Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, P.R. China.
Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
J Cell Mol Med. 2024 Jun;28(12):e18487. doi: 10.1111/jcmm.18487.
Premature ovarian insufficiency (POI) is one of the important causes of female infertility. Yet the aetiology for POI is still elusive. FBXW7 (F-box with 7 tandem WD) is one of the important components of the Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase. FBXW7 can regulate cell growth, survival and pluripotency through mediating ubiquitylation and degradation of target proteins via triggering the ubiquitin-proteasome system, and is associated with tumorigenesis, haematopoiesis and testis development. However, evidence establishing the function of FBXW7 in ovary is still lacking. Here, we showed that FBXW7 protein level was significantly decreased in the ovaries of the cisplatin-induced POI mouse model. We further showed that mice with oocyte-specific deletion of Fbxw7 demonstrated POI, characterized with folliculogenic defects, early depletion of follicle reserve, disordered hormonal secretion, ovarian dysfunction and female infertility. Impaired oocyte-GCs communication, manifested as down-regulation of connexin 37, may contribute to follicular development failure in the Fbxw7-mutant mice. Furthermore, single-cell RNA sequencing and in situ hybridization results indicated an accumulation of Clu and Ccl2 transcripts, which may alter follicle microenvironment deleterious to oocyte development and accelerate POI. Our results establish the important role of Fbxw7 in folliculogenesis and ovarian function, and might provide valuable information for understanding POI and female infertility.
卵巢早衰（POI）是女性不孕的重要原因之一。然而，POI 的病因仍然难以捉摸。FBXW7（具有 7 个串联 WD 的 F-box）是 Skp1-Cullin1-F-box（SCF）E3 泛素连接酶的重要组成部分之一。FBXW7 通过触发泛素-蛋白酶体系统介导靶蛋白的泛素化和降解，可调节细胞生长、存活和多能性，与肿瘤发生、造血和睾丸发育有关。然而，尚缺乏 FBXW7 在卵巢中功能的证据。在这里，我们表明 FBXW7 蛋白水平在顺铂诱导的 POI 小鼠模型的卵巢中显著降低。我们进一步表明，卵母细胞特异性缺失 Fbxw7 的小鼠表现出 POI，其特征是卵泡生成缺陷、卵泡储备早期耗竭、激素分泌紊乱、卵巢功能障碍和女性不孕。卵母细胞-GC 通讯受损，表现为连接蛋白 37 的下调，可能导致 Fbxw7 突变小鼠卵泡发育失败。此外，单细胞 RNA 测序和原位杂交结果表明 Clu 和 Ccl2 转录本的积累，这可能改变卵泡微环境，不利于卵母细胞发育并加速 POI。我们的研究结果确立了 Fbxw7 在卵泡发生和卵巢功能中的重要作用，可能为理解 POI 和女性不孕提供有价值的信息。
