β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

Abstract

β-catenin regulates the transcription of genes involved in diverse biological processes, including embryogenesis, tissue homeostasis and regeneration. Endothelial cell (EC)-specific gene-targeting analyses in mice have revealed that β-catenin is required for vascular development. However, the precise function of β-cateninmediated gene regulation in vascular development is not well understood, since β-catenin regulates not only gene expression but also the formation of cell-cell junctions. To address this question, we have developed a novel transgenic zebrafish line that allows the visualization of β-catenin transcriptional activity specifically in ECs and discovered that β-catenin-dependent transcription is central to the bone morphogenetic protein (Bmp)-mediated formation of venous vessels. During caudal vein (CV) formation, Bmp induces the expression of aggf1, a putative causative gene for KlippelTrenaunay syndrome, which is characterized by venous malformation and hypertrophy of bones and soft tissues. Subsequently, Aggf1 potentiates β-catenin transcriptional activity by acting as a transcriptional co-factor, suggesting that Bmp evokes β-catenin-mediated gene expression through Aggf1 expression. Bmp-mediated activation of β-catenin induces the expression of Nr2f2 (also known as Coup-TFII), a member of the nuclear receptor superfamily, to promote the differentiation of venous ECs, thereby contributing to CV formation. Furthermore, β-catenin stimulated by Bmp promotes the survival of venous ECs, but not that of arterial ECs. Collectively, these results indicate that Bmp-induced activation of β-catenin through Aggf1 regulates CV development by promoting the Nr2f2-dependent differentiation of venous ECs and their survival. This study demonstrates, for the first time, a crucial role of β-catenin-mediated gene expression in the development of venous vessels.

Real-time 3D visualization of cellular rearrangements during cardiac valve formation

“…Therefore, we investigated whether a similar activation pattern was observable for another signaling pathway also known to facilitate cell migration into the cardiac jelly. For this purpose, we imaged 75 hpf hearts of triple transgenic larvae expressing an endocardial-specific Wnt/β-catenin signaling reporter [Tg(fli1:Gal4db-TΔC-2A-mC);Tg(UAS:EGFP);Tg(fli1: Myr-mCherry)] (Asakawa et al, 2008;Kashiwada et al, 2015). In contrast to the Notch reporter data, we could detect Wnt/β-catenin reporter activity in 12±2 cells (n=14 larvae) primarily located at the abluminal side of the valve (Fig.…”

“…The following transgenic and mutant lines were used: Tg(kdrl: EGFP) s843 , Tg(7xTCF-Xla.Siam:nls-mCherry) ia5 (Moro et al, 2012), Tg(kdrl:nls-EGFP) zf109 (Blum et al, 2008), Tg(kdrl:rasmCherry) s896 (Chi et al, 2008), Tg(UAS:Kaede) rk8Tg (Hatta et al, 2006), Tg(fli1a:Gal4FF) ubs4 (Zygmunt et al, 2011), Tg(UAS:Brainbow) s1997t (Robles et al, 2013), Tg(UAS:GFP) nkuasgfp1a (Asakawa et al, 2008), Tg(TP1:VenusPEST) s940 (Ninov et al, 2012), apc hu745/+ (Hurlstone et al, 2003), Tg(fli1:Gal4db-TΔC-2A-mC) ncv15 and Tg(fli1:Myr-mCherry) ncv1 (Kashiwada et al, 2015).…”

Development of the lymphatic system: new questions and paradigms

“…In zebrafish, Bmp2b upregulation at 25-26 hpf induces ectopic venous sprouting, whereas forced expression of Noggin 3, which is an endogenous inhibitor of BMP signaling, results in impaired caudal vein plexus formation (Wiley et al, 2011). Interestingly, a recent study has shown that Bmp2b induces venous differentiation through the activation of a novel β-catenin/Coup-TFII axis (Kashiwada et al, 2015).…”

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

“…During embryogenesis, AGGF1 is required for differentiation of multipotent hemangioblasts, which eventually differentiate into vascular cells and blood cells in zebrafish 34. AGGF1 is required for specific differentiation of veins and development of intersegmental vessels during zebrafish embryogenesis,35 which was confirmed by Kashiwada et al 36. Our recent studies using AGGF1 +/− knockout (KO) mice showed that AGGF1 is essential for early embryogenesis and vascular development, and blocks vascular permeability 37.…”