Notch signal strength controls cell fate in the haemogenic endothelium

Abstract

Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta–gonad–mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage.

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…In this respect, it is attractive to speculate that the interaction between Notch and vimentin would serve as a hub to coordinate cytoskeletal and developmental signaling in the regulation of angiogenesis. Vimentin is required for efficient Jagged-Notch signaling and provides dynamic control of the strength of signal activity as cellular effects of Notch signaling are highly dose sensitive (36,53,66). Such control is important, because Jagged recycling and surface accumulation is enhanced, but Jagged surface levels are decoupled from signaling strength in vimentin-depleted cells.…”

“…Dll4 activation of Notch in neighboring cells reduces expression of VEGFR2 and inhibits tip cell selection. In contrast to Dll4, Jagged-Notch signaling promotes tip cell selection and sprouting by antagonizing Dll4-Notch signaling (31,(33)(34)(35)(36). How the competition between the ligands is balanced and how ligand-receptor signaling specificity is achieved is under intense investigation (31,33,34,37,38).…”

The developmental biology of genetic Notch disorders

“…This suggests that Notch signaling strength, which can be modified by these interactions, translates into a given output. In support of this, it has been shown that, in the haemogenic endothelium of mice, distinct levels of Notch signal activation in response to Jag1 versus Dll4 create a switch between acquiring a haemogenic versus an arterial endothelial fate (Gama-Norton et al, 2015). It is thus likely that modifications to genes that impact Notch signaling also impact disease presentation.…”

The Notch meeting: an odyssey from structure to function

“…Different DSL ligands, for example, can activate the same Notch receptor with differential effects on cell fate. As reported at the meeting by Anna Bigas (Institut Hospital del Mar d'Investigacions Mediques, Spain), Jag1-and Dll4-mediated Notch1 signaling in mouse aorta, gonad or mesonephros progenitors drives different transcriptomic and differentiation programs -hematopoietic stem cell or arterial specification (Gama-Norton et al, 2015). As presented by David Traver (University of California San Diego, USA), work in the zebrafish suggests that these distinct ligandNotch interactions are conserved across species (e.g.…”