Atypical E2fs Control Lymphangiogenesis through Transcriptional Regulation of Ccbe1 and Flt4
- Weijts, B.G., van Impel, A., Schulte-Merker, S., and de Bruin, A.
- PLoS One 8(9): e73693 (Journal)
- Registered Authors
- Schulte-Merker, Stefan, van Impel, Andreas, Weijts, Bart
- MeSH Terms
- Blotting, Western
- Calcium-Binding Proteins/genetics
- Calcium-Binding Proteins/metabolism*
- Chromatin Immunoprecipitation
- Electrophoresis, Polyacrylamide Gel
- Vascular Endothelial Growth Factor Receptor-3/genetics
- Vascular Endothelial Growth Factor Receptor-3/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 24069224 Full text @ PLoS One
Weijts, B.G., van Impel, A., Schulte-Merker, S., and de Bruin, A. (2013) Atypical E2fs Control Lymphangiogenesis through Transcriptional Regulation of Ccbe1 and Flt4. PLoS One. 8(9):e73693.
Lymphatic vessels are derived from venous endothelial cells and their formation is governed by the Vascular endothelial growth factor C (VegfC)/Vegf receptor 3 (Vegfr3; Flt4) signaling pathway. Recent studies show that Collagen and Calcium Binding EGF domains 1 protein (Ccbe1) enhances VegfC-dependent lymphangiogenesis. Both Ccbe1 and Flt4 have been shown to be indispensable for lymphangiogenesis. However, how these essential players are transcriptionally regulated remains poorly understood. In the case of angiogenesis, atypical E2fs (E2f7 and E2f8) however have been recently shown to function as transcriptional activators for VegfA. Using a genome-wide approach we here identified both CCBE1 and FLT4 as direct targets of atypical E2Fs. E2F7/8 directly bind and stimulate the CCBE1 promoter, while recruitment of E2F7/8 inhibits the FLT4 promoter. Importantly, inactivation of e2f7/8 in zebrafish impaired venous sprouting and lymphangiogenesis with reduced ccbe1 expression and increased flt4 expression. Remarkably, over-expression of e2f7/8 rescued Ccbe1- and Flt4-dependent lymphangiogenesis phenotypes. Together these results identified E2f7/8 as novel in vivo transcriptional regulators of Ccbe1 and Flt4, both essential genes for venous sprouting and lymphangiogenesis.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes