title: Reck enables cerebrovascular development by promoting canonical Wnt signaling.
abstract: The cerebral vasculature provides the massive blood supply that the brain needs to grow and survive. By acquiring distinctive cellular and molecular characteristics it becomes the blood-brain barrier (BBB), a selectively permeable and protective interface between the brain and the peripheral circulation that maintains the extracellular milieu permissive for neuronal activity. Accordingly, there is great interest in uncovering the mechanisms that modulate the formation and differentiation of the brain vasculature. By performing a forward genetic screen in zebrafish we isolated no food for thought (nft (y72)), a recessive late-lethal mutant that lacks most of the intracerebral central arteries (CtAs), but not other brain blood vessels. We found that the cerebral vascularization deficit of nft (y72) mutants is caused by an inactivating lesion in reversion-inducing cysteine-rich protein with Kazal motifs [reck; also known as suppressor of tumorigenicity 15 protein (ST15)], which encodes a membrane-anchored tumor suppressor glycoprotein. Our findings highlight Reck as a novel and pivotal modulator of the canonical Wnt signaling pathway that acts in endothelial cells to enable intracerebral vascularization and proper expression of molecular markers associated with BBB formation. Additional studies with cultured endothelial cells suggest that, in other contexts, Reck impacts vascular biology via the vascular endothelial growth factor (VEGF) cascade. Together, our findings have broad implications for both vascular and cancer biology.
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Ulrich
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Carretero-Ortega
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Menéndez
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Narvaez
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Sun
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Lancaster
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Pershad
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Trzaska
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Véliz
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamei
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Prendergast
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kameha R
authors.initials: KR
authors.lastname: Kidd
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kenna M
authors.initials: KM
authors.lastname: Shaw
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Castranova
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Van N
authors.initials: VN
authors.lastname: Pham
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brigid D
authors.initials: BD
authors.lastname: Lo
authors.affiliation: Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Martin
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Raible
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brant M
authors.initials: BM
authors.lastname: Weinstein
authors.affiliation: Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA torres@saturn.med.nyu.edu.
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Vázquez
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier / Q000166:cytology*; D001921:Brain / Q000098:blood supply / Q000196:embryology*; D002460:Cell Line; D002560:Cerebrovascular Circulation / Q000235:genetics* / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology; D058851:GPI-Linked Proteins / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; C000605632:RECK protein, zebrafish; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins
keywords: Angiogenesis; Blood-brain barrier; Brain vasculature; Reck; VEGF; Wnt