Regulation of angiogenesis and lymphangiogenesis in zebrafish

Abstract

The circulatory system consists of blood and lymphatic vessels. Both vessel types act in concert but differ significantly from each other in several structural and functional aspects. In addition, the mechanisms orchestrating their development are different. The blood vasculature transports oxygen, nutrients and cells to tissues whereas the lymphatic vessels collect extravasated fluid, macromolecules and cells of the immune system and return them back to the blood circulation. In comparison to what is known on the molecular mechanisms behind the developmental and functional regulation of blood vasculature, the lymphatic system yet remains behind. However, several markers specific for the lymphatic endothelium have been identified and key factors controlling the development and function of the lymphatic vessels have been discovered. Recently, the crucial importance of lymphatic vessels in certain pathological conditions such as lymphedema, inflammation and tumor metastasis has been recognized, thus increasing the interest in the biology of this vessel type. For quite a long time, it was believed that teleost fishes do not have a lymphatic system. However, in 2006 this long-standing controversy in developmental vascular biology was resolved. Importantly, mechanisms of the early development of the lymphatic vasculature in zebrafish show a high degree of conservation with higher vertebrates. Today, only a few genes (Prox-1, Flt-4, Vegf-C and Sox18) have been reported so far to be important for lymphangiogenesis. Zebrafish constitute a powerful genetic tool to discover new genes involved in lymphangiogenesis. For that purpose, forward genetic screens can be set up to identify mutants that either lack or have abnormal lymphatic vessels. In 2009, Hogan et al reported ccbe-1 gene to have a regulatory function in zebrafish lymphangiogenesis. Shortly after that, Alders et al reported that mutations in CCBE1 cause generalized lymph vessel dysplasia in humans, one of the hallmarks of lymphedema-lymphangiectasia-mental retardation or otherwise designated as the Hennekam syndrome. Taken together, these data demonstrate that this novel gene function, initially discovered to be essential for zebrafish lymphangiogenesis is also relevant for human lymphatic vessel formation and/or function. These findings have given new insight into the regulation of normal lymphatic development, as well as into the pathogenesis of diseases involving the lymphatic vasculature. Several interesting questions were posed that still need to be addressed. Ccbe-1 is an otherwise completely uncharacterized protein with an essential role in lymphangiogenesis. Therefore, investigating the role of CCBE-1 in more detail not only in zebrafish but also in the mouse model might provide crucial insights into the biological activity of the CCBE- 1 protein during development of the lymphatic system.