ZFIN ID: ZDB-PUB-150108-9
β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels
Kashiwada, T., Fukuhara, S., Terai, K., Tanaka, T., Wakayama, Y., Ando, K., Nakajima, H., Fukui, H., Yuge, S., Saito, Y., Gemma, A., Mochizuki, N.
Date: 2015
Source: Development (Cambridge, England)   142(3): 497-509 (Journal)
Registered Authors: Fukuhara, Shigetomo, Fukui, Hajime, Mochizuki, Naoki, Nakajima, Hiroyuki
Keywords: β-Catenin, Venous vessel development, Bmp, Aggf1, Nr2f2, Zebrafish
MeSH Terms:
  • Angiogenic Proteins/metabolism
  • Animals
  • Animals, Genetically Modified
  • Bone Morphogenetic Proteins/metabolism
  • COUP Transcription Factor II/metabolism
  • DNA, Complementary/genetics
  • Endothelial Cells/physiology*
  • Endothelial Cells/ultrastructure
  • Gene Expression Regulation, Developmental/physiology*
  • HEK293 Cells
  • Humans
  • In Situ Nick-End Labeling
  • Luciferases
  • Luminescent Proteins
  • Microscopy, Fluorescence
  • Morpholinos/genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Veins/cytology
  • Veins/embryology*
  • Zebrafish
  • Zebrafish Proteins/metabolism
  • beta Catenin/metabolism*
PubMed: 25564648 Full text @ Development
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.