{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCollagen and calcium-binding EGF domains 1 (CCBE1) is a secreted protein that plays an essential role in embryonic and postnatal lymphangiogenesis by enhancing vascular endothelial growth factor‐C (VEGF‐C) signaling. CCBE1 accomplishes this through distinct domain functions: its C-terminal domain facilitates the proteolytic activation of pro-VEGF-C by ADAMTS3, while its N-terminal domain promotes the colocalization of pro-VEGF-C with its activating protease at the lymphatic endothelial cell surface. This dual mechanism strengthens VEGFR-3 signaling, which is crucial for the proper formation and maintenance of lymphatic vessels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its lymphangiogenic functions, CCBE1 is critically involved in cardiac development. It is expressed early in the cardiac progenitor fields—including the first and second heart fields and the proepicardium—and contributes to the commitment of cardiac mesoderm during embryonic stem cell differentiation. CCBE1’s modulatory effects on VEGF-C signaling are also implicated in the formation of the coronary vasculature, underscoring its significance in orchestrating proper heart organogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in the vascular and cardiac systems, CCBE1 also exerts non–cell-autonomous effects on definitive erythropoiesis in the fetal liver by modulating the hematopoietic microenvironment, including the formation of erythroblastic islands and the function of macrophages. Moreover, studies in zebrafish have offered additional insights into CCBE1’s regulatory influence on the lymphatic network, while investigations in mammals point to its importance in the development and in the age-dependent maintenance of meningeal lymphatics critical for macromolecule drainage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Frank L Bos, Maresa Caunt, Josi Peterson-Maduro, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.113.002779"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.113.002779"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24552833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24552833"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "M Guy Roukens, Josi Peterson-Maduro, Yvonne Padberg, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-04982-1"}], "href": "https://doi.org/10.1038/s41598-017-04982-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28687807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28687807"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "João Facucho-Oliveira, Margaret Bento, José-António Belo "}, {"type": "b", "children": [{"type": "t", "text": "Ccbe1 expression marks the cardiac and lymphatic progenitor lineages during early stages of mouse development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Dev Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1387/ijdb.113394jf"}], "href": "https://doi.org/10.1387/ijdb.113394jf"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22252499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22252499"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Fernando Bonet, Paulo N G Pereira, Oriol Bover, et al. 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