Multipotent Drosophila hemocyte progenitors (akin to hematopoietic stem cells) express domeless, but activate Hemolectin and Peroxidasin expression upon differentiation. However, a small population co-expresses domeless and Peroxidasin but not cell-specific markers of mature blood cells (such as Lozenge, which labels platelet-like crystal cells). Although this evidence indicates that hemocytes indirectly transition into mature cells, intermediate cell types have been difficult to study due to the lack of tools available. Now, Utpal Banerjee and colleagues have developed a ‘split GAL4’ Drosophila line, which labels only ‘intermediate progenitors’ (IPs) that co-express domeless and Hemolectin. Through cell cycle experiments, the authors show that the majority of IPs are in S and G2 phase, and lineage tracing reveals that they contribute to all mature blood populations. To understand the molecular mechanism, they show that the Ras/Raf pathway increases or reduces IP populations when inhibited or activated, respectively. In addition, activation of Ras/Raf activity promotes IP maturation, suggesting Ras/Raf signaling promotes IP exit from the transitional state. Finally, the researchers show that IPs activate the Notch pathway in neighboring cells, which leads to crystal cell differentiation. Taken together, this system provides a model for studying IPs in hematopoiesis, highlighting the importance of characterizing similar intermediate cell populations in mammals.
