title: 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-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.
authors.affiliation: 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.
authors.forename: Takeru
authors.initials: T
authors.lastname: Kashiwada
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan fuku@ncvc.go.jp nmochizu@ncvc.go.jp.
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Laboratory of Function and Morphology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Terai
authors.affiliation: 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.
authors.forename: Toru
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Wakayama
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yuge
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan JST-CREST, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan fuku@ncvc.go.jp nmochizu@ncvc.go.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D008156:Luciferases; D008164:Luminescent Proteins; D008856:Microscopy, Fluorescence; D060172:Morpholinos / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D014680:Veins / Q000166:cytology / Q000196:embryology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000097573:Red Fluorescent Protein
chemical_list: D042501:Angiogenic Proteins; D019485:Bone Morphogenetic Proteins; D051837:COUP Transcription Factor II; D018076:DNA, Complementary; D008156:Luciferases; D008164:Luminescent Proteins; D060172:Morpholinos; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097573:Red Fluorescent Protein; C587102:AGGF1 protein, zebrafish
keywords: Aggf1; Bmp; Nr2f2; Venous vessel development; Zebrafish; β-catenin