Hematopoiesis is the induction of self-renewing stem cells (HSC), and their subsequent maintenance, proliferation, and differentiation into all the blood cell lineages. Dysregulation of hematopoietic development can lead to leukemia and other stem cell disorders. The HSC are derived from a bipotential precursor, the hemangioblast, which gives rise to both blood and endothelial cells. We have chosen to take a genetic approach in zebrafish and isolate novel genes important in HSC specification. As part of a large-scale mutagenesis screen, we are identifying zebrafish with mutations that result in altered expression of SCL, the earliest known specifier of hemangioblasts, as detected by RNA in situ hybridization, or aberrant blood morphology at day 4 by visual inspection under a dissecting microscope. This will generate a complete collection of mutations from HSC induction through early hematopoietic development. The mutants identified will be further characterized using molecular markers for genes expressed in both ventral mesoderm and blood. The identification and characterization of such novel genes, and the positioning of these genes and known genes in the genetic pathway of early hematopoiesis, will provide potential new targets far drug design in the treatment of leukemia and other stem cell disorders.
