ADAM5 is required for sperm-zona pellucida binding and sperm oviduct migration†

ADAM5 is a testis-specific transmembrane protein whose role in male fertility remains poorly understood. In this study, we report that Adam5 knockout (KO) male mice are severely subfertile, despite exhibiting normal testicular morphology, sperm structure, and motility. Adam5 KO sperm failed to transit the uterotubal junction (UTJ) and displayed severe defects in zona pellucida (ZP) binding, phenotypes that resemble those observed in Adam2 and Adam3 knockout mice. Western blot analysis revealed a significant reduction in the levels of ADAM2 and ADAM3 in Adam5 KO spermatozoa, supporting the previous finding that ADAM5 interacts with these proteins to form a complex. Additionally, Adam5 KO spermatozoa exhibited reduced binding to extracellular matrix (ECM) components, including Laminin I and Fibronectin. These findings suggest that ADAM5 plays a crucial role in sperm ECM interaction, a process likely critical for successful UTJ transit and ZP binding. While ADAM5 is a pseudogene in humans, our results provide valuable insights into the function of ADAM family proteins in mammalian reproduction.