Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development.
The lymphatic system plays a key role in tissue fluid homeostasis. Lymphatic dysfunction contributes to the pathogenesis of many human diseases, including lymphedema and tumor metastasis. However, the mechanisms regulating lymphangiogenesis remain largely unknown. Here, we show that COUP-TFII (also known as Nr2f2), an orphan member of the nuclear receptor superfamily, mediates both developmental and pathological lymphangiogenesis in mice. Conditional ablation of COUP-TFII at an early embryonic stage resulted in failed formation of pre-lymphatic ECs (pre-LECs) and lymphatic vessels. COUP-TFII deficiency at a late developmental stage resulted in loss of LEC identity, gain of blood EC fate, and impaired lymphatic vessel sprouting. siRNA-mediated downregulation of COUP-TFII in cultured primary human LECs demonstrated that the maintenance of lymphatic identity and VEGF-C-induced lymphangiogenic activity, including cell proliferation and migration, are COUP-TFII-dependent and cell-autonomous processes. COUP-TFII enhanced the pro-lymphangiogenic actions of VEGF-C, at least in part by directly stimulating expression of neuropilin-2, a coreceptor for VEGF-C. In addition, COUP-TFII inactivation in a mammary gland mouse tumor model resulted in inhibition of tumor lymphangiogenesis, suggesting that COUP-TFII also regulates neo-lymphangiogenesis in the adult. Thus, COUP-TFII is a critical factor that controls lymphangiogenesis in embryonic development and tumorigenesis in adults.
Lin
Fu-Jung
FJ
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Xinpu
X
Qin
Jun
J
Hong
Young-Kwon
YK
Tsai
Ming-Jer
MJ
Tsai
Sophia Y
SY
D000818:Animals; D001665:Binding Sites; D051837:COUP Transcription Factor II / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D042583:Lymphangiogenesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D039943:Neuropilin-2 / Q000096:biosynthesis* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
D051837:COUP Transcription Factor II; D039943:Neuropilin-2; D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C