Dosage-sensitive requirement for mouse Dll4 in artery development

Abstract

Involvement of the Notch signaling pathway in vascular development has been demonstrated by both gain-and loss-of-function mutations in humans, mice, and zebrafish. In zebrafish, Notch signaling is required for arterial identity by suppressing the venous fate in developing artery cells. In mice, the Notch4 receptor and the Delta-like 4 (Dll4) ligand are specifically expressed in arterial endothelial cells, suggesting a similar role. Here we show that the Dll4 ligand alone is required in a dosage-sensitive manner for normal arterial patterning in development. This implicates Dll4 as the specific mammalian endothelial ligand for autocrine endothelial Notch signaling, and suggests that Dll4 may be a suitable target for intervention in arterial angiogenesis.

Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesis

“…Of the Notch receptors, the loss of Notch1 proved to be the most deleterious to vascular development (Conlon et al, 1995;Krebs et al, 2000;Swiatek et al, 1994). Furthermore, several studies have demonstrated expression of Notch receptors and ligands in blood vessels and mural cells (Alva and Iruela-Arispe, 2004;Benedito and Duarte, 2005;Claxton and Fruttiger, 2004;Duarte et al, 2004;Gale et al, 2004;Shutter et al, 2000;Villa et al, 2001). These studies have also generally agreed that in addition to capillaries, Notch ligands and receptors are mostly confined to arteries, a finding that was subsequently supported by the requirement of Notch in establishing arterial identity through expression of EphrinB2 (Lawson et al, 2001).…”

“…In terms of the ligands, only the loss of either Jag1 or Dll4 results in vascular defects, indicating that the other three Notch DSL ligands may not be as involved in vessel development. Notably, analysis of the phenotypes exhibited by Jag1 (Xue et al, 1999) and Dll4 (Duarte et al, 2004;Gale et al, 2004;Krebs et al, 2004) knockout mice, suggested that these two ligands are not functionally redundant. Indeed, the onset of lethality would indicate that each one of these molecules might provide a different array of signals through activation of Notch receptors.…”

“…Jag1 knockout mice have remodeling defects in the vasculature of the embryo and the yolk sac, resulting in hemorrhage and death by E11.5, indicating the contribution of this ligand at later stages of angiogenesis (Xue et al, 1999). Three separate studies of Dll4 deletion exhibited severe cardiovascular abnormalities including aortic stenosis, defective branching, arteriovenous connections, and pericardial edema (Duarte et al, 2004;Gale et al, 2004;Krebs et al, 2004). These mutant mice exhibit an array of defects far more extensive than those displayed by Jag1 and result in lethality between E9.5-10.5 with varying degrees of haploinsufficiency depending on the genetic background.…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…Endothelial cell-specific gain-of-function mutation of b-catenin in mice results in upregulation of Notch signaling, thereby altering vascular remodeling during embryonic development (36). Particularly, b-catenin stabilization in endothelial cells increases DLL4 transcription, leading to vascular phenotypes resembling those produced by DLL4 overexpression, including endothelial cell arterialization, lack of vascular remodeling, defects in branching, and loss of venous identity (39) …”

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

“…Jag2 is expressed in OFT myocardium from E11.5-E15.5 [149]. Of the Dll ligands, only Dll4 is expressed in the developing heart within the cardiac crescent, endocardium (after E8.5) and ventricular endocardium after E11.5 [150,151]. The Notch targets, Hey1 and Hey2 are expressed in the heart tube, endocardium (Hey2 specifically in the AVC and OFT endocardium at E11) and atrial (Hey1) and ventricular (Hey2) myocardium at E10.5 [152,144].…”