Oligodendrocytes in the central nervous system (CNS) produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. β1 integrins regulate the myelination of peripheral nerves, but their function during the myelination of axonal tracts in the CNS is unclear. Here we show that genetically modified mice lacking β1 integrins in the CNS present a deficit in myelination but no defects in the development of the oligodendroglial lineage. Instead, in vitro data show that β1 integrins regulate the outgrowth of myelin sheaths. Oligodendrocytes derived from mutant mice are unable to efficiently extend myelin sheets and fail to activate AKT(also known as AKT1), a kinase that is crucial for axonal ensheathment. The inhibition of PTEN, a negative regulator of AKT, or the expression of a constitutively active form of AKT restores myelin outgrowth in culturedβ1-deficient oligodendrocytes. Our data suggest that β1 integrins play an instructive role in CNS myelination by promoting myelin wrapping in a process that depends on AKT.
We thank T. Bossing for critical reading of the manuscript; M. Wood for EM technical support; D. Park for technical support; and Dr Bian-Hua Jiang for the generous gift of MYR-AKT-GFP. This work was supported by funding from the National Institutes of Health (U.M., NS046456, MH078833; H.C., NS054042), a Christopher Reeve Foundation fellowship (C.S.B.), a National Multiple Sclerosis Society Career Transition Fellowship (H.C.)and a NSF/IGERT 3MT fellowship (T.N., 0549370). Deposited in PMC for release after 12 months.
