（通讯员 施泓如）在卵泡期，快速的卵泡腔扩张、成熟是维持雌性生育力与周期性发情行为的生理基础。在这一过程中，促卵泡素（FSH）信号扮演“总指挥”角色。然而，FSH信号需要 “放大”到足够强度，才能支撑快速的卵泡腔扩张与成熟。长期以来，关于该信号如何实现微弱启动后迅速放大，尚不完全清楚。
近日，五楼自拍
研究团队联合湖北省妇幼保健院等单位，就这一问题给出了新解释。他们在卵巢中发现一个名为FOSL2的转录因子，是FSH信号放大不可或缺的“倍增器”。基于空间组学、基因编辑与动物实验，研究团队首次展示了FOSL2放大FSH信号的分子路径（图1）：
1. 启动阶段： FSH作用于卵泡颗粒细胞，通过cAMP-PKA-CREB通路，快速刺激FOSL2基因的转录与翻译；
2. 放大阶段: 反过来，FOSL2结合于FSH受体（FSHR）的启动子，持续激活FSHR的转录，从而迅速放大卵泡中FSH信号；
3. 并行放大阶段： 在增强FSHR转录的同时，FOSL2直接激活类固醇合成酶CYP11A1与CYP19A1转录，刺激雌激素分泌。从而进一步提高卵泡对FSH信号的敏感性，并诱导动物进入发情期。
图1. FOSL2驱动的FSH信号放大环刺激卵泡快速扩张、成熟
通过上述过程，卵泡内迅速建立起1条由FOSL2驱动的FSH信号正反馈放大环，它推动卵泡腔快速扩张、成熟。经验证，这一放大环在羊、小鼠和人上保守存在，是卵泡发育必不可少的。卵泡细胞缺失FOSL2后，FSH信号无法放大，小鼠卵泡发育被完全阻断在小腔卵泡阶段，血液中几乎检测不到雌激素，发情周期停止并彻底失去生育力。该放大环就像车辆的涡轮增压器，FSH的作用是踩下油门，而FOSL2就是那个让发动机动力倍增的涡轮。没有它，即便油门踩到底，也无法完成超车。
这项研究以“Fosl2 regulates FSH-dependent follicle maturation through feedback amplification of FSH/FSHR signaling”为题，发表于国际期刊《Advanced Science》。它证实了“FOSL2驱动的FSH信号放大环”在卵泡腔快速扩张与成熟时期不可或缺的作用，为优化超数排卵方案、治疗FSH抵抗相关不孕、培育家畜多胎品种提供了潜在靶点。何长久、李翔、任为是论文共同通讯作者；施泓如、陈朝丽、冉早红为共同一作；廖建宁、吴子安、王晓东、赵永恒、柯文凯、谭博文等参与了研究工作；山东大学苏友强教授为研究提供了帮助。该研究由中央高校基本科研资金、国家自然科学基金等项目资助。
论文链接：//advanced.onlinelibrary.wiley.com/doi/10.1002/advs.75223
【英文摘要】
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.
