Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan
Development. 2015 Feb 1;142(3):497-509. doi: 10.1242/dev.115576. Epub 2015 Jan 6.
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-catenin-mediated 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 Klippel-Trenaunay 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.
β-连环蛋白调节参与多种生物学过程的基因转录，包括胚胎发生、组织稳态和再生。小鼠内皮细胞（EC）特异性基因靶向分析表明，β-连环蛋白是血管发育所必需的。然而，β-连环蛋白介导的基因调控在血管发育中的精确功能尚不清楚，因为β-连环蛋白不仅调节基因表达，还调节细胞-细胞连接的形成。为了解决这个问题，我们开发了一种新型的转基因斑马鱼系，允许特异性地在 EC 中可视化β-连环蛋白的转录活性，并发现β-连环蛋白依赖性转录对于骨形态发生蛋白（Bmp）介导的静脉血管形成至关重要。在尾静脉（CV）形成过程中，Bmp 诱导 aggf1 的表达，aggf1 是 Klippel-Trenaunay 综合征的一个假定致病基因，其特征是静脉畸形和骨骼和软组织肥大。随后，Aggf1 通过作为转录共因子增强β-连环蛋白的转录活性，表明 Bmp 通过 Aggf1 表达引发β-连环蛋白介导的基因表达。Bmp 介导的β-连环蛋白激活诱导 Nr2f2（也称为 Coup-TFII）的表达，Nr2f2 是核受体超家族的成员，促进静脉 EC 的分化，从而促进 CV 的形成。此外，Bmp 刺激的β-连环蛋白促进静脉 EC 的存活，但不促进动脉 EC 的存活。总之，这些结果表明，Bmp 通过 Aggf1 诱导的β-连环蛋白激活通过促进 Nr2f2 依赖性静脉 EC 的分化及其存活来调节 CV 的发育。本研究首次表明，β-连环蛋白介导的基因表达在静脉血管发育中起关键作用。
