Zebrafish forward genetic screens: powerful approaches to identify new players in hematopoiesis

Hematopoiesis is defined as the formation of all types of blood cells from hematopoietic stem cells (HSCs) (Orkin and Zon, 2008). This complex process involves the coordination of intrinsic master blood transcriptional regulators and signaling molecules from the surrounding tissues (Huang and Zon, 2008). Understanding the molecular and cellular mechanisms that drive normal hematopoiesis and hematopoietic malignancies is crucial for developing new treatments for blood diseases. Despite the identification of many essential genes involved in hematopoiesis, the underlying mechanisms still remain poorly understood. Zebrafish are being increasingly used as a model organism to study vertebrate hematopoiesis. This genetically tractable model has many appealing features, such as the ease of manipulation of transparent embryos and the capacity to carry out largescale genetic and chemical screens (Lieschke and Currie, 2007). Similar to other vertebrates, zebrafish have sequential waves of hematopoiesis (Fig. 1A) (Davidson and Zon, 2004; de Jong and Zon, 2005); however, hematopoiesis in zebrafish occurs in sites that are distinct from other vertebrates. For example, zebrafish HSCs reside in the kidney marrow, which is functionally equivalent to the bone marrow niche of mammals. Nonetheless, the developmental processes and genetic programs of hematopoiesis are highly conserved in zebrafish (Fig. 1B) (Chen and Zon, 2009; Huang and Zon, 2008; Paik and Zon, 2010). In the past two decades, a wealth of studies has been published that has supplied many novel insights and discoveries into the field of hematology. Additionally, the parallels between the hematopoietic system in zebrafish and humans prompt the increasing use of zebrafish to model hematological disorders. Excellent recent reviews cover the different aspects of these studies in great detail (Bertrand and Traver, 2009; Carradice and Lieschke, 2008; Chen and Zon, 2009; Ellett and Lieschke, 2010; Huang and Zon, 2008; Paik and Zon, 2010; Payne and Look, 2009). In this Primer article, we survey various methods for research in zebrafish, illustrate the advantages of using zebrafish to study normal and pathogenic hematopoiesis, highlighting key recent advances, and discuss the contribution and potential of zebrafish to identify new disease treatments.