Accumulation of a differentiation regulator specifies transit amplifying division number in an adult stem cell lineage.

In tissues that rapidly replace themselves, such as skin, intestinal epithelium, the male germline, and blood, a relatively few number of infrequently dividing adult stem cells are responsible for regenerating the designated tissue for the life of the organism. Adult stem cells divide asymmetrically to produce another stem cell and a differentiating daughter cell. In many systems, that differentiating daughter cell will go through many transit amplifying progenitor cell divisions before stopping division and becoming highly specialized mature cells. Transit amplifying progenitor cell divisions are important because they amplify cell number so that a small number of adult stem cells can maintain a great deal of differentiated tissue. Regulating the number of transit amplifying divisions is important because too few divisions could result in a paucity of mature tissue, while too many divisions may result in precancerous growth. We use fruit fly spermatogenesis to investigate how the number of transit amplifying divisions is regulated. We found through genetic perturbations and gene expression analyses that the rate of accumulation of a testis tumor suppressor protein determines the number of amplifying divisions. We also find that the interplay between the accumulation of the tumor suppressor protein and the rate of the cell cycle determine the final number of divisions. This study illuminates one regulatory strategy by which progenitor divisions may be counted in human stem cell lineages.