β8 integrin regulates neurogenesis and neurovascular homeostasis in the adult brain

Central nervous system (CNS) neurovascular units are multicellular complexes consisting of neural cells, blood vessels and a milieu of extracellular matrix (ECM) proteins. ECM-mediated adhesion and signaling events within neurovascular units probably contribute to proper CNS development and physiology; however, the molecular mechanisms that control these events remain largely undetermined. Previous studies from our group and others showed that ablation of the ECM receptor, alpha v beta 8 integrin, in neural progenitor cells (NPCs) of the embryonic mouse brain results in severe developmental neurovascular pathologies and premature death. Here, we have investigated the functions for this integrin in the adult brain by studying mice harboring a homozygous-null beta 8 gene mutation generated on an outbred background that permits survival for several months. We show that adult beta 8(-/-) mice display widespread defects in neurovascular unit homeostasis, including increased numbers of intracerebral blood vessels with pronounced perivascular astrogliosis. Furthermore, in neurogenic regions of the adult brain, where NPCs cluster around blood vessels in neurovascular niches, beta 8 integrin is essential for normal control of NPC proliferation and survival. Analysis of NPCs cultured ex vivo reveals that the growth and survival defects correlate, in part, with diminished integrin-mediated activation of latent transforming growth factor beta 1 (TGF beta 1), which is an ECM protein ligand for alpha v beta 8 integrin. Collectively, these data identify essential functions for beta 8 integrin in regulating neurovascular unit physiology in the postnatal mouse brain.