Institute of Cellular and Molecular Biology, College of Natural Sciences, The University of Texas at Austin, Austin, TX, United States of America.
The Center for Molecular Carcinogenesis and Toxicology, Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States of America.
PLoS One. 2019 Apr 19;14(4):e0215522. doi: 10.1371/journal.pone.0215522. eCollection 2019.
An imbalance in copper (Cu) tissue homeostasis has a degenerative effect on spermatogenesis and male fertility. The high-affinity Cu transporter 1 (CTR1; SLC31A1) is the major protein responsible for Cu acquisition in eukaryotes and is highly expressed in mouse testes. Studies on yeast and Drosophila have demonstrated the conserved essential function of Cu and CTR1 for meiosis and fertility, implying that CTR1 may play an essential function in mammalian spermatogenesis. In mice, spermatogenesis takes place within the seminiferous epithelium, where tight junctions between somatic Sertoli cells (SCs) create a specialized microenvironment for the development of meiotic germ cells (GCs) by tightly regulating the free transport of metabolites and ions to reach these cells. Here, it is demonstrated that within the seminiferous epithelium, CTR1 is expressed on the membrane of primary pachytene spermatocytes and SCs. To examine the physiological significance of CTR1 in spermatogenesis, mice with a GC-specific (Ctr1ΔGC) and SC-specific (Ctr1ΔSC) disruption of the Ctr1 gene were generated. The testis of Ctr1ΔGC mice exhibits a severe progressive loss of GCs starting at postnatal day (PND) 28 leading to testis hypoplasia by adulthood. No spermatogenic recovery was observed in Ctr1ΔGC testis beyond PND 41, despite the presence of FOXO-1 expressing undifferentiated spermatogonial cells. However, Ctr1ΔSC mice displayed functional spermatogenesis and were fertile, even though testicular Cu levels and Cu-dependent cellular activities were significantly reduced. These results reveal, for the first time, the importance of CTR1 expression by GCs for maintaining functional spermatogenesis.
铜 (Cu) 组织内稳态失衡对精子发生和男性生育力具有退行性影响。高亲和力 Cu 转运蛋白 1 (CTR1; SLC31A1) 是真核生物中负责 Cu 摄取的主要蛋白，在小鼠睾丸中高度表达。酵母和果蝇的研究表明，Cu 和 CTR1 对减数分裂和生育力具有保守的必需功能，这意味着 CTR1 在哺乳动物精子发生中可能发挥着重要作用。在小鼠中，精子发生发生在生精上皮内，生精上皮内体细胞支持细胞 (SCs) 之间的紧密连接通过严格调节代谢物和离子的自由转运来达到这些细胞，从而为减数分裂生殖细胞 (GCs) 的发育创造了一个特殊的微环境。在这里，研究表明在生精上皮内，CTR1 表达在初级粗线期精母细胞和 SC 的膜上。为了研究 CTR1 在精子发生中的生理意义，生成了 GC 特异性 (Ctr1ΔGC) 和 SC 特异性 (Ctr1ΔSC) 破坏 Ctr1 基因的小鼠。Ctr1ΔGC 小鼠的睾丸表现出严重的进行性 GC 丢失，从出生后第 28 天 (PND) 开始导致成年时睾丸发育不良。尽管存在表达 FOXO-1 的未分化精原细胞，但在 PND 41 之后，Ctr1ΔGC 睾丸中没有观察到精子发生恢复。然而，Ctr1ΔSC 小鼠表现出功能性精子发生并且可育，尽管睾丸 Cu 水平和 Cu 依赖性细胞活性显著降低。这些结果首次揭示了 GC 表达 CTR1 对维持功能性精子发生的重要性。
