Reduced Fertility and Altered Epididymal and Sperm Integrity in Mice Lacking ADAM71

Abstract

The mammalian epididymis is a highly convoluted tubule that connects the testis to the vas deferens. Its proper functions in sperm transport, storage, and maturation are essential for male reproduction. One of the genes predominantly expressed in the epididymis is ADAM7 (a disintegrin and metalloprotease 7). Previous studies have shown that ADAM7 synthesized in the epididymis is secreted into the epididymal lumen and is then transferred to sperm membranes, where it forms a chaperone complex that is potentially involved in sperm fertility. In this study, we generated and analyzed mice with a targeted disruption in the Adam7 gene. We found that the fertility of male mice was modestly but significantly reduced by knockout of Adam7. Histological analyses revealed that the cell heights of the epithelium were dramatically decreased in the caput of the epididymis of Adam7-null mice, suggesting a requirement for ADAM7 in maintaining the integrity of the epididymal epithelium. We found that sperm from Adam7-null mice exhibit decreased motility, tail deformation, and altered tyrosine phosphorylation, indicating that the absence of ADAM7 leads to abnormal sperm functions and morphology. Western blot analyses revealed reduced levels of integral membrane protein 2B (ITM2B) and ADAM2 in sperm from Adam7-null mice, suggesting a requirement for ADAM7 in normal expression of sperm membrane proteins involved in sperm functions. Collectively, our study demonstrates for the first time that ADAM7 is required for normal fertility and is important for the maintenance of epididymal integrity and for sperm morphology, motility, and membrane proteins.

An update of the regulatory factors of sperm migration from the uterus into the oviduct by genetically manipulated mice

“…Despite their common characteristics for processing and localization, except for ADAM1, these ADAM proteins differ in the regulation and maintenance of their integrity. Previous studies based on the protein expression phenotypes in mouse KO models of Adam1a , Adam1b , Adam2 , Adam3 , Adam6 , and Adam7 have indicated that these ADAMs have intricate regulatory relationships (Figure ; Cho et al, , ; Kim, Yamashita, et al, 2006; Nishimura et al, ; Shamsadin et al, ; Voronina et al, ; Yamaguchi et al, ). In Adam1a ‐null mice, ADAM1B and ADAM2 are expressed normally in both testicular germ cells and epididymal mature sperm.…”

“…With the exception of Adam1b ‐null mice, these KO mice exhibit complicated phenotypes of fertilization defects, among which Adam1a , Adam2 , Adam3 , and Adam6 ‐deficient male mice are sterile because of a failure of the sperm to pass through the UTJ in the female genital tract (Cho et al, ; Kim, Yamashita, et al, 2006; Nishimura, Kim, Nakanishi, & Baba, ; Shamsadin et al, ; Voronina et al, ; Yamaguchi et al, ). The phenotypes of Adam7 ‐null mice slightly differ from those of Adam1a −/− , Adam2 −/− , Adam3 −/− , and Adam6 −/− strains (Choi et al, ). The sperm from Adam7 ‐deficient mice display decreased motility and tail deformation (Choi et al, ).…”

“…The phenotypes of Adam7 ‐null mice slightly differ from those of Adam1a −/− , Adam2 −/− , Adam3 −/− , and Adam6 −/− strains (Choi et al, ). The sperm from Adam7 ‐deficient mice display decreased motility and tail deformation (Choi et al, ). Although there are currently no mouse KO models for Adam4 and Adam5 , it is still believed that these two ADAMs are likely to participate in fertilization, such as the ascent of sperm into the oviduct, because ADAM4 or ADAM5 and ADAM2–ADAM3 always exist in a trimeric complex (Cho, ; Han et al, ; Kim, Oh, et al, 2006).…”

“…In Adam6 ‐deficient mice, the expression of ADAM2 and ADAM3 proteins is mostly unchanged in the testis when compared to that in wild‐type mice, while the ADAM2 levels are reduced and the mature form of ADAM3 is undetected in the epididymides and sperm of Adam6 ‐null mice (Voronina et al, ). In Adam7 ‐deficient mice, the level of the small, minor form of ADAM2 is also reduced, but the amounts of other proteins, such as ADAM3, ADAM4, ADAM5, and ADAM6, are not affected (Figure ; Choi et al, ).…”

“…Furthermore, the fertility of Adam7 ‐deficient mice is significantly reduced, and the cell heights of the epithelium are dramatically decreased in the caput of the epididymis of Adam7 ‐null mice. The sperm from Adam7 ‐deficient mice also exhibits decreased motility, tail deformation, and altered tyrosine phosphorylation (Choi et al, ). This finding implies that ADAM7 is essential for normal fertility and is important for the maintenance of epididymal integrity and for morphology and motility of sperm but is not crucial for sperm migration across the UTJ and penetration of the ZP.…”