Lcn9, a member of the lipocalin family, is specifically expressed in the initial segment of the mouse caput epididymis. Lipocalins are a structurally conserved and functionally diverse protein family potentially important for epididymal functions. Lcn9's potential roles in sperm maturation have been a focus of study, and genetic mouse models have been crucial in uncovering its functions [3,7].

In Lcn9 knockout (KO) male mice, spermatogenesis and fertility remained normal, and there were no effects on the ratio of morphologically abnormal sperm, sperm motility, and sperm spontaneous acrosome reaction frequencies [1]. However, in studies involving multiple gene knockouts, the lipocalin family quadruple KO (including Lcn9) and quintuple KO male mice showed subfertility or infertility, potentially due to reduced amounts of ADAM3, an essential protein for sperm binding to the zona pellucida [6]. Additionally, Lcn9-Cre knock-in (KI) mouse lines have been generated. These mice express Cre recombinase in the principal cells of the epididymal initial segment, enabling entire IS-specific conditional gene editing for gene functional study [2]. This has been used in conditional knockout (CKO) models for genes like Exosc10 and DIS3, showing that their deficiency in the initial segment did not affect sperm maturation and male fertility [4,5].

In conclusion, while Lcn9 single-KO mice do not exhibit obvious sperm-related phenotypes, its involvement in multi-gene knockout models suggests it may play a role in sperm maturation and male fertility when combined with other lipocalin family members. The Lcn9-Cre mouse model has significantly contributed to in vivo functional studies of genes in the epididymal initial segment, potentially providing insights into male infertility and related conditions [1,2,4-6].

References:

1. Wen, Zongzhuang, Liu, Dongyue, Zhu, Haixia, Ye, Chao, Gao, Jiangang. 2021. Deficiency for Lcn8 causes epididymal sperm maturation defects in mice. In Biochemical and biophysical research communications, 548, 7-13. doi:10.1016/j.bbrc.2021.02.052. https://pubmed.ncbi.nlm.nih.gov/33631677/

2. Gong, Qian-Qian, Wang, Xiao, Dou, Zhi-Lin, Gao, Jian-Gang, Sun, Xiao-Yang. 2021. A novel mouse line with epididymal initial segment-specific expression of Cre recombinase driven by the endogenous Lcn9 promoter. In PloS one, 16, e0254802. doi:10.1371/journal.pone.0254802. https://pubmed.ncbi.nlm.nih.gov/34310634/

3. Li, Xiangqi, Zhan, Xiaoni, Liu, Shigui, Liu, Qiang, Zhang, Yonglian. . Cloning and primary characterizations of rLcn9, a new member of epididymal lipocalins in rat. In Acta biochimica et biophysica Sinica, 44, 876-85. doi:. https://pubmed.ncbi.nlm.nih.gov/23017836/

4. Zhou, Meiyang, Yu, Junjie, Xu, Yu, Li, Nana, Wang, Zhengpin. 2024. Exosc10 deficiency in the initial segment is dispensable for sperm maturation and male fertility in mice. In Zygote (Cambridge, England), 32, 437-445. doi:10.1017/S0967199424000418. https://pubmed.ncbi.nlm.nih.gov/39552503/

5. Qiu, Fanyi, Wang, Xiao, Zhou, Meiyang, Yu, Junjie, Wang, Zhengpin. 2023. Epididymal DIS3 exosome ribonuclease is not necessary for mouse sperm maturation or fertility. In Biochemical and biophysical research communications, 666, 36-44. doi:10.1016/j.bbrc.2023.05.023. https://pubmed.ncbi.nlm.nih.gov/37172450/

6. 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/

7. Suzuki, Kichiya, Lareyre, Jean-Jacques, Sánchez, Diego, Matusik, Robert J, Orgebin-Crist, Marie-Claire. . Molecular evolution of epididymal lipocalin genes localized on mouse chromosome 2. In Gene, 339, 49-59. doi:. https://pubmed.ncbi.nlm.nih.gov/15363845/