Hematopoiesis is a complex process with a variety of different signaling pathways influencing every step of blood cell formation from the earliest precursors to final differentiated blood cell types. Formation of blood cells is crucial for survival. Blood cells carry oxygen, promote organ development and protect organs in different pathological conditions. Hematopoietic stem and progenitor cells (HSPCs) are responsible for generating all adult differentiated blood cells. Defects in HSPCs or their downstream lineages can lead to anemia and other hematological disorders including leukemia. The zebrafish has recently emerged as a powerful vertebrate model system to study hematopoiesis. The developmental processes and molecular mechanisms involved in zebrafish hematopoiesis are conserved with higher vertebrates, and the genetic and experimental accessibility of the fish and the optical transparency of its embryos and larvae make it ideal for in vivo analysis of hematopoietic development. Defects in zebrafish hematopoiesis reliably phenocopy human blood disorders, making it a highly attractive model system to screen small molecules to design therapeutic strategies. In this review, we summarize the key developmental processes and molecular mechanisms of zebrafish hematopoiesis. We also discuss recent findings highlighting the strengths of zebrafish as a model system for drug discovery against hematopoietic disorders. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Vertebrate Organogenesis > Musculoskeletal and Vascular Nervous System Development > Vertebrates: Regional Development Comparative Development and Evolution > Organ System Comparisons Between Species.

During vertebrate development, the initial wave of hematopoiesis produces cells that help to shape the developing circulatory system and oxygenate the early embryo. The differentiation of primitive erythroid and myeloid cells occurs within a short transitory period, and is subject to precise molecular regulation by a hierarchical cascade of transcription factors. The TALE-class homeodomain transcription factors Meis and Pbx function to regulate embryonic hematopoiesis, but it is not known where Meis and Pbx proteins participate in the hematopoietic transcription factor cascade. To address these questions, we have ablated Meis1 and Pbx proteins in zebrafish, and characterized their molecular effects on known markers of primitive hematopoiesis. Embryos lacking Meis1 and Pbx exhibit a severe reduction in the expression of gata1, the earliest marker of erythroid cell fate, and fail to produce visible circulating blood cells. Concomitant with a loss of gata1, Meis1- and Pbx-depleted embryos exhibit downregulated embryonic hemoglobin (hbae3) expression, and possess increased numbers of pu.1-positive myeloid cells. gata1-overexpression rescues hbae3 expression in Pbx-depleted; meis1-morphant embryos, placing Pbx and Meis1 upstream of gata1 in the erythropoietic transcription factor hierarchy. Our study conclusively demonstrates that Meis1 and Pbx act to specify the erythropoietic cell lineage and inhibit myelopoiesis.

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