ICA1L Forms BAR-domain Complexes with PICK1 and is Critical for Acrosome Formation in Spermiogenesis

Mutations of the Pick1 gene cause globozoospermia, a male infertility disorder in both mice and human. PICK1 is critical for vesicle trafficking and its deficiency in sperm cells leads to abnormal vesicle trafficking from the Golgi to acrosome. This eventually disrupts acrosome formation and leads to male infertility. We identified a novel BAR-domain binding partner of PICK1: ICA1L, which has sequence similarities to ICA69. ICA1L is expressed in testes and brain, and is the major binding partner for PICK1 in testes. ICA1L and PICK1 are highly expressed in spermatids and trafficked together at different stages of spermiogenesis. ICA1L knockout mice were generated by CRISPR-Cas technology. PICK1 expression was reduced by 80% in the testes of male mice lacking ICA1L. Sperms from ICA1L knockout mice had abnormalities in acrosome, nucleus and mitochondrial sheath formation. Both total and mobile sperms were reduced in number and about half of the remaining sperms had characteristics of globozoospermia. These defects ultimately resulted in reduced fertility of male ICA1L knockout mice and the fertility of male mice was completely eliminated in ICA69/ICA1L double knockout mice. Running Title: ICA1L in acrosome formation