Qiu Yumiao, Shimada Keisuke, Yamamoto Kaito, Ikawa Masahito
Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Graduate School of Medicine, Osaka University, Osaka, Japan.
Biol Reprod. 2025 Jan 14;112(1):169-178. doi: 10.1093/biolre/ioae137.
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.
无头精子症是一种罕见的遗传和生殖疾病，其定义为精液中大多是无头精子。颈部区域的连接段，也称为头尾连接装置，在精子头部和尾部的紧密连接中起关键作用。这种结构的功能障碍可导致精子头部和尾部分离以及男性不育。以小鼠为实验模型，已鉴定出几种与头尾连接装置相关的蛋白质，这些蛋白质的破坏会导致无头精子。然而，这种形态异常和头尾连接装置背后的分子机制仍然难以捉摸。在本研究中，我们聚焦于富含睾丸表达的卷曲螺旋结构域包含188（Ccdc188）。为阐明CCDC188的生理作用，我们使用CRISPR/Cas9系统构建了一个基因敲除小鼠品系。Ccdc188基因敲除的雄性小鼠不育，表明CCDC188对雄性生育力不可或缺。大多数Ccdc188基因缺失的精子是无头的。透射电子显微镜显示，虽然没有CCDC188时精子头尾连接装置仍能正常组装，但在精子发生过程中头尾连接装置未能附着于细胞核，导致精子头部和颈部分离。此外，我们发现附睾尾部几乎所有精子都缺乏线粒体鞘。综上所述，我们证明CCDC188在形成紧密的精子头颈部连接中起关键作用。
