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ccbe1 is required for embryonic lymphangiogenesis and venous sprouting

Nature Genetics volume 41, pages 396–398 (2009)Cite this article

Abstract

Lymphatic vessels have important roles in fluid homeostasis, fat absorption, inflammation and cancer metastasis and develop in a dynamic process (called lymphangiogenesis) involving budding, migration and proliferation of lymphangioblasts. Using a genetic screen in zebrafish we identify ccbe1 (collagen and calcium-binding EGF domain-1) as indispensible for embryonic lymphangiogenesis. Ccbe1 acts at the same stage of development as Vegfc and is required for lymphangioblast budding and angiogenic sprouting from venous endothelium.

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Figure 1: full of fluid mutants lack trunk lymphatic vessels.
Figure 2: ccbe1 and vegfc are required for lymphangioblast budding and angiogenic sprouting from venous endothelium.

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Acknowledgements

B.M.H. was supported by an EMBO long term fellowship and an NH&MRC CJ Martin Fellowship and J.B. by the Stichting Vrienden van het Hubrecht. N.C.C. is supported by K08 grants from the NHLBI, GSK Research & Education Foundation Cardiovascular Awards, and Fellow to Faculty AHA postdoctoral awards. N.C.C. also thanks D. Stainier for support. H.J.D. received an NWO VIDI grant. The authors thank the Hubrecht Screen Team, J. Korving for sectioning, R. Korswagen, A. MacInnes, K. Smith and H. Clevers for critical reading of the manuscript.

Author information

Author notes

  1. Neil C Chi

    Present address: Present address: Department of Medicine, University of California San Diego, Division of Cardiology, La Jolla, California, USA.,

  2. Frank L Bos, Jeroen Bussmann and Merlijn Witte: These authors contributed equally to this work.

Authors and Affiliations

  1. Hubrecht Institute-KNAW & University Medical Centre, Utrecht, The Netherlands

    Benjamin M Hogan, Frank L Bos, Jeroen Bussmann, Merlijn Witte & Stefan Schulte-Merker

  2. Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands

    Frank L Bos & Henricus J Duckers

  3. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA

    Neil C Chi

  4. Programs in Developmental Biology, Genetics, and Human Genetics, University of California San Francisco, San Francisco, California, USA

    Neil C Chi

  5. Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA

    Neil C Chi

  6. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Neil C Chi

Authors
  1. Benjamin M Hogan
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  2. Frank L Bos
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Contributions

B.M.H. conceived, carried out experiments and co-wrote manuscript. F.L.B., J.B., N.C.C. and M.W. conceived and carried out experiments. H.J.D. conceived experiments. S.S.M. conceived experiments and co-wrote the manuscript.

Corresponding author

Correspondence to Stefan Schulte-Merker.

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Competing interests

A patent has been filed: “Methods for identifying modulating compounds of lymphangiogenesis, means therefore, compounds and used thereof.” Holder of the patent is the Royal Dutch Academie of Sciences (KNAW).

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1399 kb)

Supplementary Movie S1

Confocal timelapse analysis of early venous budding in the trunk of wildtype stabilin1:YFP transgenic embryo viewed laterally from 24 to 68hpf (movie representative of n=5 wildtype movies, arrow indicates budding of lymphangioblast to the horizontal myoseptum). (MOV 7041 kb)

Supplementary Movie S2

Confocal timelapse analysis of lymphangioblast migration in the trunk of wildtype stabilin1:YFP transgenic embryo viewed laterally from 32 to 86hpf (movie representative of n=3 wildtype movies, arrows indicates migration of lymphangioblasts from the horizontal myoseptum, both dorsally and ventrally). (AVI 51589 kb)

Supplementary Movie S3

Confocal timelapse analysis of the trunk of ccbe1 ATG MO injected stabilin1:YFP transgenic embryo viewed laterally from 24 to 68hpf, demonstrating the absence of venous sprouts or buds (movie representative of n=4 morphant movies). (AVI 101485 kb)

Supplementary Movie S4

Confocal timelapse analysis of the trunk of vegfc MO injected stabilin1:YFP transgenic embryo viewed laterally from 24 to 68hpf, demonstrating the absence of venous sprouts or buds (movie representative of n=4 morphant movies). (MOV 7457 kb)

Supplementary Movie S5

Confocal timelapse analysis of the trunk of double transgenic (kdr-l:RFP, fli1:GFP) wildtype embryos between 56 and 82hpf. Arrows indicate the movement of cells out of the horizontal myoseptum region during the time-period and the concurrent movement of cells dorsally and ventrally to initiate the morphogenesis of the DLLV and thoracic duct. (MOV 4453 kb)

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Hogan, B., Bos, F., Bussmann, J. et al. ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 41, 396–398 (2009). https://doi.org/10.1038/ng.321

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