Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants

Abstract

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

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

“…N1ICD staining labels arterial endothelium (Supplementary Figure 1o and Del Monte et al 30 ), so the observation that Tie2-Cre-driven ectopic N1ICD expression promotes arterial differentiation of venous endothelium is consistent with the requirement of Notch in arterial endothelium differentiation. 34 LacZ staining of Tie2-Cre;R26R embryos (Supplementary Figure 1p) indicates that this driver is active throughout the endothelium and circulating cells and is an excellent tool for studying the effect of Notch overexpression in these tissues.…”

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

“…Rbpj null mice have additional embryonic abnormalities such as growth retardation, incomplete turning, and placenta, neural tube and somite defects, which result in embryonic lethality at E10.5 [153]. Endothelial-specific Rbpj null embryos have a comparable phenotype to the complete loss of Rbpj with severe growth retardation and vascular remodelling abnormalities [153,154]. Interestingly, in Rbpj null embryos the endocardium overlying AVC cardiac cushions appears to be activated but the cells fail to invade the cushions due to preservation of their adherens junctions and maintenance of close associations [144,51].…”

“…Of the Dll ligands, only Dll4 is expressed in the embryonic heart in mice. Dll4 heterozygous mice display pericardial effusions, growth retardation, vascular remodelling defects and are haploinsufficient lethal [154]. Dll4 heterozygous mice have a similar vascular phenotype to Notch receptor and Rbpj knockout mice, suggesting that Dll4 is the predominant Notch ligand required for vascular development.…”

Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells

“…[6][7][8][9][10][11] In the hematopoietic system, Jagged1 25 and Delta1 14,26 are key regulators of Notch signaling. Accordingly, to understand the role of Notch signaling in human, we examined whether Jagged1 (Jag1) and Delta1 (Dll1) contribute to hematopoietic development from hPSCs.…”

“…4,5 Perturbation of Notch signaling has deleterious effects on embryonic hematopoiesis and vascular development. [6][7][8][9][10][11] In mouse models, Notch1 was shown to be required for generation of hematopoietic cells from bipotent hemogenic endothelial precursors, known as hemangioblasts. 7 In humans, a critical role for Notch signaling, through the Notch ligand Jagged1, has been demonstrated in the proliferation and differentiation of normal primitive human hematopoietic progenitors.…”