Luo Jiali, Zhang Jian, Zhang Yu, Li Meihui, Yu Lin, Song Di, Sun Zhaogui
Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Clinical Medical School, Fudan University, Shanghai, China.
Department of Assisted Reproduction, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
Mol Cell Endocrinol. 2025 Feb 1;597:112440. doi: 10.1016/j.mce.2024.112440. Epub 2024 Dec 10.
Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme specifically highly expressed in the brain and gonads. Inhibition of UCHL1 hydrolase activity impairs oocyte maturation. Uchl1 knockout mice exhibit reproductive dysfunction, but the underlying pathogenesis remains unclear.
Uchl1 knockout mice were used to explore the role of UCHL1 in oocyte maturation and follicle development. Oocyte development potential and mitochondrial membrane potential were also assessed to determine UCHL1 function on early embryo development. Transcriptome and proteomic analyses were conducted to elucidate molecular changes associated with Uchl1 knockout.
Uchl1 mice exhibited ovarian dysfunction and infertility, with decreased serum estrogen, reduced antral follicle number, and diminished oocyte developmental potential compared to wild types. Histological examination revealed compromised follicle development and disrupted granulosa cell function in Uchl1 ovaries. In vitro, Uchl1 follicles had impaired preantral follicle development and poor FSH response. Loss of UCHL1 not only leads to mitochondrial dysfunction in oocytes, but also negatively affected estrogen biosynthesis with downregulation of steroidogenic acute regulatory protein (STAR) and estrogen receptor alpha (ER-α) in granulosa cells. Additionally, downregulated expression of connexin 37 (CX37), which is known to impair gap junction intercellular communication between oocyte and granulosa cells, transmitted the Uchl1 gene damage from oocyte to granulosa cells, which in turn affected functions of follicles and even the whole ovary.
Loss of UCHL1 leads to significant disruptions in follicular development and oocyte quality, resulting in infertility. UCHL1 in oocytes influences not only the quality and quantity of the oocytes themselves, but also the follicles and the ovaries as a whole. This disruption ultimately manifests in symptoms similar to diminished ovarian reserve (DOR).
泛素C末端水解酶L1（UCHL1）是一种去泛素化酶，在大脑和性腺中特异性高表达。抑制UCHL1水解酶活性会损害卵母细胞成熟。UCHL1基因敲除小鼠表现出生殖功能障碍，但其潜在发病机制仍不清楚。
使用UCHL1基因敲除小鼠来探索UCHL1在卵母细胞成熟和卵泡发育中的作用。还评估了卵母细胞发育潜能和线粒体膜电位，以确定UCHL1在早期胚胎发育中的功能。进行转录组和蛋白质组分析以阐明与UCHL1基因敲除相关的分子变化。
与野生型相比，UCHL1基因敲除小鼠表现出卵巢功能障碍和不育，血清雌激素降低，窦状卵泡数量减少，卵母细胞发育潜能降低。组织学检查显示UCHL1基因敲除小鼠卵巢中的卵泡发育受损，颗粒细胞功能紊乱。在体外，UCHL1基因敲除的卵泡前卵泡发育受损，对促卵泡生成素（FSH）反应不佳。UCHL1的缺失不仅导致卵母细胞线粒体功能障碍，还通过下调颗粒细胞中的类固醇生成急性调节蛋白（STAR）和雌激素受体α（ER-α）对雌激素生物合成产生负面影响。此外，已知连接蛋白37（CX37）表达下调会损害卵母细胞与颗粒细胞之间的间隙连接细胞间通讯，将UCHL1基因损伤从卵母细胞传递到颗粒细胞，进而影响卵泡甚至整个卵巢的功能。
UCHL1的缺失导致卵泡发育和卵母细胞质量的显著破坏，导致不育。卵母细胞中的UCHL1不仅影响卵母细胞本身的质量和数量，还影响卵泡和整个卵巢。这种破坏最终表现出类似于卵巢储备功能减退（DOR）的症状。
