title: PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature.
abstract: The transmembrane ligand ephrinB2 and its cognate Eph receptor tyrosine kinases are important regulators of embryonic blood vascular morphogenesis. However, the molecular mechanisms required for ephrinB2 transduced cellular signaling in vivo have not been characterized. To address this question, we generated two sets of knock-in mice: ephrinB2DeltaV mice expressed ephrinB2 lacking the C-terminal PDZ interaction site, and ephrinB2(5F) mice expressed ephrinB2 in which the five conserved tyrosine residues were replaced by phenylalanine to disrupt phosphotyrosine-dependent signaling events. Our analysis revealed that the homozygous mutant mice survived the requirement of ephrinB2 in embryonic blood vascular remodeling. However, ephrinB2DeltaV/DeltaV mice exhibited major lymphatic defects, including a failure to remodel their primary lymphatic capillary plexus into a hierarchical vessel network, hyperplasia, and lack of luminal valve formation. Unexpectedly, ephrinB2(5F/5F) mice displayed only a mild lymphatic phenotype. Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.
authors.affiliation: Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany.
authors.forename: Taija
authors.initials: T
authors.lastname: Mäkinen
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: John
authors.initials: J
authors.lastname: Bailey
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Andrew
authors.initials: A
authors.lastname: Ziemiecki
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.forename: George A
authors.initials: GA
authors.lastname: Wilkinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D036388:Ephrin-B2; D014443:Tyrosine; D036224:Receptor, EphB4