mTORC1 Activation Promotes Spermatogonial Differentiation and Causes Subfertility in Mice1

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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.

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