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.
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Luke T
LT
Krebs
John R
JR
Shutter
Kenji
K
Tanigaki
Tasuku
T
Honjo
Kevin L
KL
Stark
Thomas
T
Gridley
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities / Q000033:anatomy & histology / Q000196:embryology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology; D018628:Gene Dosage; D005838:Genotype; D006652:Histological Techniques; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051880:Receptors, Notch; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D009687:Nuclear Proteins; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C064045:delta protein