Dr. Leonard Zon's laboratory focuses on the developmental biology of hematopoiesis and cancer. Over the past five years, we have collected over 30 mutants affecting the hematopoietic system. Some of the mutants represent excellent animal models of human disease. For instance, the isolation of the ferroportin iron transporter was based on a mutant zebrafish and subsequently was shown to be mutated in patients with iron overload disorders. The mutants also represent interesting key regulatory steps in the development of stem cells. Recently, a mutant was found that lacked blood stem cells and the mutated gene proved to be a caudal related homeoprotein called, CDX4. A Cdx-hox pathway was found to participate in early hematopoietic stem cell development and overexpression of CDX4 leads to ectopic blood development, within the zebrafish embryo and in mouse embryonic stem cells. We recently have developed hematopoietic cell transplantation for the zebrafish using blood cells labeled with green fluorescent protein and DSred. We were able to image the hematopoietic cells as they migrate to the marrow and to the thymus.
The laboratory has also developed zebrafish models of cancer. A screen for cell cycle mutants found 19 mutants. Some of these mutants get cancer at a very high rate as heterozygotes based on a carcinogenesis assay. The mutant genes appear to be new cancer genes and we have used small molecules in a chemical suppressor gene to find chemicals that bypass the mutant cell cycle problem. We also have generated a melanoma model in the zebrafish system using transgenics. Transgenic fish get nevi, and in a combination with a p53 mutant fish develop melanomas.