Essential role of COUP-TFII in vascular formation

Abstract

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is a member of the orphan nuclear receptor superfamily. The spatiotemporal expression pattern of COUP-TFII suggests that it participates in mesenchymal-epithelial interactions required for organogenesis. The null mutants of COUP-TFII die around embryonic (E) day E10 due to defects in angiogenesis and heart formation. To further understand the biologic functions of COUP-TFII during development, LacZ knockin mice and floxed COUP-TFII mice were generated. 5-bomo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining of COUP-TFII-LacZ knockin mice shows high COUP-TFII expression in the endothelium of the vein but not in the artery. In contrast, COUP-TFII is highly expressed in the smooth muscle layer surrounding the artery. This differential expression pattern suggests that COUP-TFII may play a role in establishing arterial-venous identity. To further elucidate the functional role of COUP-TFII in the formation of endothelium of the vein, COUP-TFII was specifically knocked out in the endothelium using Tie-2 Cre mice. In mutant mice lacking COUP-TFII in the endothelium, the vein acquires arterial characteristics and ectopic expression of Notch signal pathway. In addition, NP-1, an upstream regulator of Notch signaling, is also up-regulated. Finally, ectopic formation of hematopieitic cell clusters (HCC) is observed in the mutant veins. Our results are consistent with the notion that cell fate determination of the vein is under genetic control rather than deriving from a default pathway as proposed previously. In addition, COUP-TFII is the first transcription factor identified that specifically marks the endothelium of the vein. Understanding the role of COUP-TFII during the vasculature development will provide insights into the molecular mechanism for the establishment of arterial-venous identity.