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- Title
Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development.
- Authors
Fu-Jung Lin; Xinpu Chen; Jun Qin; Young-Kwon Hong; Ming-Jer Tsai; Tsai, Sophia Y.; Lin, Fu-Jung; Chen, Xinpu; Qin, Jun; Hong, Young-Kwon; Tsai, Ming-Jer
- Abstract
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.
- Subjects
TRANSCRIPTION factors; NEUROPILINS; MOUSE leukemia; LYMPHATIC cancer; METASTASIS; CELL proliferation; MAMMARY glands; PROTEIN metabolism; RNA metabolism; ANIMAL experimentation; BINDING sites; CELL physiology; CELL receptors; CELL motility; COMPARATIVE studies; GENES; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; RESEARCH funding; EVALUATION research; FETAL development; ENDOTHELIAL growth factors; GENOTYPES
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 5, p1694
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI40101