) Hematopoiesis in the vertebrate is characterized by the induction of ventral mesoderm to form hematopoietic stem cells and the eventual differentiation of these progenitors to form the final peripheral blood lineages. Several genes have been implicated in the differentiation and development of hematopoietic and vascular progenitor cells yet our understanding of the discrete steps involved in the induction of these cells from the ventral mesoderm is still incomplete. One method to delineate these processes is by the generation of hematopoietic mutants. In this regard, the zebrafish (Danio rerio) is an especially robust vertebrate system to both isolate and characterize such mutational events. Several hematopoietic mutants in zebrafish have been generated and characterized to date. The strength of the zebrafish system is illustrated by the fact that these hematopoietic mutants represent many of the proposed steps of both the primitive and definitive hematopoietic programs. One such gamma-induced mutation, b462B, has no blood formation in its homozygous state and is lethal at five days of embryogenesis. Whole embryo in-situ hybridization studies show diminished expression of Gata-1, Gata-2, Imo2, and cmyb, which are normally expressed early in hematopoiesis. This pattern of expression suggests that b462B is a gene that is critical for the early steps of hematopoiesis, and implies that b462B is the earliest hematopoietic mutant that has been obtained to date. In this application, the investigator plans to further characterize b462B, and to ultimately isolate the defective gene by either positional or phenotypic rescue methods. By characterizing and cloning this mutation, unique insights will be made into the genetic cascade that regulates hematopoiesis. This new knowledge has therapeutic value for bone marrow transplantation, stem cell gene therapy, aplastic anemia and myelodysplasia.
| Bahary, Nathan; Goishi, Katsutoshi; Stuckenholz, Carsten et al. (2007) Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish. Blood 110:3627-36 |
