Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity

Abstract

They may both look like small tubes but arteries and veins are in fact anatomically and functionally distinct. Little is known about how vein identity is established, but studies in mouse embryos now show that the transcription factor COUP-TFII specifically marks the venous endothelium and regulates vein identity, thus challenging the current notion that vein identity results from a default pathway. COUP-TFII, a member of the orphan nuclear receptor superfamily, is expressed at high levels in the endothelium of veins but not in arteries. Selective removal of COUP-TFII in the venous endothelium results in activation of the Notch signalling pathway (an arterial marker) and ectopic induction of haematopoietic cell clusters (an arterial function), thus converting the mutant vein to acquire molecular and functional characteristics of an artery. Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial–venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor—Flk1 and neuropilin 1 (NP-1; also called Nrp1)—activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity1,2,3,4. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.