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

Identifying factors that regulate the balance between stem cell self-renewal and differentiation into specialized cells is key to understanding tissue homeostasis and regeneration. Long before the identification of the four factors sufficient to define stemness, a single gene named bag of marbles (bam) was shown to be necessary and sufficient to control the transition from stem cell to differentiated cell in the germ-line lineage of Drosophila females (1). In the absence of bam, germ-line stem cells (GSCs) cannot differentiate into cystoblasts and accumulate as round cells forming a bam in the germarium at the tip of the ovary (2). In contrast, ectopic expression of bam in GSCs is sufficient to induce their differentiation and the subsequent loss of all germ-line cells (3). Bam thus acts as an ON and OFF switch of the stem cell vs. differentiated fate. This switch is controlled by a short-range Dpp signal (bone morphogenetic protein-like) sent from neighboring somatic cells, which directly inhibits bam transcription in GSCs (4, 5). The GSC daughter cell that is not in contact with these somatic cells does not receive enough Dpp signal, and can thus express bam and differentiate into a cystoblast (Fig. 1). During the window of bam expression, cystoblasts go through four rounds of incomplete divisions to form a cyst of 16 interconnected germ cells. This simple model provides a paradigm in the stem cell field to explain both how asymmetric divisions balance self-renewal and differentiation, and how external signals regulate asymmetric divisions. Two decades of intense research have refined this model to include many other signaling pathways (6). However, despite being at the heart of it, the biochemical activity of Bam remained mysterious. The lack of clear homologs at the sequence level has not helped. In an exciting research article published in PNAS, Ji et al. convincingly show that Bam and ovarian tumor (Otu) proteins associate and deubiquitinate cyclin A (CycA) (7). The resulting stabilization of CycA is sufficient to explain the loss of GSCs when expressing Bam ectopically. Thus, a long-standing question in the stem cell field has been clarified. Dahua Chen and colleagues identified Bam binding partners by immunoprecipitation andmass-spectrometry analysis. Bam strongly interacted with free ubiquitin, suggesting that Bam could bind proteins bearing a ubiquitin chain, which can be marked for degradation. Previous work by the authors had shown that ubiquitinmediated degradation of CycA was necessary for GSC maintenance (8). Expression of a nondegradable CycA in GSCs leads to their loss by differentiation, a phenotype identical to the ectopic expression of Bam (8). In PNAS, Ji et al. (7) discover that CycA can be coimmunoprecipitated with Bam from S2 cells and ovarian extracts. They further show that increasing the levels of Bam leads to a corresponding increase in CycA levels, and that decreasing the levels of Bam leads to a decrease in CycA levels. The authors propose that Bam could act as a deubiquitinating enzyme (Dub) for CycA. Furthermore, ectopic expression of bam in the GSC could be enhanced by coexpression of cycA, and suppressed by cycA reduction. BAM OTU