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

Area of Science:

• Reproductive Biology
• Spermatogenesis
• Male Infertility

Background:

• Spermiogenesis involves critical morphological changes for fertilization, including sperm flagella and acrosome formation.
• Multiple Morphological Abnormalities of the Flagella (MMAF) is a male infertility syndrome linked to flagellar defects.
• Acrosomal hypoplasia can impair embryonic development, but its association with MMAF is not well-established.

Purpose of the Study:

• To investigate the role of coiled-coil domain-containing 38 (Ccdc38) in sperm development and male fertility.
• To determine if Ccdc38 deficiency leads to acrosomal hypoplasia in the context of MMAF phenotypes.
• To explore the underlying mechanisms of Ccdc38-related infertility.

Main Methods:

• Generation of Ccdc38 knockout (Ccdc38-KO) mice using base editing to induce a nonsense mutation.
• Phenotypic analysis of Ccdc38-KO sperm, including morphological assessment of flagella and acrosomes.
• Biochemical analysis to evaluate TEKT3 protein levels and distribution in testes and sperm.

Main Results:

• Ccdc38-KO male mice exhibit infertility with typical MMAF phenotypes and acrosomal hypoplasia.
• Ccdc38-KO sperm show loosely anchored acrosomal membranes and disorganized fibrous sheaths.
• Ccdc38 knockout leads to reduced TEKT3 levels and aberrant TEKT3 distribution in testes and sperm.

Conclusions:

• CCDC38 plays a crucial, previously unrecognized role in acrosome biogenesis.
• This study provides new evidence linking acrosomal hypoplasia to MMAF.
• Intracytoplasmic sperm injection can overcome Ccdc38-related infertility, suggesting a potential therapeutic approach.