Distinct germline progenitor subsets defined through Tsc2– mTORC 1 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; SPC s) by differential response to hyperactivation of mTORC 1, a key growth‐promoting pathway. We find that conditional deletion of the mTORC 1 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 SPC s 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 SPC s have elevated mTORC 1 activity when compared to SPC s with high self‐renewal potential. Moreover, SPC s insensitive to Tsc2 deletion are preferentially associated with mTORC 1‐active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC 1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC 1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self‐renewal and differentiation.