Li Chao, Feng Yuming, Fu Zhenxin, Deng Junjie, Gu Yue, Wang Hanben, Wu Xin, Huang Zhengyun, Zhu Yichen, Liu Zhiwei, Huang Moli, Wang Tao, Hu Shijun, Yao Bing, Zeng Yizhun, Zhou Chengji J, Brown Steve D M, Liu Yi, Vidal-Puig Antonio, Dong Yingying, Xu Ying
Cambridge-Su Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China.
Department of Reproductive Medical Center, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
Cell Death Discov. 2022 Aug 2;8(1):345. doi: 10.1038/s41420-022-01139-6.
Exploring the functions of human-specific genes (HSGs) is challenging due to the lack of a tractable genetic model system. Testosterone is essential for maintaining human spermatogenesis and fertility, but the underlying mechanism is unclear. Here, we identified Cancer/Testis Antigen gene family 47 (CT47) as an essential regulator of human-specific spermatogenesis by stabilizing arginine methyltransferase 5 (PRMT5). A humanized mouse model revealed that CT47 functions to arrest spermatogenesis by interacting with and regulating CT47/PRMT5 accumulation in the nucleus during the leptotene/zygotene-to-pachytene transition of meiosis. We demonstrate that testosterone induces nuclear depletion of CT47/PRMT5 and rescues leptotene-arrested spermatocyte progression in humanized testes. Loss of CT47 in human embryonic stem cells (hESCs) by CRISPR/Cas9 led to an increase in haploid cells but blocked the testosterone-induced increase in haploid cells when hESCs were differentiated into haploid spermatogenic cells. Moreover, CT47 levels were decreased in nonobstructive azoospermia. Together, these results established CT47 as a crucial regulator of human spermatogenesis by preventing meiosis initiation before the testosterone surge.
由于缺乏易于处理的遗传模型系统，探索人类特异性基因（HSGs）的功能具有挑战性。睾酮对于维持人类精子发生和生育能力至关重要，但其潜在机制尚不清楚。在此，我们通过稳定精氨酸甲基转移酶5（PRMT5）鉴定出癌症/睾丸抗原基因家族47（CT47）是人类特异性精子发生的关键调节因子。一种人源化小鼠模型显示，CT47在减数分裂细线期/偶线期向粗线期转变过程中，通过与CT47/PRMT5在细胞核中的积累相互作用并进行调节，从而起到阻止精子发生的作用。我们证明，睾酮诱导人源化睾丸中CT47/PRMT5的核内耗竭，并挽救细线期停滞的精母细胞进程。通过CRISPR/Cas9在人类胚胎干细胞（hESCs）中敲除CT47导致单倍体细胞增加，但当hESCs分化为单倍体生精细胞时，会阻断睾酮诱导的单倍体细胞增加。此外，非梗阻性无精子症患者的CT47水平降低。总之，这些结果确定CT47是人类精子发生的关键调节因子，它通过在睾酮激增之前阻止减数分裂启动来发挥作用。
