Acephalic spermatozoa syndrome represents a rare genetic and reproductive disease, which is defined as semen composed of mostly headless spermatozoa. The connecting piece in the neck region, also known as the head-to-tail coupling apparatus, plays a crucial role in the tight linkage between the sperm head and tail. Dysfunction of this structure can lead to separation of sperm heads and tails, and male infertility. Using the mouse as an experimental model, several proteins have been identified as associated with the head-to-tail coupling apparatus and disruption of these proteins causes acephalic spermatozoa. However, the molecular mechanism underlying this morphologic anomaly and head-to-tail coupling apparatus remains elusive. In this study, we focused on coiled-coil domain containing 188 (Ccdc188), which shows testis-enriched expression. To elucidate the physiological role of CCDC188, we generated a knockout mouse line using the CRISPR/Cas9 system. Ccdc188 knockout male mice were sterile, indicating that CCDC188 is indispensable for male fertility. Most Ccdc188-null spermatozoa were acephalic. Transmission electron microscopy revealed that while the sperm head-to-tail coupling apparatus could assemble properly without CCDC188, the head-to-tail coupling apparatus failed to attach to the nucleus during spermiogenesis, leading to sperm head and neck separation. In addition, we found almost all of the spermatozoa in the cauda epididymis lacked a mitochondrial sheath. Taken together, we demonstrated that CCDC188 plays a crucial role in forming a tight sperm head–neck junction.

Summary Sentence

Ccdc188 is essential for a tight linkage between the sperm head and neck, and loss of CCDC188 leads to infertility in male mice due to acephalic spermatozoa with motility defects.

Graphical Abstract