Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain

Document Type

Article

Abstract

© 2015. Published by The Company of Biologists Ltd. 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.

Keywords

Endothelial cell, Extracellular matrix, Itgb8, Neurovascular unit, Nrp1, Tgfbr2

Publication Date

12-15-2015

Publication Title

Development (Cambridge)

ISSN

09501991

E-ISSN

14779129

Volume

142

Issue

24

First Page

4363

Last Page

4373

PubMed ID

26586223

Digital Object Identifier (DOI)

10.1242/dev.113746

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