Abstract
Myelin abnormalities are increasingly being recognized as an important component of a number of neurologic developmental disorders. The integration of many signaling pathways and cell types are critical for correct myelinogenesis. The PI3-K and mechanistic target of rapamycin (mTOR) pathways have been found to play key roles. mTOR is found within two distinct complexes, mTORC1 and mTORC2. mTORC1 activity has been shown to play a major role during myelination, while the role of mTORC2 is not yet well understood. To determine the role of mTORC2 signaling in myelinogenesis, we generated a mouse lacking the critical mTORC2 component Rictor in oligodendrocyte precursors (OPCs). Targeted deletion of Rictor in these cells decreases and delays the expression of myelin related proteins and reduces the size of cerebral white matter tracts. This is developmentally manifest as a transient reduction in myelinated axon density and g-ratio. OPC cell number is reduced at birth without detectable change in proliferation with proportional reductions in mature oligodendrocyte number at P15. The total number of oligodendrocytes as well as extent of myelination, does improve over time. Adult conditional knock-out (CKO) animals do not demonstrate a behavioral phenotype likely due in part to preserved axonal conduction velocities. These data support and extend prior studies demonstrating an important but transient contribution of mTORC2 signaling to myelin development.
Highlights
Myelin abnormalities are implicated in the pathogenesis of multiple neurodevelopmental disorders including Tuberous Sclerosis Complex (TSC) [1], autism spectrum disorders [2] and Angelman syndrome [3]
Multiple studies indicate that Akt phosphorylation and subsequent mechanistic target of rapamycin complex 1 activation promote myelin formation and increase myelin thickness [5,6] with loss of Akt/mTORC1 activity being associated with decreased myelination [5,6,7]
The degree of hypomyelination decreased over time and by P137, both myelin associated glycoprotein (MAG) and CNPase levels had normalized though MBP remained slightly, but significantly reduced
Summary
Myelin abnormalities are implicated in the pathogenesis of multiple neurodevelopmental disorders including Tuberous Sclerosis Complex (TSC) [1], autism spectrum disorders [2] and Angelman syndrome [3]. Translational studies involving multiple sclerosis (MS), a neurological disorder associated with myelin inflammation, have extended our knowledge of myelin formation and tissue response to injury. Loss of mTORC2 signaling in oligodendrocyte precursor cells delays myelination differentiation are not precisely defined, important proteins include neuregulin, IGF-1, and Laminin-2 [4]. While contributions of other pathways are less clear, a role for PI3-K/Akt signaling has recently become more evident. Multiple studies indicate that Akt phosphorylation and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation promote myelin formation and increase myelin thickness [5,6] with loss of Akt/mTORC1 activity being associated with decreased myelination [5,6,7]. Lebrun-Julien et al [8] and our group[9] demonstrated an opposite requirement for mTORC1 with decreased myelination due to mTORC1 hyperactivity following loss of Tsc in the spinal cord or Tsc in the brain and spinal cord
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