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Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues.

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.

Pubmed ID: 21539827


  • Dravis C
  • Henkemeyer M


Developmental biology

Publication Data

July 1, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: 2R01 MH66332
  • Agency: NEI NIH HHS, Id: R01 EY017434
  • Agency: NEI NIH HHS, Id: R01 EY017434
  • Agency: NEI NIH HHS, Id: R01 EY017434-05
  • Agency: NIMH NIH HHS, Id: R01 MH066332
  • Agency: NIMH NIH HHS, Id: R01 MH066332-09
  • Agency: NIGMS NIH HHS, Id: T32 GM08203

Mesh Terms

  • Abnormalities, Multiple
  • Animals
  • Claudins
  • Cytoskeleton
  • Disease Models, Animal
  • Ephrin-B2
  • Ephrin-B3
  • Esophagus
  • Female
  • Larynx
  • Male
  • Mice
  • Morphogenesis
  • PDZ Domains
  • Palate
  • Phosphorylation
  • Protein Binding
  • Receptors, Eph Family
  • Signal Transduction
  • Trachea
  • Tyrosine