title: Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues.
abstract: We report that the disruption of bidirectional signaling between ephrin-B2 and EphB receptors impairs morphogenetic cell-cell septation and closure events during development of the embryonic midline. A novel role for reverse signaling is identified in tracheoesophageal foregut septation, as animals lacking the cytoplasmic domain of ephrin-B2 present with laryngotracheoesophageal cleft (LTEC), while both EphB2/EphB3 forward signaling and ephrin-B2 reverse signaling are shown to be required for midline fusion of the palate. In a third midline event, EphB2/EphB3 are shown to mediate ventral abdominal wall closure by acting principally as ligands to stimulate ephrin-B reverse signaling. Analysis of new ephrin-B2(6YFΔV) and ephrin-B2(ΔV) mutants that specifically ablate ephrin-B2 tyrosine phosphorylation- and/or PDZ domain-mediated signaling indicates there are at least two distinct phosphorylation-independent components of reverse signaling. These involve both PDZ domain interactions and a non-canonical SH2/PDZ-independent form of reverse signaling that may utilize associations with claudin family tetraspan molecules, as EphB2 and activated ephrin-B2 molecules are specifically co-localized with claudins in epithelia at the point of septation. Finally, the developmental phenotypes described here mirror common human midline birth defects found with the VACTERL association, suggesting a molecular link to bidirectional signaling through B-subclass Ephs and ephrins.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
authors.forename: Christopher
authors.initials: C
authors.lastname: Dravis
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D057167:Claudins / Q000502:physiology; D003599:Cytoskeleton; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000235:genetics / Q000502:physiology*; D036389:Ephrin-B3 / Q000235:genetics / Q000502:physiology*; D004947:Esophagus / Q000002:abnormalities / Q000254:growth & development; D005260:Female; D007830:Larynx / Q000002:abnormalities / Q000254:growth & development; D008297:Male; D051379:Mice; D009024:Morphogenesis; D054731:PDZ Domains; D010159:Palate / Q000002:abnormalities / Q000254:growth & development; D010766:Phosphorylation; D011485:Protein Binding; D036081:Receptors, Eph Family / Q000502:physiology*; D015398:Signal Transduction; D014132:Trachea / Q000002:abnormalities / Q000254:growth & development; D014443:Tyrosine / Q000378:metabolism
chemical_list: D057167:Claudins; D036388:Ephrin-B2; D036389:Ephrin-B3; D014443:Tyrosine; D036081:Receptors, Eph Family