Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis

Le Guen, Ludovic, Karpanen, Terhi, Dorte, Schulte, Harris, Nicole C., Koltowska, Katarzyna, Roukens, Guy, Bower, Neil I., van Impel, Andreas, Stacker, Steven A., Achen, Marc G., Schulte-Merker, Stefan and Hogan, Benjamin M. (2014) Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development, 141 6: 1239-1249. doi:10.1242/dev.100495

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Author Le Guen, Ludovic
Karpanen, Terhi
Dorte, Schulte
Harris, Nicole C.
Koltowska, Katarzyna
Roukens, Guy
Bower, Neil I.
van Impel, Andreas
Stacker, Steven A.
Achen, Marc G.
Schulte-Merker, Stefan
Hogan, Benjamin M.
Title Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis
Journal name Development   Check publisher's open access policy
ISSN 1239-1249
0950-1991
1477-9129
Publication date 2014
Year available 2014
Sub-type Article (original research)
DOI 10.1242/dev.100495
Open Access Status File (Publisher version)
Volume 141
Issue 6
Start page 1239
End page 1249
Total pages 11
Place of publication Cambridge, United Kingdom
Publisher The Company of Biologists
Collection year 2015
Language eng
Formatted abstract
The VEGFC/VEGFR3 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from pre-existing vasculature) during embryonic development, tissue regeneration and tumor progression. The recently identified secreted protein CCBE1 is indispensible for lymphangiogenesis during development. The role of CCBE1 orthologs is highly conserved in zebrafish, mice and humans with mutations in CCBE1 causing generalized lymphatic dysplasia and lymphedema (Hennekam syndrome). To date, the mechanism by which CCBE1 acts remains unknown. Here, we find that ccbe1 genetically interacts with both vegfc and vegfr3 in zebrafish. In the embryo, phenotypes driven by increased Vegfc are suppressed in the absence of Ccbe1, and Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression. Moreover, Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1. Finally, CCBE1 is capable of upregulating the levels of fully processed, mature VEGFC in vitro and the overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes in zebrafish. Taken together, these data identify Ccbe1 as a crucial component of the Vegfc/Vegfr3 pathway in the embryo.
Keyword Angiogenesis
Lymphangiogenesis
Lymphedema
Vasculature
Zebrafish
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 12 Feb 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 27 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 26 May 2015, 22:09:26 EST by Ben Hogan on behalf of Institute for Molecular Bioscience