A Fisheye View on Lymphangiogenesis
Zebrafish have been widely used to study vasculogenesis and angiogenesis, and the vascular system is one of the most intensively studied organ systems in teleosts. It is a little surprising, therefore, that the development of the zebrafish lymphatic netwo
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A Fisheye View on Lymphangiogenesis Andreas van Impel and Stefan Schulte-Merker
Abstract Zebrafish have been widely used to study vasculogenesis and angiogenesis, and the vascular system is one of the most intensively studied organ systems in teleosts. It is a little surprising, therefore, that the development of the zebrafish lymphatic network has only been investigated in any detail for less than a decade now. In those last few years, however, significant progress has been made. Due to favorable imaging possibilities within the early zebrafish embryo, we have a very good understanding of what cellular behavior accompanies the formation of the lymphatic system and which cells within the vasculature are destined to contribute to lymphatic vessels. The migration routes of future lymphatic endothelial cells have been monitored in great detail, and a number of transgenic lines have been developed that help to distinguish between arterial, venous, and lymphatic fates in vivo. Furthermore, both forward and reverse genetic tools have been systematically employed to unravel which genes are involved in the process. Not surprisingly, a number of known players were identified (such as vegfc and flt4), but work on zebrafish has also distinguished genes and proteins that had not previously been connected to lymphangiogenesis. Here, we will review these topics and also compare the equivalent stages of lymphatic development in zebrafish and mice. We will, in addition, highlight some of those studies in zebrafish that have helped to identify and to further characterize human disease conditions.
Research on the lymphatic system in teleosts has taken a somewhat convoluted path through the years: the first description can be found as early as 1769 by Hewson and Hunter (1769), but in the last century the notion prevailed that fish do not have lymphatics (Vogel and Claviez 1981), and there was certainly very little work done on them. Only with the description of embryonic lymphatic vessels, paired with the A. van Impel • S. Schulte-Merker (*) Hubrecht Institute, KNAW and UMC Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands e-mail: [email protected] F. Kiefer and S. Schulte-Merker (eds.), Developmental Aspects of the Lymphatic Vascular System, Advances in Anatomy, Embryology and Cell Biology 214, DOI 10.1007/978-3-7091-1646-3_12, © Springer-Verlag Wien 2014
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demonstration that these vessels can take up substances from the interstitium and are dependent on vegfc function (Ku¨chler et al. 2006; Yaniv et al. 2006), it has been fully appreciated that lymphatic vessels exist in fish. Very quickly, the existence of transgenic lines and the favorable imaging opportunities in zebrafish larvae have led to a detailed understanding of how lymphangiogenesis occurs in early teleost embryos, and functional studies, based on morpholino approaches or on dedicated mutant screens, led to the identification of key genes in the process. In this review, we would like to discuss our current knowle
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