The β8 integrin cytoplasmic domain activates extracellular matrix adhesion to promote brain neurovascular development

Abstract

In the developing mammalian brain, neuroepithelial cells interact with blood vessels to regulate angiogenesis, blood-brain barrier maturation and other key neurovascular functions. Genetic studies in mice have shown that neurovascular development is controlled, in part, by Itgb8, which encodes the neuroepithelial cell-expressed integrin β8 subunit. However, these studies have involved complete loss-of-function Itgb8 mutations, and have not discerned the relative roles for the β8 integrin extracellular matrix (ECM) binding region versus the intracellular signaling tail. Here, Cre/lox strategies have been employed to selectively delete the cytoplasmic tail of murine Itgb8 without perturbing its transmembrane and extracellular domains. We report that the β8 integrin cytoplasmic domain is essential for inside-out modulation of adhesion, including activation of latent-TGFβs in the ECM. Quantitative sequencing of the brain endothelial cell transcriptome identifies TGFβ-regulated genes with putative links to blood vessel morphogenesis, including several genes linked to Wnt/β-catenin signaling. These results reveal that the β8 integrin cytoplasmic domain is essential for the regulation of TGFβ-dependent gene expression in endothelial cells and suggest that cross-talk between TGFβs and Wnt pathways is crucial for neurovascular development.