mTORC1 Activation Promotes Spermatogonial Differentiation and Causes Subfertility in Mice.
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.
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Caixia
C
Wang
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Zilong
Z
Wang
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Zhi
Z
Xiong
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Huaiqian
H
Dai
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Zhipeng
Z
Zou
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Chunhong
C
Jia
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China baixc15@smu.edu.cn.
Xiaochun
X
Bai
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China czg1984@smu.edu.cn.
Zhenguo
Z
Chen
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D007246:Infertility / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D013076:Sperm Count; D013091:Spermatogenesis / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000378:metabolism*
D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
mTORC1; spermatogenesis; spermatogonial differentiation; subfertility