Using Zebrafish (Danio rerio) to Assess Gene Function in Thrombus Formation

Abstract

Cardiovascular and cerebrovascular disease is the major cause of death in the developed world, with a high burden of disease and substantial pharmaceutical investment to manage it (WHO, Global Burden of Disease, 2004 Update, W.H. Organisation, Editor. 2008). Platelets, as the principal mediators of thrombus formation, are a primary pharmaceutical target, with attenuation of platelet function and thrombus formation significantly reducing the incidence of myocardial infarction and stroke. Haemostasis, however, may also be affected by antithrombotics, leading to spontaneous and/or prolonged bleeding as a potentially severe side effect. Developing a comprehensive understanding of the mechanisms involved in platelet function and thrombus formation is anticipated to identify drug targets that may effectively manage vascular disease without an impact on haemostasis. Despite the progress in characterising individual genes in platelet function and thrombosis, using gene knockout and transgenic mice over the past decade or so, there is still much to be uncovered. Investigating gene function using mouse models is a substantial investment and a considerable amount of work, with a relevant phenotype not guaranteed. As such, a new model is needed for the effective screening of novel genes that have been identified as having potential roles in platelet function or cardiovascular disease by genomic association and comparative expression studies (Nature, 447(7145): 661-678, 2007; Nat Genet, 41(11): 1182-1190, 2009; N Engl J Med, 357(5): 443-453, 2007; Blood, 109(8): 3260-3269, 2007). Here, we highlight and discuss the relevance of the zebrafish (Danio rerio) as a model for studying thrombosis, the current techniques that are employed to assess gene function in a zebrafish model of thrombosis, and how an effective genetic screen may be constructed.