Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation and Mediates mTORC1-Dependent Myelination in Brain

Abstract

Rheb1 is an immediate early gene that functions to activate mammalian target of rapamycin (mTor) selectively in complex 1 (mTORC1).We have demonstrated previously that Rheb1 is essential for myelination in the CNS using a Nestin-Cre driver line that deletes Rheb1 in all neural cell lineages, and recent studies using oligodendrocyte-specific CNP-Cre have suggested a preferential role for mTORC1 is myelination in the spinal cord. Here, we examine the role of Rheb1/mTORC1 in mouse oligodendrocyte lineage using separate Cre drivers for oligodendrocyte progenitor cells (OPCs) including Olig1-Cre and Olig2-Cre as well as differentiated and mature oligodendrocytes including CNP-Cre and Tmem10-Cre. Deletion of Rheb1 in OPCs impairs their differentiation to mature oligodendrocytes. This is accompanied by reduced OPC cell-cycle exit suggesting a requirement for Rheb1 in OPC differentiation. The effect of Rheb1 on OPC differentiation is mediated by mTor since Olig1-Cre deletion of mTor phenocopies Olig1-Cre Rheb1 deletion. Deletion of Rheb1 in mature oligodendrocytes, in contrast, does not disrupt developmental myelination or myelin maintenance. Loss of Rheb1 in OPCs or neural progenitors does not affect astrocyte formation in gray and white matter, as indicated by the pan-astrocyte marker Aldh1L1. We conclude that OPC-intrinsic mTORC1 activity mediated by Rheb1 is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require Rheb1 to make myelin or maintain it in the adult brain. These studies reveal mechanisms that may be relevant for both developmental myelination and impaired remyelination in myelin disease.

Myelination and mTOR

“…mTORC1 was shown to promote differentiation of OLs from OPCs. In the absence of Rheb1 or Raptor, a reduction in OLs and an accumulation of OPCs were detected (Bercury et al, 2014; Zou et al, 2014), in line with a previous report in which rapamycin inhibited the progression of O4‐positive late OPCs to GalC‐positive immature OLs in vitro (Tyler et al, 2009). Besides its direct regulation of metabolic reactions, mTORC1 has a profound impact on the cell transcriptome (Düvel et al, 2010) and controls several transcription factors directly or via its downstream targets.…”

“…Alternatively, the differences could depend on the Cre lines that were used to drive recombination and loss of proteins in these studies. Different from the results obtained with CNPCre, conditional ablation of Rheb1 using Olig1Cre or Olig2Cre impaired also brain and optic nerve myelination (Zou et al, 2014). Because expression of the latter Cre transgenes is reported to be active earlier than CNPCre (Zou et al, 2014), a conceivable hypothesis is that some brain OL‐lineage cells may require mTORC1 mainly in a narrow temporal window.…”

“…Different from the results obtained with CNPCre, conditional ablation of Rheb1 using Olig1Cre or Olig2Cre impaired also brain and optic nerve myelination (Zou et al, 2014). Because expression of the latter Cre transgenes is reported to be active earlier than CNPCre (Zou et al, 2014), a conceivable hypothesis is that some brain OL‐lineage cells may require mTORC1 mainly in a narrow temporal window. Analogous considerations concerning Cre‐driver lines should be kept in mind also when interpreting the loss‐of‐mTORC2 function results described above.…”

“…Ablation of Raptor or Rheb1 was used to suppress mTORC1 function (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Norrmén et al, 2014; Zou et al, 2014), ablation of Rictor to suppress mTORC2 function (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Norrmén et al, 2014), and ablation of mTOR itself to disrupt the functions of both complexes (Sherman et al, 2012; Wahl, McLane, Bercury, Macklin, & Wood, 2014). In each case, persistent hypomyelination was observed only in the absence of mTORC1 function, alone or in combination with loss of mTORC2.…”

“…Deletion of Raptor, Rheb1, or mTOR in OL‐lineage cells caused hypomyelination in the spinal cord and cerebellum, but not in the brain and optic nerve (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Wahl et al, 2014; Zou et al, 2014). It was proposed that an increase in Mek‐Erk1/2 signaling selectively in the corpus callosum of Raptor mutants may compensate for the loss of mTORC1 function (Bercury et al, 2014).…”