-dependent folliculogenesis. In vivo studies using conditional FOSL2 deletion in mouse granulosa cells corroborated these results, demonstrating a complete halt in GTH-dependent folliculogenesis and resultant infertility. Mechanistic exploration unveiled that FSH/FSHR initiates FOSL2 expression via the cAMP/PKA/CREB cascade, while FOSL2 in turn enhances FSHR transcription through direct promoter binding, thereby establishing a self-amplifying loop. This loop represents a molecular switch, modeled to the all-or-nothing dynamics of GTH-dependent folliculogenesis. The evolutionary conservation of this mechanism was confirmed through cross-species analyses in sheep, where FOSL2 deficiency similarly attenuated FSH/FSHR signaling and inhibited follicular growth. Our findings advance the understanding of folliculogenesis by revealing a novel FOSL2-centered amplification loop for FSH/FSHR signaling, highlighting the indispensable role of FOSL2 in reproductive biology.

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Shi, H., Chen, C., Ran, Z., Liao, J., Wu, Z., Wang, X., Zhao, Y., Ke, W., Tan, B., Liu, Y., Ren, W., Li, X., He, C.. 2025-03-13. FOSL2 Directly Regulates FSHR and CYP11A1 Transcription: An Essential Transcription Factor for Gonadotropin-Dependent Folliculogenesis. https://doi.org/10.1101/2025.03.11.642212

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