Distinct Notch signaling outputs pattern the developing arterial system

Abstract

Differentiation of arteries and veins is essential for the development of a functional circulatory system. In vertebrate embryos, genetic manipulation of Notch signaling has demonstrated the importance of this pathway in driving artery endothelial cell differentiation. However, when and where Notch activation occurs to affect endothelial cell fate is less clear. Using transgenic zebrafish bearing a Notch-responsive reporter, we demonstrate that Notch is activated in endothelial progenitors during vasculogenesis prior to blood vessel morphogenesis and is maintained in arterial endothelial cells throughout larval stages. Furthermore, we find that endothelial progenitors in which Notch is activated are committed to a dorsal aorta fate. Interestingly, some arterial endothelial cells subsequently downregulate Notch signaling and then contribute to veins during vascular remodeling. Lineage analysis, together with perturbation of both Notch receptor and ligand function, further suggests several distinct developmental windows in which Notch signaling acts to promote artery commitment and maintenance. Together, these findings demonstrate that Notch acts in distinct contexts to initiate and maintain artery identity during embryogenesis.

Vegfa signals through ERK to promote angiogenesis, but not artery differentiation

“…Our studies using confocal microscopy at single-cell resolution and at multiple stages clearly demonstrate that pERK is found within endothelial cells that contribute to sprouting ISVs, but not within arterial cells remaining in the aorta. This pattern is distinct from that seen for Notch activation, which we have previously found to mark committed DA progenitors in the lateral mesoderm (Quillien et al, 2014), further underscoring a role for ERK in ISV sprouting, but not initial artery differentiation. Earlier work also applied a much higher SL327 dose (60 µM) and overall effects of this treatment on development were not reported.…”

“…1B,C-D″). This pattern was different from that of Notch activation, which marks the numerous DA-committed endothelial progenitors in the lateral mesoderm at this stage (Quillien et al, 2014). By 18 ss, we detected robust pERK in selected endothelial cells in the nascent DA, whereas endothelial progenitors still in the lateral mesoderm remained negative (Fig.…”

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

“…Although hemodynamic influences are involved, genetic programs also determine arterial or venous EC fate, even in the absence of blood flow Lawson et al, 2001Lawson et al, , 2002Quillien et al, 2014;Thurston and Yancopoulos, 2001;Wang et al, 1998;Zhong et al, 2001). Notch signaling has an established role in cell fate determination in many cell types.…”

“…Notch signaling has an established role in cell fate determination in many cell types. In the developing vasculature, Notch receptors and ligands are expressed by arterial ECs (Villa et al, 2001) and are involved in determining arterial EC fate (Lawson et al, 2001(Lawson et al, , 2002Quillien et al, 2014;Thurston and Yancopoulos, 2001;Zhong et al, 2001); thus, perturbations to Notch signaling affect AV gene expression. During vertebrate embryogenesis, loss of Notch signaling leads to numerous vascular abnormalities and the altered expression of arterial and venous marker genes Krebs et al, 2004Krebs et al, , 2010Krebs et al, , 2000Lawson et al, 2001;Limbourg et al, 2005).…”

Le somite : l’organe central de l’hématopoïèse aortique

“…On sait depuis peu que l'identité artérielle est induite dès le stade 5 somites, soit bien avant la formation de l'aorte. Ce processus est contrôlé par la voie Notch [5] qui agit directement sur les précurseurs endothé-liaux. La modulation précoce de la voie Notch affecte la formation de l'aorte, mais aussi celle des CSH.…”