Research Department

Pediatric Oncology

Interest

oncology

Area of Research

Biography

Dr. Zon received his MD in 1983 from Jefferson Medical College, followed by a residency in internal medicine at New England Deaconess Hospital. He served a clinical fellowship in medical oncology at DFCI from 1986 to 1989, when he joined the staff of Children's Hospital and DFCI. His postdoctoral research was in the laboratory of Dr. Stuart Orkin. Dr. Zon is also an associate investigator at Howard Hughes Medical Institute.

Research

Our laboratory focuses on the developmental biology of hematopoiesis. Hematopoietic stem cells are derived early during vertebrate embryogenesis. Because the mammalian embryo is difficult to evaluate, as an alternative we have used the zebrafish, which is externally fertilized. The zebrafish embryo is clear, and all organs can be visualized including circulating blood. A large number of animals can be kept in a relatively small space and each mother lays 200 to 300 eggs weekly. These qualities enable a forward genetic approach to vertebrate blood formation. Our studies show that the zebrafish provides information about hematopoiesis relevant to vertebrate biology and to disorders of blood formation.

Mutant zebrafish. We have collected more than 26 complementation groups of mutants with hematopoietic problems. Peripheral blood and hematopoietic kidney smears were examined. We cloned more than 100 gene homologues of mouse or human factors important in hematopoiesis and evaluated gene expressions by whole-mount in situ hybridization. We developed technology for hematopoietic progenitor assays and stem cell transplantation. Our studies show there are mutants with hematopoietic stem cell defects, proliferation difficulties, and differentiation problems.

Stem cell biology. We have studied gene expression using whole-embryo in situ hybridization to determine the spatial localization of the hematopoietic program during zebrafish ontogeny. Using complementary DNAs encoding the GATA-binding proteins as probes, we have defined the region of the intermediate cell mass as the equivalent of the yolk sac hematopoiesis. In addition, GATA-2+, GATA-1- cells in the posterior of the embryo appear to represent hematopoietic stem cells. We have characterized in great depth three zebrafish mutations of stem cell formation called bloodless, spadetail, and cloche.

Hypochromic mutants of zebrafish. There are five complementation groups of mutants with a hypochromic microcytic anemia. This is characteristic of human patients with thalassemia or a defect in hemoglobin production. We initiated a positional cloning approach to isolate the sauternes gene and demonstrated that it was a defect in ALAS-2. The ALAS-2 gene is responsible for heme biosynthesis, and defects in this gene in humans lead to congenital sideroblastic anemia. The fish and human diseases are very similar, and the fish is the first animal model of this human disease.

Select Publications

• Brownlie A, Donovan A, Pratt SJ, Paw BH, Oates AC, Brugnara C, Witkowska HE, Sassa S, Zon LI. Positional cloning of the zebrafish sauternes gene: a model for congenital sideroblastic anemia. Nat Genet 1998; 20:244-50.
• Thompson MA, Ransom DG, Pratt SJ, MacLennan H, Kieran MW, Detrich HW, Vail B, Huber TL, Paw B, Brownlie AJ, Oates AC, Fritz A, Gates MA, Amores A, Bahary N, Talbot WS, Her H, Beier DR, Postlethwait JH, Zon LI. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev Biol 1998; 197:248-69.
• Oates AC, Brownlie A, Pratt SJ, Irvine DV, Liao EC, Paw B, Dorian K, Johnson SL, Postlethwait JH, Zon LI, Wilks AF. Gene duplication of zebrafish JAK2 homologs is accompanied by divergent embryonic expression patterns; only jak2a is expressed during erythropoiesis. Blood 1999; 94(8):2622-36.
• Mead PE, Zhou Y, Lustig KD, Huber TL, Kirschner MW, Zon LI. Cloning of Mix related homeodomain proteins using a novel technique for the isolation of DNA binding proteins. Proc Natl Acad Sci USA 1998; 95:11251-56.
• Liao EC, Paw BH, Oates AC, Pratt SJ, Postlethwait JH, Zon LI. SCL/Tal-1 transcription factor acts downstream of cloche to specify hematopoietic and vascular progenitors in zebrafish. Gene Dev 1998; 12:621-26.
• Lee K-H, Marden JL, Thompson MS, MacLennan H, Kishimoto Y, Pratt SJ, Schulte-Merker S, Hammerschmidt M, Johnson SL, Postlethwait JH, Beier DC, Zon LI. Genetic mapping of zebrafish BMP-2. Dev Genet 1998; 23:97-103.
• Hukriede NA, Joly L, Tsang M., Miles J, Tellis P, Epstein JA, Barbazuk WB, Li FN, Paw B, Postlethwait JH, Hudson TJ, Zon LI, McPherson JD, Chevrette M, Dawid IB, Johnson SL, Ekker M. Radiation hybrid mapping of the zebrafish genome. Proc Natl Acad Sci USA 1999; 96:9745-50.
• Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow MA, Zon LI. SEK1 deficiency reveals unitogen-activated protein kinase cascade cross-regulation and leads to abnormal hepatogenesis. Proc Natl Acad Sci USA 1998; 95:6881-86.

Investigators

• Amatruda, James, MD, PhD
• Paw, Barry, MD, PhD
• Trede, Nikolaus, MD, PhD
• Zhou, Yi, PhD

Trainees

• Agarwal, Sadhana, PhD
• Bahary, Nathan, MD, PhD
• Davidson, Alan, PhD
• Ransom, David, PhD