Testis-enriched ferlin, FER1L5, is required for Ca2+-activated acrosome reaction and male fertility

Spermatozoa need to undergo an exocytotic event called the acrosome reaction before fusing with eggs. Al-though calcium ion (Ca2+) is essential for the acrosome reaction, its molecular mechanism remains unknown. Ferlin is a single transmembrane protein with multiple Ca2+-binding C2 domains, and there are six ferlins, dys-ferlin (DYSF), otoferlin (OTOF), myoferlin (MYOF), fer-1-like 4 (FER1L4), FER1L5, and FER1L6, in mammals. Dysf, Otof, and Myof knockout mice have been generated, and each knockout mouse line exhibited membrane fusion disorders such as muscular dystrophy in Dysf, deafness in Otof, and abnormal myogenesis in Myof. Here, by generating mutant mice of Fer1l4, Fer1l5, and Fer1l6, we found that only Fer1l5 is required for male fertility. Fer1l5 mutant spermatozoa could migrate in the female reproductive tract and reach eggs, but no acrosome reaction took place. Even a Ca2+ ionophore cannot induce the acrosome reaction in Fer1l5 mutant spermatozoa. These results suggest that FER1L5 is the missing link between Ca2+ and the acrosome reaction.

Automated summary

Spermatozoa undergo the acrosome reaction before fusing with eggs, and the molecular mechanism of this reaction involving calcium ion (Ca2+) remains unclear. Ferlin proteins, including Fer1l5, have C2 domains that bind to Ca2+. In this study, Fer1l5 was found to be essential for male fertility, as mutant spermatozoa lacking Fer1l5 were unable to undergo the acrosome reaction even with the use of a Ca2+ ionophore. These findings suggest that FER1L5 acts as the missing link between Ca2+ and the acrosome reaction.