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

Abstract

Spermatozoa need to undergo an exocytotic event called the acrosome reaction before fusing with eggs. Although 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, dysferlin (DYSF), otoferlin (OTOF), myoferlin (MYOF), fer-1-like 4 (FER1L4), FER1L5, and FER1L6, in mammals. <i>Dysf</i>, <i>Otof</i>, and <i>Myof</i> knockout mice have been generated, and each knockout mouse line exhibited membrane fusion disorders such as muscular dystrophy in <i>Dysf</i>, deafness in <i>Otof</i>, and abnormal myogenesis in <i>Myof</i>. Here, by generating mutant mice of <i>Fer1l4</i>, <i>Fer1l5</i>, and <i>Fer1l6</i>, we found that only <i>Fer1l5</i> is required for male fertility. <i>Fer1l5</i> 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 <i>Fer1l5</i> mutant spermatozoa. These results suggest that FER1L5 is the missing link between Ca²⁺ and the acrosome reaction.