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

Dev Biol. 2011 Jul 1;355(1):138-51. doi: 10.1016/j.ydbio.2011.04.020. Epub 2011 Apr 22.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / genetics
  • Animals
  • Claudins / physiology
  • Cytoskeleton
  • Disease Models, Animal
  • Ephrin-B2 / genetics
  • Ephrin-B2 / physiology*
  • Ephrin-B3 / genetics
  • Ephrin-B3 / physiology*
  • Esophagus / abnormalities
  • Esophagus / growth & development
  • Female
  • Larynx / abnormalities
  • Larynx / growth & development
  • Male
  • Mice
  • Morphogenesis
  • PDZ Domains
  • Palate / abnormalities
  • Palate / growth & development
  • Phosphorylation
  • Protein Binding
  • Receptors, Eph Family / physiology*
  • Signal Transduction*
  • Trachea / abnormalities
  • Trachea / growth & development
  • Tyrosine / metabolism

Substances

  • Claudins
  • Ephrin-B2
  • Ephrin-B3
  • Tyrosine
  • Receptors, Eph Family