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.
Development (Cambridge, England)   142(3): 497-509 (Journal)
Registered Authors
Fukuhara, Shigetomo, Fukui, Hajime, Mochizuki, Naoki, Nakajima, Hiroyuki
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*
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes