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Male mammals produce sperm for most of postnatal life and therefore require a robust germ line stem cell system, with precise balance between self-renewal and differentiation. Prior work established  doublesex-  and  mab-3 -related transcription factor 1 ( Dmrt1 ) as a conserved transcriptional regulator of male sexual differentiation. Here we investigate the role of  Dmrt1  in mouse spermatogonial stem cell (SSC) homeostasis. We find that  Dmrt1  maintains SSCs during steady state spermatogenesis, where it regulates expression of  Plzf , another transcription factor required for SSC maintenance. We also find that  Dmrt1  is required for recovery of spermatogenesis after germ cell depletion. Committed progenitor cells expressing  Ngn3  normally do not contribute to SSCs marked by the  Id4-Gfp  transgene, but do so when spermatogonia are chemically depleted using busulfan. Removal of  Dmrt1  from  Ngn3 -positive germ cells blocks the replenishment of Id4-GFP-positive SSCs and recovery of spermatogenesis after busulfan treatment. Our data therefore reveal that  Dmrt1  supports SSC maintenance in two ways: allowing SSCs to remain in the stem cell pool under normal conditions; and enabling progenitor cells to help restore the stem cell pool after germ cell depletion.

DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment