Clonal development in the spermatogenic lineages of rodents, monkeys and humans. Undifferentiated spermatogonia are described as A_s, A_pr or A_al in the rodents and A_dark or A_pale in monkey and human. During spermatogenic development, A_single (A_s) and A_dark and/or A_pale undergo one or more mitotic divisions to give rise to cells of larger clones (chains) of interconnected cells sizes through transit-amplifying mitotic divisions. A) Clonal development in rodents features 3–4 transit amplifying divisions in the pool of undifferentiated A_s, A_pr and A_al spermatogonia followed by 6 amplifying divisions in the pool of differentiated spermatogonia (A1–A4, Intermediate, B), which give rise to primary spermatocytes. Two additional meiotic divisions produce round spermatids that undergo spermiogenesis to produce sperm. B) Clonal development of spermatogonia in monkeys features 0, 1 or 2 transit amplifying divisions in the pool of undifferentiated A_dark/A_pale spermatogonia, followed by 4 transit amplifying divisions of differented spermatogonia (B1–B4), which give rise to primare spermatocytes. C) Clonal development of spermatogonia in humans features 0, 1 or 2 transit amplifying divisions in the pool of undifferentiated A_dark/A_pale spermatogonia followed by a single a single transit amplyfying division in differentiated B spermatogonia that give rise to primary spermatocytes. Thus, there are typically 12 transit amplifying divisions in rodents; 8 in monkeys and 5 in humans between stem cell and sperm. The reduced number of transit amplyfing divisions in monkeys and humans is compensated in part by a larger stem cell pool (see ).

Schematic comparison of the stem cell pools and sperm output in mice, monkeys and humans. A) The spermatogenic lineage in mice features a relatively small pool of A_s, A_pr and A_al undifferentiated spermatogonia (0.3% of germ cells). However, with about 12 transit amplifying divisions between stem cells and sperm (see ), the small pool of stem cells produced 40 million sperm per gram of testicular tissue per day. B) The spermatogenic lineage in monkeys features a relatively larger pool of Adark/Apale spermatogonia (4% of germ cells) and this compensates for the reduced number of transit amplying divisions between stem cell and sperm. Sperm output in monkeys is similar to mice: 41 million sperm per gram of testicular tissue per day. C) The spermatogenic lineage in humans features the largest pool of undifferentiated Adark/Apale spermatogonia (22% of germ cells). However, with only one transit amplifying division of differentiated spermatogonia, sperm output in humans is reduced to 4.4 million sperm per gram of testicular tissue per day. Thus distinguishing features of spermatogenic lineage development in mice, monkeys and men include 1) the size of the pool of undifferentiated stem/progenitor spermatogonia; 2) the number of transit amplifying divisions in differentiated spermatogonia and 3) sperm output.

Spermatogonial markers in rodents, monkeys and humans. A) Rodents; B) Monkeys; C) Humans. Several markers are conserved from rodents to monkeys to humans, suggesting their importance in spermatogenic lineage development. GFRa1, PLZF, SALL4 and LIN28 are conserved markers of undifferentiated spermatogonia. cKIT is a conserved marker of differentiating/differentiated spermatogonia. The following references describe markers in this figure that were not referenced elsewhere in the text: NGN3 (); SOHLH1 ().

Histological and immunohistochemical evaluation of A_dark and A_pale spermatogonia in monkeys and humans. Periodic acid, Schiffs’ and Hematoxylin (PAS-H) staining in monkey (A and C) and human (B and D) testis section reveals A_dark (black arrows) and A_pale (red arrows) spermatogonia on the basement membrane of the seminiferous tubules. The sub-population of A_dark spermatogonia with a rarefraction zone are indicated by a green arrow in (B). Colorimetric staining for UTF1 (brown color) with PAS-H staining confirms that UTF1 is a conserved marker of most, but not all A_dark (black arrow) and A_pale (red arrows) spermatogonia in monkey (C) and Human (D) testes. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)