The laboratory focuses on the developmental biology of hematopoiesis and cancer. 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, we found a mutant in the notch pathway called mindbomb that has no blood stem cells. Using a heat shock inducible fish that overexpresses notch, we demonstrated that notch signaling was sufficient to confer a stem cell fate. These pathways (and others) are being transferred into embryonic stem cells to evaluate induction of blood stem cells. We also have undertaken chemical genetic approach to blood development and have found that prostaglandins upregulates blood stem cells.

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. We also recently have generated a model of muscle tumors in the zebrafish. This faithfully recapitulates the human muscle tumors and the tumors arise at 10 days of life, making this an ideal system for looking for enhancers and suppressors of cancer.

References:

• North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber G, Jang IH, Grosser T, FitzGerald GA, Daley GQ, Orkin SH, and Zon LI.  Prostaglandin E2 regulates vertebrate hematopoietic stem cell homeostasis.  Nature, 2007, 447:1007-1011.
• White RM , Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, Zon LI.  Transparent adult zebrafish as a tool for in vivo transplantation analysis.  Cell Stem Cell, 2008, 2:183-189.
• Goessling W, North TE, Loewer S, Lord AM, Sang L, Stoick-Cooper C, Weidinger G, Puder M, Daley GQ, Moon RT, and Zon LI.  Genetic interaction between PGE2 and wnt signaling regulates developmental specification of stem cells and regeneration.  Cell, 2009 March 20;136:1136-1146.
• North TE, Goessling W, Peeters M, Li P, Lord AM, Dzierzak E, and Zon LI.  Hematopoietic stem cell development is dependent on blood flow and nitric oxide signaling. Cell, 2009, May 15;137(4):736-748.

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