We are interested in understanding the regulation of cell fate choice. To accomplish this goal we study hematopoiesis in the fruit fly, Drosophila melanogaster.

Hematopoiesis, the most extensively characterized stem cell system, serves as a model for the development of specialized cell types from a single pluripotential stem cell. This process is coordinated by key regulatory molecules that drive lineage-specific developmental programs. Current models depict lineage commitment as a process that involves cross-antagonism between blood cell programs, which promotes one lineage at the expense of the others. Our long-term goal is to better define the molecular genetic strategies that regulate hematopoiesis. To this end, we recently showed that combinatorial interactions between the evolutionarily conserved GATA, Friend of GATA (FOG) and Runx families of transcriptional regulators control hematopoietic lineage commitment in Drosophila. Specifically, we showed that the GATA factor SerpentNC (SrpNC) acts as both a negative and positive regulator of lineage commitment, lending support to current models of hematopoiesis. In its capacity as a negative regulator, SrpNC forms a complex with the FOG protein (U-shaped). This complex blocks development of one of the two primary Drosophila blood cell lineages. In contrast, the interaction of SrpNC with the Runx1-related protein (Lozenge) activates this blood cell program. As part of the activation process, the SrpNC:Lozenge complex down-regulates the repressor component U-shaped. Remarkably, the functions of these complexes are conserved across taxa. Our current studies involve more fully assessing the molecular genetic mechanisms that direct the SrpNC cross-regulatory network during lineage commitment.

During vertebrate embryogenesis, the blood and vasculature are thought to arise from a single progenitor known as the hemangioblast. While a close relationship between the progenitors of these organ systems has been documented, in vivo evidence for the hemangioblast is lacking. Moreover, the underlying molecular mechanisms that drive hematopoietic and vascular lineage divergence are not well understood. Recently, multi-potent progenitors that give rise to both hematopoietic and vascular cells have been identified in the fly. This paves the way for detailed studies of the genetic regulation of hemangioblast differentiation. U-shaped is required for both blood and dorsal vessel development and is expressed in the thoracic mesoderm from which both organ systems are derived. Our studies of the transcriptional regulation of the u-shaped gene suggest that a single cis-regulatory region may orchestrate expression in the cells of the blood and dorsal vessel. We are investigating the transcriptional regulation of this region as a means to identify potential regulators of hemangioblast diversification. 1R01DK072229-01