Abstract
The circulatory system, consisting of the heart, blood, blood vessels and lymphatic vessels is one of the major organ systems required for maintaining homeostasis in humans. Its main functions are the transport of nutrients, gases, signaling molecules and cells to and from tissues to maintain an array of body parameters
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including tissue oxygen levels, temperature and pH, and to help fight diseases. During recent years, the zebrafish has emerged as an important and instructive model organism for studying development of the vertebrate circulatory system. In this thesis we use the unique possibility to combine genetics with in vivo imaging in the zebrafish to get insights into several aspects of the development of the circulatory system. We have generated a transgenic zebrafish line based on regulatory elements of the zebrafish VEGF receptor flt1 (flt1enh:rfp). This line allows the identification of arterial, venous and lymphatic endothelial cells in embryonic and adult zebrafish. Interestingly, a fourth vessel type is identified in adults (lymph-arteries) with distinct flt1enh:rfp expression levels. Lymph-arteries represent the afferent component of the lymphatic vasculature in lower vertebrates. We further analyse several mutant zebrafish lines identified from forward genetic screens. One of these mutants display dilation of blood vessels throughout the embryo. We show that the phenotype is due to a mutation in cavernous cerebral malformation 1 (ccm1). This gene is associated with a human syndrome, which presents as a cerebral hemorrhage and dilated-vessel phenotype at multiple sites throughout the body. We show that the ccm1 gene acts cell-autonomously in endothelial cells and is not associated with defects in arteriovenous differentiation. The secand mutants we have analysed have a defect in arterial differentiation and hematopoiesis. The mutant phenotype is due to a mutation in T-cell acute leukemia 1 (tal1). Over- or misexpression of tal1 is a frequent cause of leukemia in humans. We show that tal1 has an additional role during heart development. Development of the inner lining of the heart (the endocardium) is severely perturbed, and is associated with defects in cardiac morphogenesis. Finally, we report the identification and characterization a mutants lack lymphatic vessels and have a defect in venous angiogenic sprouting. We show that the phenotype is due to a mutation in collagen and calcium-binding EGF domain containing protein 1(ccbe1). This gene has no previous described role in (lymph) vascular development, and presents a novel candidate gene for human syndromes associated with defects in lymphangiogenesis. Since many of the genes essential for embryonic vascular development are required for the activation of blood and lymphatic vessel growth in adult pathology, identifying these genes involved in vascular development, or understand the interactions between known genes will allow the development of new drugs that target these genes in order to inhibit or promote vessel formation
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