title: Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain.
abstract: Angiogenesis in the developing central nervous system (CNS) is regulated by neuroepithelial cells, although the genes and pathways that couple these cells to blood vessels remain largely uncharacterized. Here, we have used biochemical, cell biological and molecular genetic approaches to demonstrate that β8 integrin (Itgb8) and neuropilin 1 (Nrp1) cooperatively promote CNS angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells. β8 integrin in the neuroepithelium promotes the activation of extracellular matrix (ECM)-bound latent transforming growth factor β (TGFβ) ligands and stimulates TGFβ receptor signaling in endothelial cells. Nrp1 in endothelial cells suppresses TGFβ activation and signaling by forming intercellular protein complexes with β8 integrin. Cell type-specific ablation of β8 integrin, Nrp1, or canonical TGFβ receptors results in pathological angiogenesis caused by defective neuroepithelial cell-endothelial cell adhesion and imbalances in canonical TGFβ signaling. Collectively, these data identify a paracrine signaling pathway that links the neuroepithelium to blood vessels and precisely balances TGFβ signaling during cerebral angiogenesis.
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirota
authors.affiliation: Department of Biosciences, Rice University, Houston, TX 77005, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Clements
authors.affiliation: College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Leung K
authors.initials: LK
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Morales
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hye Shin
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainseville, FL 32610, USA.
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Gonzalo M
authors.initials: GM
authors.lastname: Rivera
authors.affiliation: Department of Biosciences, Rice University, Houston, TX 77005, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wagner
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA jhmccarty@mdanderson.org.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: McCarty
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D020964:Embryo Loss / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D039641:Integrin beta Chains / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D046569:Neuroepithelial Cells / Q000166:cytology / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000199:Actins; D039641:Integrin beta Chains; D016212:Transforming Growth Factor beta; C094865:integrin beta8; D039942:Neuropilin-1
keywords: Endothelial cell; Extracellular matrix; Neurovascular unit; itgb8; nrp1; tgfbr2