mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system

Abstract

AbstractIn the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, which is essential for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR (Mechanistic Target of Rapamycin), which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both corpus callosum and spinal cord, Rictor loss in OPCs resulted in early reduction in myelin RNAs and some myelin proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin abundance and thickness was noted at post-natal day 21 and 1.5 months. By contrast, the losses in corpus callosum resulted in severe hypomyelination, and increased unmyelinated axons. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.Significance StatementmTORC1 and mTORC2 signaling have differential impact on myelination in the central nervous system. Numerous studies identify a role for mTORC1, but deletion of Rictor (mTORC2 signaling) in late-stage oligodendrocytes had little impact on myelination in the CNS. However, the current studies establish that deletion of mTORC2 signaling from oligodendrocyte progenitor cells results in reduced myelination of brain axons. These studies also establish a regional impact of mTORC2, with little change in spinal cord in these conditional Rictor deletion mice. Importantly, in both, brain and spinal cord, mTORC2 downstream signaling targets were impacted by Rictor deletion. Yet, these signaling changes had little impact on myelination in spinal cord, while they resulted in long term alterations in myelination in brain.