The proteasome, an evolutionarily conserved proteolytic complex comprising the 20S core particle and 19S regulatory particles, performs both shared and distinct functions across various tissues and organs. Spermatogenesis, a highly complex developmental process, relies on proteasome activity at multiple stages to regulate protein turnover. In this study, we selected the 20S subunit PSMA1 and 19S regulatory subunit PSMD2 to investigate the potential functions of the proteasome in spermatogenesis. Using Psma1-EGFP and Psmd2-mCherry knock-in mouse models, we confirmed the expression of both subunits in all spermatogenic cell types, with pronounced presence in early germ cell development. To further clarify their functional significance, we specifically knocked out Psma1 and Psmd2 in germ cells. Deletion of either PSMA1 or PSMD2 led to disrupted spermatogenesis, characterized by the complete absence of sperm in the epididymis. Subsequent analysis indicated that loss of these proteasome components impaired meiotic initiation. Psma1 and Psmd2 knockout germ cells showed accumulation of DMRT1, a key regulator of mitosis-to-meiosis transition, leading to a reduction in STRA8 levels and consequent disruption of meiosis initiation. This study sheds light on the molecular mechanisms that govern meiotic initiation and identifies potential genes associated with male infertility.
蛋白酶体是一种进化保守的蛋白水解复合物，由20S核心颗粒和19S调节颗粒组成，在不同的组织或器官中表现出一致和独特的功能。精子发生是一个高度复杂的过程，并在各个阶段依赖蛋白酶体来调节蛋白质周转。为了研究蛋白酶体在精子发生过程中的潜在功能，我们选择了20S亚基PSMA1和19S亚基PSMD2进行进一步研究。我们建立了 Psma1-EGFP和 Psmd2-mCherry敲入小鼠模型，发现这两种成分在精子发生过程中的所有细胞类型中都有表达，特别是在生殖细胞发育的早期阶段。为了进一步研究它们的潜在功能，我们分别在生殖细胞中敲除 Psma1和 Psmd2。生殖细胞中PSMA1或PSMD2的缺失导致精子发生阻滞，附睾中精子的完全缺失。进一步的分析表明，这些蛋白酶体成分的缺失损害了减数分裂的起始过程。我们发现在 Psma1或 Psmd2敲除的生殖细胞中有丝分裂-减数分裂转换的关键调节因子DMRT1积累，导致STRA8的减少，从而破坏减数分裂的起始。我们的研究揭示了控制减数分裂起始的分子机制，并确定了与男性不育相关的潜在基因。.
Keywords: Meiotic initiation; PSMA1; PSMD2; Proteasome; Spermatogenesis.