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

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 beta 8 subunit. However, these studies have involved complete loss-of-function Itgb8 mutations, and have not discerned the relative roles for the beta 8 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 beta 8 integrin cytoplasmic domain is essential for inside-out modulation of adhesion, including activation of latent-TGF beta s in the ECM. Quantitative sequencing of the brain endothelial cell transcriptome identifies TGF beta-regulated genes with putative links to blood vessel morphogenesis, including several genes linked to Wnt/beta-catenin signaling. These results reveal that the beta 8 integrin cytoplasmic domain is essential for the regulation of TGF beta-dependent gene expression in endothelial cells and suggest that cross-talk between TGF beta s and Wnt pathways is crucial for neurovascular development.