title: Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis.
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.
authors: Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4073, Australia.
authors: Ludovic
authors: L
authors: Le Guen
authors: Terhi
authors: T
authors: Karpanen
authors: Dörte
authors: D
authors: Schulte
authors: Nicole C
authors: NC
authors: Harris
authors: Katarzyna
authors: K
authors: Koltowska
authors: Guy
authors: G
authors: Roukens
authors: Neil I
authors: NI
authors: Bower
authors: Andreas
authors: A
authors: van Impel
authors: Steven A
authors: SA
authors: Stacker
authors: Marc G
authors: MG
authors: Achen
authors: Stefan
authors: S
authors: Schulte-Merker
authors: Benjamin M
authors: BM
authors: Hogan
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D029961:Zebrafish Proteins; C493178:vascular endothelial growth factor C, zebrafish; D004247:DNA; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Angiogenesis; Lymphangiogenesis; Lymphedema; Vasculature; Zebrafish