Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis.
Amino Acid Sequence
Animals
Endothelial Cells
/ metabolism
Evolution, Molecular
HEK293 Cells
Humans
Ligands
Lymphangiogenesis
Mice
Protein Binding
Proteolysis
Reproducibility of Results
Vascular Endothelial Growth Factor C
/ chemistry
Vascular Endothelial Growth Factor Receptor-2
/ genetics
Zebrafish
/ embryology
Zebrafish Proteins
/ chemistry
Kdr
VEGF
VEGF receptor
Vegfd
developmental biology
lymphangiogenesis
lymphatic
organotypic
vascular biology
zebrafish
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
20 08 2019
20 08 2019
Historique:
received:
05
12
2018
revised:
11
06
2019
accepted:
16
07
2019
entrez:
22
8
2019
pubmed:
23
8
2019
medline:
1
9
2020
Statut:
ppublish
Résumé
Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integral in disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop in an organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven by vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, we define the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directs craniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homolog) but surprisingly, unlike in mammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a kdr mutant confirm receptor-binding analyses, demonstrating that Kdr is indispensible for rostral craniofacial lymphangiogenesis, but not caudal trunk lymphangiogenesis, in which Flt4 is central. We further demonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. This work reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially restricted mechanisms of developmental lymphangiogenesis.
Identifiants
pubmed: 31433980
pii: S2211-1247(19)30959-3
doi: 10.1016/j.celrep.2019.07.055
pii:
doi:
Substances chimiques
Ligands
0
Vascular Endothelial Growth Factor C
0
Zebrafish Proteins
0
vascular endothelial growth factor C, zebrafish
0
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
kdr protein, zebrafish
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2023-2036.e4Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.