LIN28A Marks the Spermatogonial Progenitor Population and Regulates Its Cyclic Expansion

One of the hallmarks of highly proliferative adult tissues is the presence of a stem cell population that produces progenitor cells bound for differentiation. Progenitor cells undergo multiple transit amplifying (TA) divisions before initiating terminal differentiation. In the adult male germline, daughter cells arising from the spermatogonial stem cells undergo multiple rounds of TA divisions to produce undifferentiated clones of interconnected 2, 4, 8, and 16 cells, collectively termed A(undifferentiated) (A(undiff)) spermatogonia, before entering a stereotypic differentiation cascade. Although the number of TA divisions markedly affects the tissue output both at steady state and during regeneration, mechanisms regulating the expansion of the TA cell population are poorly understood in mammals. Here, we show that mice with a conditional deletion of Lin28a in the adult male germline, display impaired clonal expansion of the progenitor TA A(undiff) spermatogonia. The in vivo proliferative activity of A(undiff) spermatogonial cells as indicated by BrdU incorporation during S-phase was reduced in the absence of LIN28A. Thus, contrary to the role of LIN28A as a key determinant of cell fate signals in multiple stem cell lineages, in the adult male germline it functions as an intrinsic regulator of proliferation in the population of A(undiff) TA spermatogonia. In addition, neither precocious differentiation nor diminished capacity for self-renewal potential as assessed by transplantation was observed, suggesting that neither LIN28A itself nor the pool of A(al) progenitor cells substantially contribute to the functional stem cell compartment. Stem Cells 2014;32:860-873