Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 5650871, Japan.
PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, 3320012, Japan.
Nat Commun. 2023 Apr 24;14(1):2354. doi: 10.1038/s41467-023-37984-x.
The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the epididymis. Males lacking Nicol are sterile due to impaired NELL2-mediated lumicrine signalling, leading to defective epididymal differentiation and deficient sperm maturation but can be restored by NICOL expression in testicular germ cells. Our results demonstrate how lumicrine signalling regulates epididymal function for successful sperm maturation and male fertility.
哺乳动物精子在睾丸中产生，需要在附睾中进行功能成熟才能完全成熟。附睾精子成熟受管腔旁信号通路调控，其中睾丸来源的分泌信号迁移到附睾管腔，并促进功能分化。然而，管腔旁信号调控的详细机制尚不清楚。本文中，我们证明了一种小分泌蛋白，NELL2 管腔旁信号的相互作用共因子（NICOL），在小鼠的管腔旁信号中发挥关键作用。NICOL 在包括睾丸在内的男性生殖器官中表达，并与睾丸分泌的蛋白 NELL2 形成复合物，该复合物从睾丸穿过细胞层转运到附睾。缺乏 Nicol 的雄性由于 NELL2 介导的管腔旁信号受损而不育，导致附睾分化缺陷和精子成熟不足，但通过睾丸生殖细胞中 NICOL 的表达可以恢复。我们的研究结果证明了管腔旁信号如何调节附睾功能以实现精子成熟和男性生育能力。
