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

Abstract

A key feature of many adult stem cell lineages is that stem cell daughters destined for differentiation undergo several transit amplifying (TA) divisions before initiating terminal differentiation, allowing few and infrequently dividing stem cells to produce many differentiated progeny. Although the number of progenitor divisions profoundly affects tissue (re)generation, and failure to control these divisions may contribute to cancer, the mechanisms that limit TA proliferation are not well understood. Here, we use a model stem cell lineage, the Drosophila male germ line, to investigate the mechanism that counts the number of TA divisions. bam ͉ spermatogenesis ͉ Drosophila ͉ transit amplifying cell division A dult stem cells act throughout life to replenish differentiated cells lost to normal turnover or injury. In many adult stem cell lineages, stem cell daughters undergo transit amplifying (TA) mitotic division before terminal differentiation. The number of TA divisions strongly influences the capacity of adult stem cells to regenerate and repair tissues (1). In addition, strict limits on TA cell proliferation may help prevent accumulation of oncogenic replication errors. Defects in the mechanisms that count and limit the number of TA divisions may therefore predispose to cancer. Indeed, recent evidence points toward cancer initiating events occurring in TA cells in leukemia (2, 3).Despite the importance for normal tissue homeostasis and cancer, the mechanisms that specify the number of TA divisions are not understood. Here, we use the Drosophila male germ line model adult stem cell lineage to investigate the mechanisms that normally set developmentally programmed limits on proliferation of TA cells. Drosophila melanogaster male germ line stem cells (GSCs) lie in a niche at the tip of the testis, attached to somatic hub cells, and are maintained by signals from the hub and f lanking somatic stem cells (4 -7). When a GSC divides, one daughter remains in the niche and self-renews, while the other is displaced away and initiates differentiation. The resulting differentiating gonialblast, which is enveloped by a pair of somatic cells, founds a clone of 16 spermatogonia through four synchronous TA divisions with incomplete cytokinesis. Soon after the fourth TA division, the resulting 16 germ cells undergo premeiotic DNA synthesis in synchrony and switch to the spermatocyte program of cell growth, meiosis, and terminal differentiation. As spermatocytes, the cells increase in volume 25-fold, take on a distinctive morphology, and turn on a unique gene expression program for spermatid differentiation (8) (Fig. 1A).The anatomy of developing germ cell cysts makes the Drosophila germ line especially well suited for investigating how the number of TA divisions is controlled. Because TA sister cells descended from a common gonialblast are contained within a common somatic cell envelope and divide in synchrony, the number of rounds of TA division executed prior to differentiation can be assessed by counting the number of dif...

Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes

“…1A) (20). In control testes, expression of GFP from a Bam-GFP fusion protein (21) was detected in 4-, 8-, and 16-cell spermatogonial cysts, but not in GSCs or Gbs (Fig.…”

Bam and Otu can regulate stem cell fate by stabilizing cyclin A

“…The repression of Mei-P26 translation would limit the number of divisions and induce the transition to meiosis. The results by Ji et al (7) (i.e., only in dividing cyst cells) (13). In contrast, Ji et al (7) used a heat-shock promoter to overexpress Bam in both GSCs and dividing cysts.…”

“…However, in bam mutant testis, cysts undergo several rounds of extra divisions and fail to enter meiosis (12). An elegant model suggests that increasing levels of Bam protein during the four mitoses would limit the number of divisions above a specific threshold (13). Increasing artificially the levels of Bam limits the number of divisions to three and leads to the formation of cysts made of eight cells only (13).…”

“…An elegant model suggests that increasing levels of Bam protein during the four mitoses would limit the number of divisions above a specific threshold (13). Increasing artificially the levels of Bam limits the number of divisions to three and leads to the formation of cysts made of eight cells only (13). In addition, Bam was shown to associate with Bgcn, as in ovaries, and to inhibit the translation of Mei-P26 mRNA (14).…”

Hematopoietic stem cells count and remember self-renewal divisions

“…These studies reveal that after several rounds of division a genetic factor accumulates, reaching a threshold to initiate a cell fate change (Dugas et al, 2007;Insco et al, 2009;Levine et al, 2012). Alternatively, one could imagine dilution of a factor wherein progressive loss of this factor extends cell cycle progression leading to dormancy during homeostatic aging.…”