An mTORC1-dependent switch orchestrates the transition between mouse spermatogonial stem cells and clones of progenitor spermatogonia.
An mTORC1-dependent switch orchestrates the transition between mouse spermatogonial stem cells and clones of progenitor spermatogonia.
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DOI：
10.1016/j.celrep.2021.108752
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发表时间：
2021-02-16
期刊：
影响因子：
8.8
通讯作者：
Hermann BP
中科院分区：
文献类型：
--
作者：
Suzuki S;McCarrey JR;Hermann BP
精原干细胞（ssc）通过平衡自我更新和开始分化来产生致力于形成精子的前精原细胞来维持精子发生。为了确定ssc和祖细胞之间的调控逻辑，我们进行了单细胞RNA速度分析，并在体内验证了结果。主要的静止SSC群体通过丝裂原激活蛋白激酶(MAPK)/AKT信号传导产生一小部分细胞周期激活的SSC。激活的SSC形成早期祖细胞，mTORC1抑制驱动激活的SSC积累，与阻断祖细胞形成一致。从机制上讲，mTORC1抑制抑制精原细胞间的转录，并特异性地改变早期祖细胞中胰岛素生长因子（IGF）信号的表达。缺乏细胞间桥的Tex14−/−睾丸在mTORC1抑制后不会积累活化的SSCs，这表明稳态mTORC1信号驱动活化的SSCs产生祖细胞克隆。这些结果与SSC自我更新依赖于激活和静止SSC之间的相互转换以及mtorc1依赖的SSC向祖体细胞分化的启动模型一致。Suzuki等人通过单细胞RNA速度分析和体内验证，定义了成年小鼠ssc亚群与祖精原细胞之间的关系。静止的SCCs通过MAPK/AKT信号传导转化为细胞周期激活的SCCs。激活的SCCs通过mTORC1信号被驱动成为准备开始分化的早期祖细胞克隆。
Spermatogonial stem cells (SSCs) sustain spermatogenesis by balancing self-renewal and initiation of differentiation to produce progenitor spermatogonia committed to forming sperm. To define the regulatory logic among SSCs and progenitors, we performed single-cell RNA velocity analyses and validated results in vivo. A predominant quiescent SSC population spawns a small subset of cell-cycle-activated SSCs via mitogen-activated protein kinase (MAPK)/AKT signaling. Activated SSCs form early progenitors and mTORC1 inhibition drives activated SSC accumulation consistent with blockade to progenitor formation. Mechanistically, mTORC1 inhibition suppresses transcription among spermatogonia and specifically alters expression of insulin growth factor (IGF) signaling in early progenitors. Tex14−/− testes lacking intercellular bridges do not accumulate activated SSCs following mTORC1 inhibition, indicating that steady-state mTORC1 signaling drives activated SSCs to produce progenitor clones. These results are consistent with a model of SSC self-renewal dependent on interconversion between activated and quiescent SSCs, and mTORC1-dependent initiation of differentiation from SSCs to progenitor clones. Suzuki et al. define relationships between subsets of adult mouse SSCs and progenitor spermatogonia using single-cell RNA velocity analyses and in vivo validations. Quiescent SCCs convert to cell-cycle-activated SCCs via MAPK/AKT signaling. Activated SCCs are driven to become early progenitor clones ready to initiate differentiation through mTORC1 signaling.
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