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A Fisheye View on Lymphangiogenesis

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Developmental Aspects of the Lymphatic Vascular System

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 214))

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.

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References

  • Alders, M., Hogan, B. M., Gjini, E., Salehi, F., Al-Gazali, L., Hennekam, E. A., et al. (2009). Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature Genetics, 41(12), 1272–1274.

    Article  PubMed  CAS  Google Scholar 

  • Aranguren, X. L., Beerens, M., Vandevelde, W., Dewerchin, M., Carmeliet, P., & Luttun, A. (2011). Transcription factor COUP-TFII is indispensable for venous and lymphatic development in zebrafish and Xenopus laevis. Biochemical and Biophysical Research Communications, 410(1), 121–126.

    Article  PubMed  CAS  Google Scholar 

  • Bos, F. L., Caunt, M., Peterson-Maduro, J., Planas-Paz, L., Kowalski, J., Karpanen, T., et al. (2011). CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circulation Research, 109(5), 486–491.

    Article  PubMed  CAS  Google Scholar 

  • Bussmann, J., Bakkers, J., & Schulte-Merker, S. (2007). Early endocardial morphogenesis requires Scl/Tal1. PLoS Genetics, 3(8), e140.

    Article  PubMed  Google Scholar 

  • Bussmann, J., Bos, F., Urasaki, A., Kawakami, K., Duckers, H. J., & Schulte-Merker, S. (2010). Arteries provide essential guidance cues for lymphatic endothelial cells in the zebrafish trunk. Development, 137, 253–257.

    Article  Google Scholar 

  • Cermenati, S., Moleri, S., Cimbro, S., Corti, P., Del Giacco, L., Amodeo, R., et al. (2008). Sox18 and Sox7 play redundant roles in vascular development. Blood, 111, 2657–2666.

    Article  PubMed  CAS  Google Scholar 

  • Cermenati, S., Moleri, S., Neyt, C., Bresciani, E., Carra, S., Grassini, D. R., et al. (2013). Sox18 genetically interacts with VegfC to regulate lymphangiogenesis in zebrafish. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(6), 1238–1247.

    Article  PubMed  CAS  Google Scholar 

  • Cha, Y. R., Fujita, M., Butler, M., Isogai, S., Kochhan, E., Siekmann, A. F., et al. (2012). Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature. Developmental Cell, 22(4), 824–836.

    Article  PubMed  CAS  Google Scholar 

  • Covassin, L. D., Villefranc, J. A., Kacergis, M. C., Weinstein, B. M., & Lawson, N. D. (2006). Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 103, 6554–6559.

    Article  PubMed  CAS  Google Scholar 

  • Dumont, D. J., Jussila, L., Taipale, J., Lymboussaki, A., Mustonen, T., Pajusola, K., et al. (1998). Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science, 282(5390), 946–949.

    Article  PubMed  CAS  Google Scholar 

  • Geudens, I., Herpers, R., Hermans, K., Segura, I., Ruiz de Almodovar, C., Bussmann, J., et al. (2010). Role of Dll4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(9), 1695–1702.

    Article  PubMed  CAS  Google Scholar 

  • Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A. W., et al. (2013). A mutation in VEGFC, a ligand for VEGFR3, is associated with autosomal-dominant Milroy-like primary lymphedema. Circulation Research, 112(6), 956–960.

    Article  PubMed  CAS  Google Scholar 

  • Hägerling, R., Pollmann, C., Andreas, M., Schmidt, C., Nurmi, H., Adams, R. H., et al. (2013). A novel multi-step mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO Journal, 32(5), 629–644.

    Article  PubMed  Google Scholar 

  • Haiko, P., Makinen, T., Keskitalo, S., Taipale, J., Karkkainen, M. J., Baldwin, M. E., et al. (2008). Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Molecular and Cellular Biology, 28(15), 4843–4850.

    Article  PubMed  CAS  Google Scholar 

  • Herpers, R., van de Kamp, E., Duckers, H. J., & Schulte-Merker, S. (2008). Redundant roles for sox7 and sox18 in arteriovenous specification in zebrafish. Circulation Research, 102, 12–15.

    Article  PubMed  CAS  Google Scholar 

  • Hewson, W., & Hunter, W. (1769). An account of the lymphatic system in fish. Philosophical Transactions (1683–1775), 59, 204–215.

    Google Scholar 

  • Hogan, B. M., Bos, F., Bussmann, J., Witte, M., Chi, N., Duckers, H., et al. (2009a). Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nature Genetics, 41, 396–398.

    Article  PubMed  CAS  Google Scholar 

  • Hogan, B. M., Herpers, R., Witte, M., Heloterä, H., Alitalo, K., Duckers, H. J., et al. (2009b). Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development, 136, 4001–4009.

    Article  PubMed  CAS  Google Scholar 

  • Jeltsch, M., Kaipainen, A., Joukov, V., Meng, X., Lakso, M., Rauvala, H., et al. (1997). Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science, 276(5317), 1423–1425.

    Article  PubMed  CAS  Google Scholar 

  • Jensen Dahl Ejby, L., Cao, R., Hedlund, E. M., Söll, I., Lundberg, J. O., Hauptmann, G., et al. (2009). Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish. Proceedings of the National Academy of Sciences of the United States of America, 106(43), 18408.

    Article  Google Scholar 

  • Joukov, V., Sorsa, T., Kumar, V., Jeltsch, M., Claesson-Welsh, L., Cao, Y., et al. (1997). Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO Journal, 16(13), 3898–3911.

    Article  PubMed  CAS  Google Scholar 

  • Kampmeier, O. F. (1925). The development of the trunk and tail lymphatics and posterior lymph hearts in anuran embryos. Journal of Morphology, 41, 1.

    Article  Google Scholar 

  • Karkkainen, M. J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T. V., et al. (2004). Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology, 5(1), 74–80.

    Article  PubMed  CAS  Google Scholar 

  • Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., et al. (2000). Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genetics, 25(2), 153–159.

    Article  PubMed  CAS  Google Scholar 

  • Karpanen, T., Heckman, C. A., Keskitalo, S., Jeltsch, M., Ollila, H., Neufeld, G., et al. (2006). Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB Journal, 20, 1462–1472.

    Article  PubMed  CAS  Google Scholar 

  • Küchler, A. M., Gjini, E., Peterson-Maduro, J., Cancilla, B., Wolburg, H., & Schulte-Merker, S. (2006). Development of the zebrafish lymphatic system requires VEGFC signaling. Current Biology, 16, 1244–1248.

    Article  PubMed  Google Scholar 

  • Mellor, R. H., Hubert, C. E., Stanton, A. W., Tate, N., Akhras, V., Smith, A., et al. (2010). Lymphatic dysfunction, not aplasia, underlies Milroy disease. Microcirculation, 17(4), 281–296.

    Article  PubMed  CAS  Google Scholar 

  • Ny, A., Koch, M., Schneider, M., Neven, E., Tong, R. T., Maity, S., et al. (2005). A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nature Medicine, 11(9), 998–1004.

    PubMed  CAS  Google Scholar 

  • Okuda, K. S., Astin, J. W., Misa, J. P., Flores, M. V., Crosier, K. E., & Crosier, P. S. (2012). lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish. Development, 139(13), 2381–2391.

    Article  PubMed  CAS  Google Scholar 

  • Pendeville, H., Winandy, M., Manfroid, I., Nivelles, O., Motte, P., Pasque, V., et al. (2008). Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. Developmental Biology, 317, 405–416.

    Article  PubMed  CAS  Google Scholar 

  • Stacker, S. A., Stenvers, K., Caesar, C., Vitali, A., Domagala, T., Nice, E., et al. (1999). Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. Journal of Biological Chemistry, 274(45), 32127–32136.

    Article  PubMed  CAS  Google Scholar 

  • Steffensen, J. F., Lomholt, J. P., & Vogel, W. O. P. (1986). In vivo observations on a specialized microvasculature. Acta Zoologica, 67(4), 193–200.

    Article  Google Scholar 

  • Tammela, T., Zarkada, G., Wallgard, E., Murtomaki, A., Suchting, S., Wirzenius, M., et al. (2008). Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature, 454(7204), 656–660.

    Article  PubMed  CAS  Google Scholar 

  • Tao, S., Witte, M., Bryson-Richardson, R. J., Currie, P. D., Hogan, B. M., & Schulte-Merker, S. (2011). Zebrafish prox1b mutants develop a lymphatic vasculature, and prox1b does not specifically mark lymphatic endothelial cells. PLoS One, 6(12), e28934.

    Article  PubMed  CAS  Google Scholar 

  • Valasek, P., Macharia, R., Neuhuber, W. L., Wilting, J., Becker, D. L., & Patel, K. (2007). Lymph heart in chick–somitic origin, development and embryonic oedema. Development, 134(24), 4427–4436.

    Article  PubMed  CAS  Google Scholar 

  • Villefranc, J. A., Nicoli, S., Bentley, K., Jeltsch, M., Zarkada, G., Moore, J. C., et al. (2013). A truncation allele in vascular endothelial growth factor C reveals distinct modes of signaling during lymphatic and vascular development. Development, 140(7), 1497–1506.

    Article  PubMed  CAS  Google Scholar 

  • Vogel, W. O. P., & Claviez, M. (1981). Vascular specialization in fish, but no evidence for lymphatics. Zeitschrift für Naturforschung, 36c, 490–492.

    Google Scholar 

  • Weijts, B. G. M. W., van Impel, A., Schulte-Merker, S., & de Bruin, A. (2013). Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. PLoS One, 8(9), e73693.

    Article  PubMed  CAS  Google Scholar 

  • Yang, Y., Garcia-Verdugo, J. M., Soriano-Navarro, M., Srinivasan, R. S., Scallan, J. P., Singh, M. K., et al. (2012). Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood, 120, 2340–2348.

    Article  PubMed  CAS  Google Scholar 

  • Yaniv, K., Isogai, S., Castranova, D., Dye, L., Hitomi, J., & Weinstein, B. M. (2006). Live imaging of lymphatic development in the zebrafish. Nature Medicine, 12(6), 711–716.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, L., Zhou, F., Han, W., Shen, B., Luo, J., Shibuya, M., et al. (2010). VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Research, 20(12), 1319–1331.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank all lab members, past and present, who have contributed directly, or in discussions, to the work related to lymphatic development. We would like to apologize to authors whose work we could not discuss in detail due to space limitations. Andreas van Impel was supported by a Marie Curie IEF fellowship; Stefan Schulte-Merker is supported by the KNAW.

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Authors and Affiliations

  1. Hubrecht Institute, KNAW and UMC Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands

    Andreas van Impel & Stefan Schulte-Merker

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  1. Andreas van Impel
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  2. Stefan Schulte-Merker
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Correspondence to Stefan Schulte-Merker .

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Editors and Affiliations

  1. MPI for Molecular Biomedicine, Münster, Germany

    Friedemann Kiefer

  2. Hubrecht Institute, Utrecht, The Netherlands

    Stefan Schulte-Merker

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van Impel, A., Schulte-Merker, S. (2014). A Fisheye View on Lymphangiogenesis. In: Kiefer, F., Schulte-Merker, S. (eds) Developmental Aspects of the Lymphatic Vascular System. Advances in Anatomy, Embryology and Cell Biology, vol 214. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1646-3_12

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  • DOI: https://doi.org/10.1007/978-3-7091-1646-3_12

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