Lcn6, a lipocalin protein, is predominantly expressed in the epididymis and located on the sperm surface. It may be involved in male fertility-related processes, and its expression is upregulated by androgen in mice [1,2]. Some studies suggest its potential roles in heart failure, epithelial ovarian carcinoma, and as a biomarker in right ventricular heart failure [3,5,6].

In conditional Lcn6 knockout (KO) mice, spermatogenesis was normal, and the natural birth rate of male mice and the in-vitro fertilization ability of their cauda epididymal sperm were unaffected. However, sperm from the cauda epididymis of Lcn6 null mice had a sustained increase in acrosome reaction frequency, whether capacitated or not, and a significantly increased intracellular calcium content when extracellular calcium was supplied. These findings indicate that Lcn6 is important in preventing calcium overload and premature acrosome reaction of sperm, suggesting its role in sperm maturation [1]. In addition, quadruple and quintuple KO of multiple lipocalin family genes including Lcn6 in mice led to subfertility or infertility, potentially due to reduced ADAM3, an essential protein for sperm-zona pellucida binding [4].

In summary, Lcn6 plays a crucial role in sperm maturation, specifically in preventing premature acrosome reaction and calcium overload in sperm. The study of Lcn6 KO mouse models has provided valuable insights into male subfertility, highlighting the importance of this gene in reproductive biology.

References:

1. Yin, Qianqian, Shen, Jia, Wan, Xiaofeng, Zhou, Yuchuan, Zhang, Yonglian. . Impaired sperm maturation in conditional Lcn6 knockout mice. In Biology of reproduction, 98, 28-41. doi:10.1093/biolre/iox128. https://pubmed.ncbi.nlm.nih.gov/29045572/

2. Hamil, Katherine G, Liu, Qiang, Sivashanmugam, P, French, Frank S, Hall, Susan H. 2003. LCN6, a novel human epididymal lipocalin. In Reproductive biology and endocrinology : RB&E, 1, 112. doi:. https://pubmed.ncbi.nlm.nih.gov/14617364/

3. Wang, Wanrong, Xia, Jie, Shen, Yu, Gao, Shan, Zhou, Kai. 2024. Potential diagnostic biomarkers in heart failure: Suppressed immune-associated genes identified by bioinformatic analysis and machine learning. In European journal of pharmacology, 986, 177153. doi:10.1016/j.ejphar.2024.177153. https://pubmed.ncbi.nlm.nih.gov/39586393/

4. Sakurai, Nobuyuki, Fujihara, Yoshitaka, Kobayashi, Kiyonori, Ikawa, Masahito. 2022. Nuclease technology-mediated disruption of lipocalins, Ly6g5b, and Ly6g5c causes male subfertility in mice. In Andrology, 12, 981-990. doi:10.1111/andr.13350. https://pubmed.ncbi.nlm.nih.gov/36428102/

5. Su, Tong, Zhang, Panpan, Zhao, Fujun, Zhang, Shu. 2021. A novel immune-related prognostic signature in epithelial ovarian carcinoma. In Aging, 13, 10289-10311. doi:10.18632/aging.202792. https://pubmed.ncbi.nlm.nih.gov/33819196/

6. di Salvo, Thomas G, Yang, Kai-Chien, Brittain, Evan, Maltais, Simon, Hemnes, Anna. 2015. Right ventricular myocardial biomarkers in human heart failure. In Journal of cardiac failure, 21, 398-411. doi:10.1016/j.cardfail.2015.02.005. https://pubmed.ncbi.nlm.nih.gov/25725476/