Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Elife. 2023 Aug 23;12:RP85380. doi: 10.7554/eLife.85380.
In adult mammals, spermatogenesis embodies the complex developmental process from spermatogonial stem cells (SSCs) to spermatozoa. At the top of this developmental hierarchy lie a series of SSC subpopulations. Their individual identities as well as the relationships with each other, however, remain largely elusive. Using single-cell analysis and lineage tracing, we discovered both in mice and humans the quiescent adult SSC subpopulation marked specifically by forkhead box protein C2 (FOXC2). All spermatogenic progenies can be derived from FOXC2 SSCs and the ablation of FOXC2 SSCs led to the depletion of the undifferentiated spermatogonia pool. During germline regeneration, FOXC2 SSCs were activated and able to completely restore the process. Germ cell-specific knockout resulted in an accelerated exhaustion of SSCs and eventually led to male infertility. Furthermore, FOXC2 prompts the expressions of negative regulators of cell cycle thereby ensures the SSCs reside in quiescence. Thus, this work proposes that the quiescent FOXC2 SSCs are essential for maintaining the homeostasis and regeneration of spermatogenesis in adult mammals.
在成年哺乳动物中，精子发生体现了从精原干细胞（SSC）到精子的复杂发育过程。在这个发育层次的顶端是一系列 SSC 亚群。然而，它们各自的身份以及彼此之间的关系在很大程度上仍然难以捉摸。通过单细胞分析和谱系追踪，我们在小鼠和人类中都发现了静止的成年 SSC 亚群，其特征是特异性表达叉头框蛋白 C2（FOXC2）。所有的生殖细胞祖细胞都可以来源于 FOXC2 SSC，而 FOXC2 SSC 的缺失导致未分化精原细胞池的耗竭。在生殖系再生过程中，FOXC2 SSC 被激活并能够完全恢复该过程。生殖细胞特异性 knockout 导致 SSC 的加速耗竭，并最终导致雄性不育。此外，FOXC2 促使细胞周期的负调控因子的表达，从而确保 SSC 处于静止状态。因此，这项工作提出静止的 FOXC2 SSC 对于维持成年哺乳动物精子发生的体内平衡和再生是必不可少的。
