title: Death receptors DR6 and TROY regulate brain vascular development.
abstract: Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development.
authors.affiliation: Neurodegeneration Labs, Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tam
authors.forename: David L
authors.initials: DL
authors.lastname: Richmond
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Baby
authors.initials: B
authors.lastname: Martin-McNulty
authors.forename: Tim C
authors.initials: TC
authors.lastname: Cao
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Nick
authors.initials: N
authors.lastname: van Bruggen
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D002450:Cell Communication; D002478:Cells, Cultured; D002490:Central Nervous System / Q000098:blood supply* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C409471:Tnfrsf19 protein, mouse; C485251:Tnfrsf21 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D048670:MAP Kinase Kinase 4