PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature

  1. Taija Mäkinen1,
  2. Ralf H. Adams2,
  3. John Bailey1,
  4. Qiang Lu3,
  5. Andrew Ziemiecki4,
  6. Kari Alitalo5,
  7. Rüdiger Klein1,6, and
  8. George A. Wilkinson1
  1. 1Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany; 2Cancer Research UK-London Research Institute, London WC2A 3PX, United Kingdom; 3Division of Neurosciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA; 4Department of Clinical Research, Faculty of Medicine, University of Bern, 3004 Bern, Switzerland; 5Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland

Abstract

The transmembrane ligand ephrinB2 and its cognate Eph receptor tyrosine kinases are important regulators of embryonic blood vascular morphogenesis. However, the molecular mechanisms required for ephrinB2 transduced cellular signaling in vivo have not been characterized. To address this question, we generated two sets of knock-in mice: ephrinB2ΔV mice expressed ephrinB2 lacking the C-terminal PDZ interaction site, and ephrinB25F mice expressed ephrinB2 in which the five conserved tyrosine residues were replaced by phenylalanine to disrupt phosphotyrosine-dependent signaling events. Our analysis revealed that the homozygous mutant mice survived the requirement of ephrinB2 in embryonic blood vascular remodeling. However, ephrinB2ΔVV mice exhibited major lymphatic defects, including a failure to remodel their primary lymphatic capillary plexus into a hierarchical vessel network, hyperplasia, and lack of luminal valve formation. Unexpectedly, ephrinB25F/5F mice displayed only a mild lymphatic phenotype. Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.330105.

  • 6 Corresponding author. E-MAIL rklein{at}neuro.mpg.de; FAX 49-8985783152.

    • Accepted December 3, 2004.
    • Received June 25, 2004.

Related Article

| Table of Contents

Life Science Alliance