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

Christopher Dravis, Mark Henkemeyer

Research output: Contribution to journalArticle

48 Scopus citations

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-B26YFΔV and ephrin-B2ΔV 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.

Original languageEnglish (US)
Pages (from-to)138-151
Number of pages14
JournalDevelopmental Biology
Volume355
Issue number1
DOIs
StatePublished - Jul 1 2011

Keywords

  • Bidirectional signaling
  • Claudin
  • Cleft palate
  • EphB2
  • Ephrin-B2
  • Omphalocele
  • Receptor tyrosine kinase
  • Tracheoesophageal septation
  • VACTERL

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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