Regenerative medicine holds great promise to alleviate morbidity and mortality in patients suffering from organ failure. Pathways that govern stem cell behavior and organ development can be modulated to affect adult organ repair and regeneration. Our laboratory focuses on developmental hematopoiesis as a key to uncovering general principles of stem cell function, self-renewal and tissue regeneration. Hematopoietic stem cells (HSCs) give rise to each of the blood lineages found in the adult vertebrate; the gene programs regulating HSC development and homeostasis are highly evolutionarily conserved. We are using the zebrafish as a model system to discover novel regulators of HSC formation. In addition, we employ murine models to document evolutionary conservation of these signaling pathways during development and in hematopoietic regeneration following injury or transplantation. Through a chemical genetic screening approach, we identified several novel compound modifiers of blood stem cell formation; each pathway isolated in the screen altered the normal expression pattern of the conserved HSC marker runx1. This methodology led to the first example of FDA approval for the investigational use of a compound identified in an unbiased screen in zebrafish for clinical application in the treatment of human disease. Our laboratory will use both chemical and genetic approaches in the zebrafish to characterize novel mechanisms controlling HSC induction in the vertebrate embryo. Additionally, through comparative genomic examination of zebrafish and murine sites of embryonic hematopoiesis, we aim to decipher regulatory networks that are central to HSC formation and function. Using chemical ablation, irradiation injury and transplantation approaches, we will further define the functional conservation of HSC regulators identified in the embryonic screens in controlling adult marrow homeostasis in zebrafish and mice. Xenotransplantation experiments using human cord blood with be employed to investigate translational potential. The work in our laboratory has direct relevance for the development of novel therapeutic strategies for controlling leukemogenesis and enhancing stem cell transplantation biology.
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1. North T, Gu TL, Stacy T, Wang Q, Howard L, Binder M, Marin-Padilla M, and Speck NA. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. 1999. Development 126: 2563-2575.
2. North TE, deBruijn M, Stacy T, Talebian L, Lind E, Robin C, Binder M, Dzierzak E, and Speck NA. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. 2002. Immunity 16: 661-672.
3. North TE, Stacy T, Matheny C, Speck NA, and deBruijn M. Runx1 is expressed in adult mouse hematopoietic stem cells, in differentiating myeloid and lymphoid cells, but not in maturing erythroid cells. 2004. Stem Cells 22: 158-168.
4. Goessling W*, North TE*, and Zon LI Ultrasound biomicroscopy enables in vivo characterization of zebrafish tumorigenesis and therapeutic response. 2007. Nature Methods 4: 551-553.
5. North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord A, Weber G, Bowman T, Jang IH, Grosser T, FitzGerald GA, Daley GQ, and Zon LI. Prostaglandin E2 regulates zebrafish hematopoietic stem cell homeostasis. 2007. Nature 447: 1007-1011.
6. Goessling W, North TE, Weber G, Zon LI. Development of a liver toxicity model in zebrafish (Danio rerio). 2007. MDIBL Bulletin 46: 169-170.
7. Goessling W, North TE, Weidinger G, Lord A, Haramis AP, Clevers H, Moon RT, and Zon LI. APC mutant zebrafish uncover a biphasic requirement for wnt signaling in liver development. 2007. Developmental Biology 320: 161-174.
8. Upadhyay G, Goessling W, North TE, Zon LI, Yajnik V. Molecular association between b-catenin degradation complex and guanine exchange factor DOCK4 is essential for Wnt signaling. 2008. Oncogene 27: 5845-5855.
9. Goessling W*, North TE*, Schmitt S, Lord AM, Lee S, Stoick-Cooper C, Puder M, Daley GQ, Moon RT, and Zon LI. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. 2009. Cell 136: 1136-1147.
10. North, TE*, Goessling W*, Peeters M, Li P, Ceol C, Lord AM, Weber GJ, Harris J, Cutting CC, Huang P, Dzierzak E, Zon LI. 2009. Cell, manuscript in press.