The b8 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 (BBB) maturation, and other key neurovascular functions. Genetic studies in mice have shown that sprouting neurovascular development is controlled, in part, by Itgb8 which encodes the neuroepithelial cell-expressed integrin b8 subunit. However, these studies have involved complete loss-of-function Itgb8 mutations, and have not discerned the relative roles for the b8 integrin extracellular matrix (ECM) binding region versus the intracellular signaling tail. Here, Cre/lox strategies have been employed to selectively delete the cytoplasmic domain of Itgb8 without perturbing its transmembrane and extracellular domains. We report that the b8 integrin cytoplasmic domain is essential for inside-out modulation of adhesion, including activation of latent-TGFbs in the ECM. Quantitative sequencing of the brain endothelial cell transcriptome identifies TGFb-regulated genes with putative links to blood vessel morphogenesis, including several genes linked to Wnt/b-catenin signaling. These results reveal that the b8 integrin cytoplasmic domain is essential for the regulation of TGFb-dependent gene expression in endothelial cells and suggest that cross-talk between TGFbs and Wnt pathways is critical for neurovascular development.