Utf1 Maintains the Balance Between SSC Renewal and Differentiation During the First Wave of Spermatogenesis
The balance between self-renewal and differentiation of spermatogonial stem cells (SSCs) is critical for the continual production of sperm, yet the molecular mechanisms that dictate this delicate balance are still mostly unknown. Undifferentiated embryonic transcription factor 1 (Utf1) participates in the maintenance of pluripotency in embryonic stem cells and exhibits a restricted expression pattern in mammalian undifferentiated spermatogonia. We hypothesized that Utf1 is necessary for maintaining SSC homeostasis. To test this hypothesis in vivo, we conditionally deleted mouse Utf1 in germ cells at each of three distinct timepoints in spermatogenesis: coincident with the change of prospermatogonia-to-undifferentiated spermatogonia, soon after establishing the SSC pool (earlier manipulation resulted in early death), and during steady-state spermatogenesis. These timepoints respectively allowed the measurement of changes in spermatogonial population dynamics in P8 cKO mice, quantification of spermatogenic end points in cKO young adults, and determination of Utf1 utility in adulthood. We utilized the Id4-eGfp transgenic mouse model to conveniently measure SSC fate, along with other genetic markers to measure changes in cell lineage; ID4-EGFPbright cells are highly enriched for SSCs, and ID4-EGFPdim are depleted of SSCs and enriched for progenitor spermatogonia. We found that by P8, germ cell-specific neonatal knockout of Utf1 results in a significant loss of ID4-EGFPbright (SSCs) and an increase in differentiating spermatogonia. Finally, loss of Utf1 during steady-state spermatogenesis resulted in no change in either undifferentiated spermatogonia or sperm count. These results are consistent with a specific role of Utf1 in maintaining SSCs during the first wave of spermatogenesis.