| Myelin is essential for proper human neurophysiology, but the precise molecular mechanisms underlying the myelination process remain poorly understood. One potential effector molecule, the beta1 integrin, has been suggested to play a critical role in CNS myelination. In support of this, alpha6beta1 integrin has been shown to modulate oligodendrocyte development in vitro and the loss of an integrin ligand, laminin, causes myelin defects in vivo. Here, we use transgenic mice (beta1-CNSko ) engineered to excise the beta1 integrin gene at the neural progenitor stage to study how beta1 integrin modulates oligodendrocyte development and myelination. Electron micrographs of the spinal cord and corpus callosum from the beta1-CNSko mouse revealed hypomyelination compared to wildtype littermate controls. Biochemical and immunohistochemical analyses of cerebral cortices showed less MBP in the beta1-CNSko compared to wildtype littermate controls. Oligodendrocytes derived from mutant mice are unable to efficiently extend myelin sheets and do not fully activate AKT, a kinase that regulates axonal ensheathment. The inhibition of PTEN, a negative regulator of AKT, or the expression of a constitutively active form of AKT, restores myelin sheet outgrowth in cultured beta1-deficient oligodendrocytes. Our data suggest that beta1 integrins play an instructive role in CNS myelination by promoting myelin wrapping in a process that depends on AKT. In addition, beta1 integrins were found to regulate oligodendrocyte process dynamics, such that Sholl analysis of process complexity in beta1-CNSko mutants showed a reduction in process outgrowth and branching. Also, in vitro differentiation studies indicated no differences in beta1-KO oligodendrocyte lineage progression, survival, and but the newly-formed beta1-deficient oligodendrocyte population had significantly more cell death compared to wildtype controls. Our findings reveal a role for beta1 integrin in oligodendrocyte development and CNS myelination, and suggest that myelin abnormalities in laminin-deficiencies may be in part due to loss of beta1 integrin signaling. |
