The role of beta-1 integrin in oligodendrocyte development and CNS myelination.
Nguyen, Tom Thanh Van
The Graduate School, Stony Brook University: Stony Brook, NY.
Myelin is essential for proper human neurophysiology, but the precise molecular mechanisms underlying the myelination process remain poorly understood. One potential effector molecule, the b1 integrin, has been suggested to play a critical role in CNS myelination. In support of this, a6b1 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 (b1-CNSko) engineered to excise the b1 integrin gene at the neural progenitor stage to study how b1 integrin modulates oligodendrocyte development and myelination. Electron micrographs of the spinal cord and corpus callosum from the b1-CNSko mouse revealed hypomyelination compared to wildtype littermate controls. Biochemical and immunohistochemical analyses of cerebral cortices showed less MBP in the b1-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 b1-deficient oligodendrocytes. Our data suggest that b1 integrins play an instructive role in CNS myelination by promoting myelin wrapping in a process that depends on AKT. In addition, b1 integrins were found to regulate oligodendrocyte process dynamics, such that Sholl analysis of process complexity in b1-CNSko mutants showed a reduction in process outgrowth and branching. Also, in vitro differentiation studies indicated no differences in b1-KO oligodendrocyte lineage progression, survival, and but the newly-formed b1-deficient oligodendrocyte population had significantly more cell death compared to wildtype controls. Our findings reveal a role for b1 integrin in oligodendrocyte development and CNS myelination, and suggest that myelin abnormalities in laminin-deficiencies may be in part due to loss of b1 integrin signaling.