Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice.

During spermiogenesis, haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes, which are required for successful fertilization. Severe deformities in flagella cause a male infertility syndrome, multiple morphological abnormalities of the flagella (MMAF), while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential. However, evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited. Here, we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38 (Ccdc38) via inducing a nonsense mutation and find that the males are infertile. The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes. We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm. Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3, a protein associated with acrosome biogenesis, in testes and an aberrant distribution of TEKT3 in sperm. We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility. Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.