Open AccessNeuropilin-1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain
Author(s) -
Shinya Hirota,
Thomas P. Clements,
Leung K. Tang,
John E. Morales,
Hye Shin Lee,
S. Paul Oh,
Gonzalo Rivera,
Daniel S. Wagner,
Joseph H. McCarty
Publication year - 2015
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.113746
Subject(s) - angiogenesis , biology , microbiology and biotechnology , neuroepithelial cell , integrin , autocrine signalling , endothelial stem cell , paracrine signalling , neuropilin 1 , signal transduction , vascular endothelial growth factor , cancer research , receptor , neural stem cell , stem cell , biochemistry , in vitro , vegf receptors
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.