State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, Guangdong, P. R. China.
Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, 100871, Beijing, P. R. China.
Nat Commun. 2021 Nov 25;12(1):6839. doi: 10.1038/s41467-021-27172-0.
Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells' identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
哺乳动物雄性生殖细胞的发育是一个逐步的细胞命运转变过程；然而，雄性生殖细胞的完整发育过程仍未确定。在这里，通过对涵盖 28 个关键时间点的 11598 个细胞的高精度转录组图谱进行分析，我们证明了从有丝分裂到有丝分裂后原始生殖细胞的细胞命运转变伴随着转录组规模的重新配置和过渡细胞状态。Notch 信号通路对于启动有丝分裂阻滞和维持雄性生殖细胞的身份是必不可少的。HELQ 的缺失会诱导雄性生殖细胞的发育停滞和异常转录组重编程，表明细胞周期调控对于正确的细胞命运转变至关重要。最后，系统的人类-小鼠比较揭示了潜在的调控因子，其缺失通过有丝分裂阻滞调控导致人类男性不育。总的来说，我们的研究提供了一个准确和全面的雄性生殖系周期转录组图谱，并允许深入了解雄性生殖细胞发育背后的细胞命运转变和决定。
