Distinct germline progenitor subsets defined through Tsc2–mTORC1 signaling

Adult tissue maintenance is often dependent on resident stem cells; however, the phenotypic and functional heterogeneity existing within this self‐renewing population is poorly understood. Here, we define distinct subsets of undifferentiated spermatogonia (spermatogonial progenitor cells; SPCs) by differential response to hyperactivation of mTORC1, a key growth‐promoting pathway. We find that conditional deletion of the mTORC1 inhibitor Tsc2 throughout the SPC pool using Vasa‐Cre promotes differentiation at the expense of self‐renewal and leads to germline degeneration. Surprisingly, Tsc2 ablation within a subset of SPCs using Stra8‐Cre did not compromise SPC function. SPC activity also appeared unaffected by Amh‐Cre‐mediated Tsc2 deletion within somatic cells of the niche. Importantly, we find that differentiation‐prone SPCs have elevated mTORC1 activity when compared to SPCs with high self‐renewal potential. Moreover, SPCs insensitive to Tsc2 deletion are preferentially associated with mTORC1‐active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self‐renewal and differentiation.