Haploinsufficiency of Delta-Like 4 Ligand Results in Embryonic Lethality Due to Major Defects in Arterial and Vascular Development

Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF). One potential such regulator is delta-like 4 ligand (Dll4), a recently identified partner for the Notch receptor...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-11, Vol.101 (45), p.15949-15954
Main Authors: Gale, Nicholas W., Dominguez, Melissa G., Noguera, Irene, Pan, Li, Hughes, Virginia, Valenzuela, David M., Murphy, Andrew J., Adams, Niels C., Lin, Hsin Chieh, Holash, Jocelyn, Thurston, Gavin, Yancopoulos, George D.
Format: Article
Language:English
Subjects:
Animals
Aorta
Arteries
Arteries - abnormalities
Base Sequence
Biological Sciences
Biology
Blood vessels
Blood Vessels - abnormalities
Cardiovascular system
Defects
Developmental biology
DNA - genetics
Embryos
Female
Fetal Death - genetics
Gene Expression Regulation, Developmental
Gene Targeting
Genes, Reporter
Heterozygote
Intracellular Signaling Peptides and Proteins
Ligands
Membrane Proteins - deficiency
Membrane Proteins - genetics
Membrane Proteins - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mortality
Placenta - abnormalities
Placenta - blood supply
Pregnancy
Tumors
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - physiology
Veins
Yolk sac
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Summary:Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF). One potential such regulator is delta-like 4 ligand (Dll4), a recently identified partner for the Notch receptors. We generated mice in which the Dll4 gene was replaced with a reporter gene, and found that Dll4 expression is initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, Dll4 is specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent albeit variable defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of the defects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicate that vascular development may be as sensitive to subtle changes in Dll4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploid insufficiency, resulting in obvious vascular abnormalities. In summary, Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro- and anti-angiogenic therapies.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407290101