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Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.

The Notch signaling pathway is essential for embryonic vascular development in vertebrates. Here we show that mouse embryos heterozygous for a targeted mutation in the gene encoding the DLL4 ligand exhibit haploinsufficient lethality because of defects in vascular remodeling. We also describe vascular defects in embryos homozygous for a mutation in the Rbpsuh gene, which encodes the primary transcriptional mediator of Notch signaling. Conditional inactivation of Rpbsuh function demonstrates that Notch activation is essential in the endothelial cell lineage. Notch pathway mutant embryos exhibit defects in arterial specification of nascent blood vessels and develop arteriovenous malformations. These results demonstrate that vascular remodeling in the mouse embryo is sensitive to Dll4 gene dosage and that Notch activation in endothelial cells is essential for embryonic vascular remodeling.

Pubmed ID: 15466160


  • Krebs LT
  • Shutter JR
  • Tanigaki K
  • Honjo T
  • Stark KL
  • Gridley T


Genes & development

Publication Data

October 15, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA34196
  • Agency: NINDS NIH HHS, Id: NS36437

Mesh Terms

  • Animals
  • Blood Vessels
  • DNA Primers
  • DNA-Binding Proteins
  • Endothelial Cells
  • Gene Dosage
  • Genotype
  • Histological Techniques
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Mice
  • Mutation
  • Nuclear Proteins
  • Receptors, Notch
  • Signal Transduction