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

Abstract

In 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.

mTORC2 coordinates the leading and trailing edge cytoskeletal programs during neutrophil migration

“…Among other immune cells, loss of Rictor in B-cells also led to drastic increase in cortical F-actin levels upon B-cell receptor (BCR) stimulation (Huang et al, 2017). Similar mechanisms could also restrict actin polymerisation at the tip of the leading edge of oligodendrocytes as they wrap around the axonal shaft during myelin sheath formation (Bercury and Macklin, 2015; Nawaz et al, 2015), as mTORC2 signaling has been shown to regulate the differentiation, shape, and actin cytoskeleton organisation of these cells (Bercury et al, 2014; Dahl et al, 2022).…”