mTORC1 Activation Promotes Spermatogonial Differentiation and Causes Subfertility in Mice
mTORC1 Activation Promotes Spermatogonial Differentiation and Causes Subfertility in Mice
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mTORC1 激活促进精原细胞分化并导致小鼠生育力低下
DOI：
10.1095/biolreprod.116.140947
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发表时间：
2016
影响因子：
3.6
通讯作者：
Chen Zhenguo
中科院分区：
文献类型：
--
作者：
Wang Caixia;Wang Zilong;Xiong Zhi;Dai Huaiqian;Zou Zhipeng;Jia Chunhong;Bai Xiaochun;Chen Zhenguo
精子发生是一个连续的过程，依赖于精原细胞的增殖和分化。雷帕霉素复合物1（mTORC 1）的机制靶点是细胞生长、增殖和分化的中心调节因子，但其在精原细胞发育和分化调节中的作用尚不清楚。在这里，我们发现，精原细胞显示阶段依赖性mTORC 1活性在其出生后的发展，与极低的活性在未分化的精原细胞和高活性在分化的精原细胞。为了研究这种差异，我们通过有条件地删除mTORC1抑制剂TSC 1，在未分化精原细胞亚群中产生了具有激活mTORC1的突变小鼠。基因敲除小鼠表现出睾丸发育缺陷、部分生精停滞、生殖细胞过度丢失、精子计数减少和生育力低下。重要的是，mTORC1激活促进精原细胞分化，但以生殖细胞维持为代价，诱导生殖细胞的早期耗竭，从而损害精子发生。总之，我们的研究确定了mTORC 1在维持精原细胞群体和功能中的关键作用。
Spermatogenesis is a continuous process, relying on the proliferation and differentiation of spermatogonia. The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, proliferation, and differentiation, yet its roles in the regulation of spermatogonial development and differentiation remain unclear. Here, we found that spermatogonia display stage-dependent mTORC1 activity during their postnatal development, with extremely low activity in undifferentiated spermatogonia and high activity in differentiated spermatogonia. To examine this difference, we generated mutant mice with activated mTORC1 in a subset of undifferentiated spermatogonia by conditionally deleting the mTORC1 inhibitor TSC1. The knockout mice demonstrated testicular developmental defects, partial spermatogenic arrest, excessive germ cell loss, sperm count reduction, and subfertility. Importantly, mTORC1 activation promoted spermatogonial differentiation at the expense of germline maintenance, inducing the early depletion of germ cells, and thus impairing spermatogenesis. In summary, our study defines the critical roles of mTORC1 in the maintenance of the spermatogonial population and functions.