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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.

Atypical E2fs Control Lymphangiogenesis through Transcriptional Regulation of Ccbe1 and Flt4