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

Developmental biology | Jul 1, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21539827

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 RIS Download

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

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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

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