ZMYND 12是小鼠精子运动所必需的IDAd亚基

ZMYND12 serves as an IDAd subunit that is essential for sperm motility in mice       

ZMYND 12是小鼠精子运动所必需的IDAd亚基

Authors: Wang C, Xie Q, Xia X, Zhang C, Jiang S, Wang S, Zhang X, Hua R, Xue J, Zheng H.

Source：Cell Mol Life Sci. 2024 Jul 27;81(1):317. doi: 10.1007/s00018-024-05344-7.

Abstract

Inner dynein arms (IDAs) are formed from a protein complex that is essential for appropriate flagellar bending and beating. IDA defects have previously been linked to the incidence of asthenozoospermia (AZS) and male infertility. The testes-enriched ZMYND12 protein is homologous with an IDA component identified in Chlamydomonas. ZMYND12 deficiency has previously been tied to infertility in males, yet the underlying mechanism remains uncertain. Here, a CRISPR/Cas9 approach was employed to generate Zmynd12 knockout (Zmynd12^-/-) mice. These Zmynd12^-/- mice exhibited significant male subfertility, reduced sperm motile velocity, and impaired capacitation. Through a combination of co-immunoprecipitation and mass spectrometry, ZMYND12 was found to interact with TTC29 and PRKACA. Decreases in the levels of PRKACA were evident in the sperm of these Zmynd12^-/- mice, suggesting that this change may account for the observed drop in male fertility. Moreover, in a cohort of patients with AZS, one patient carrying a ZMYND12 variant was identified, expanding the known AZS-related variant spectrum. Together, these findings demonstrate that ZMYND12 is essential for flagellar beating, capacitation, and male fertility.

Keywords: IDA; Knockout mice; Male fertility; PRKACA; Spermatogenesis.

摘要

内动力蛋白臂（IDAs）是由一种蛋白质复合物形成的，这种蛋白质复合物对于鞭毛的适当弯曲和跳动是必不可少的。IDA缺陷以前被认为与弱精子症（AZS）和男性不育症的发生有关。富含睾丸的ZMYND 12蛋白与衣原体中鉴定的IDA组分同源。ZMYND 12缺陷以前与男性不育有关，但其潜在机制仍不确定。在此，采用CRISPR/Cas9方法来产生Zmynd 12敲除（Zmynd 12^-/-）小鼠。这些Zmynd 12^-/-小鼠表现出显著的雄性生育力低下、精子运动速度降低和获能受损。通过免疫共沉淀和质谱的组合，发现ZMYND 12与TTC 29和PRKACA相互作用。PRKACA水平的降低在这些Zmynd 12^-/-小鼠的精子中是明显的，这表明这种变化可能是观察到的雄性生育力下降的原因。此外，在AZS患者队列中，发现了一名携带ZMYND 12变体的患者，扩大了已知的AZS相关变体谱。总之，这些发现表明ZMYND 12对于鞭毛跳动、获能和雄性生育力是必不可少的。

关键词：缺铁性贫血;基因敲除小鼠;雄性生育力; PRKACA;精子发生。