Figure 1. Undifferentiated spermatogonia which express Foxc2 may represent the entire population of spermatogonial stem cells in the adult testes of mice.

(A) Sperm is created inside seminiferous tubules (pink tubes) through spermatogenesis, a complex differentiation process that starts with the division of spermatogonial stem cells (SSCs). SSCs are difficult to distinguish from other types of undifferentiated spermatogonia (uSPGs) which also reside in the seminiferous tubules. Wang et al. propose that single uSPGs that express the gene encoding the transcription factor FOXC2 constitutes most, if not all, the SSC pool. About 95% of these cells are quiescent (green cells) and the remaining ~5% are proliferative (orange cells). Proliferating FOXC2-producing single uSPGs may divide asymmetrically to generate paired and aligned uSPGs that remain attached to each other after mitosis. These cells show differential expression of Foxc2. Some of the cells that do not produce FOXC2 (light blue cells with dark blue nucleus) will differentiate into progenitors (light blue cells) and ultimately become sperm. Others, which have retained Foxc2 expression, may split away from their sister cells through a fragmentation process (scissors) and return to a FOXC2-producing single uSPG state to contribute to the SSC pool. Self-renewal of SSCs may also be achieved by symmetrical division of a single FOXC2-producing SSC to form two single, FOXC2-producing daughter SSCs. (B) Deleting FOXC2-producing cells causes accelerated exhaustion of SSCs, and, in time (hourglass) leads to male infertility. (C) Quiescent FOXC2-producing single uSPGs are resistant to cytotoxins such as busulfan treatment; they can survive these environmental disruptions and replenish the pools of uSPGs, thereby maintaining SSC homeostasis.