Dominant-negative [beta]1 integrin mice have region-specific myelin defects accompanied by alterations in MAPK activity

Recent studies have demonstrated the importance of [beta]1 integrin in oligodendrocyte maturation in vitro. Similar studies in vivo have been difficult due to the embryonic and perinatal lethality of null mutations in integrin subunits. Here, we have generated transgenic mouse models that overexpress full length [beta]1 integrin or express a dominant-negative [beta]1 integrin [Delta]C (lacking the C-terminal tail) under the control of the proteolipid protein (PLP) promoter. We demonstrate that these transgenes are expressed predominantly in CNS tissues and more specifically in oligodendrocytes. Further analysis reveals that the dominant-negative [beta]1 integrin [Delta]C transgenic mice, but not the full length [beta]1 integrin mice, have hypomyelinated axons in spinal cords and optic nerves. In addition, there is a significant increase in the number of unmyelinated axons within the spinal cords and optic nerves of the [beta]1 integrin [Delta]C mice. In contrast, the corpus callosum from these mice did not show similar myelin defects. To assess if remyelination would be affected in the corpus callosum, mice were subjected to a cuprizone-induced demyelination. Interestingly, the dominant-negative mice recovered from this insult in a manner similar to the wild type littermates. Axons within the corpus callosum that were remyelinated had normal g-ratios; however, the actual percentage of myelinated axons was significantly reduced compared with wild type mice. We also show that the defects observed in the dominant-negative [beta]1 integrin [Delta]C mice are accompanied by disruption of the MAP-kinase signaling pathway. Our work highlights the importance of [beta]1 integrin-mediated signaling in CNS myelination in vivo.