The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation

Ornelas, Isis M.; Khandker, Luipa; Wahl, Stacey; Hashimoto, H; Macklin, Wendy B.; Wood, Teresa L.

doi:10.1002/glia.23776

Cited by 26 publications

(25 citation statements)

References 62 publications

(121 reference statements)

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“…Through both genetic and pharmacological manipulations of this pathway, it has become apparent that mTOR is a key signal transduction pathway for oligodendrocyte differentiation (Ryskalin et al, 2017; Tyler et al, 2009; Wood et al, 2013). Moreover, mTOR regulates oligodendrocyte differentiation during the transition from the late progenitor to the immature oligodendrocyte (Ornelas et al, 2020). Therefore, we hypothesized that LIF might be stimulating the mTOR pathway.…”

Section: Resultsmentioning

confidence: 99%

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Frondelli

Mather

Levison

2020

Preprint

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Traumatic brain injury (TBI) is a significant problem that affects ∼500,000 children each year. As cell proliferation is disturbed by injury and is required for normal brain development, we investigated how a pediatric closed head injury (CHI) would affect the progenitors of the subventricular zone (SVZ). Additionally, we evaluated the contribution of Leukemia Inhibitory Factor (LIF) using LIF-heterozygous mice (LIF Het), as LIF is an injury-induced cytokine, known to influence neurogenesis and gliogenesis. CHI’s were performed on P20 LIF Het and WT mice. Ki-67 staining and stereology revealed that cell proliferation increased ∼250% in injured LIF Het mice compared to the 30% increase observed in injured WT mice at 48 h post CHI. Furthermore, Olig2+ cell proliferation increased in the SVZ and white matter of LIF Het injured mice at 48 h recovery. Using an 8-color flow cytometry panel, the proliferation of three distinct multipotential progenitors were greater in LIF Het injured mice compared to WT injured mice. Early oligodendrocyte progenitor cell (OPC) proliferation was 6-fold higher in LIF Het injured mice compared to WT injured mice. In vitro, addition of LIF decreased overall cell proliferation and OPC proliferation compared to controls. Addition of LIF to OPC cultures induced an increase of phospho-Akt after 20 minutes and an increase of phospho-S6RP at 20 and 40 minutes of exposure, suggesting that LIF stimulates the mammalian target of Rapamycin pathway. Altogether, our data provide new insights into the regulatory role of LIF in suppressing neural progenitor cell proliferation after a mild TBI.Main PointsOPC proliferation is dis-inhibited in LIF haplodeficient mice.LIF directly inhibits glial progenitor cell proliferation.LIF stimulates the mTOR pathway.

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Section: Resultsmentioning

confidence: 99%

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Frondelli

Mather

Levison

2020

Preprint

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“…Hypoxic conditions result in increased HIF1/2a ( Yuen et al, 2014 ). mTOR deletion leads to increased expression of the oligodendrocyte maturation inhibiting promotor ID2 ( Ornelas et al, 2020 ). Reduction of Tsc1/2 results in hyperactive mTOR, increased translation and ER stress, and increased Fas-JNK signaling ( Jiang et al, 2016 ).…”

Section: Intrinsic Mechanisms Regulating Premyelinating Oligodendrocyte Survival and Integrationmentioning

confidence: 99%

Premyelinating Oligodendrocytes: Mechanisms Underlying Cell Survival and Integration

Hughes

Stockton

2021

Front. Cell Dev. Biol.

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In the central nervous system, oligodendrocytes produce myelin sheaths that enwrap neuronal axons to provide trophic support and increase conduction velocity. New oligodendrocytes are produced throughout life through a process referred to as oligodendrogenesis. Oligodendrogenesis consists of three canonical stages: the oligodendrocyte precursor cell (OPC), the premyelinating oligodendrocyte (preOL), and the mature oligodendrocyte (OL). However, the generation of oligodendrocytes is inherently an inefficient process. Following precursor differentiation, a majority of premyelinating oligodendrocytes are lost, likely due to apoptosis. If premyelinating oligodendrocytes progress through this survival checkpoint, they generate new myelinating oligodendrocytes in a process we have termed integration. In this review, we will explore the intrinsic and extrinsic signaling pathways that influence preOL survival and integration by examining the intrinsic apoptotic pathways, metabolic demands, and the interactions between neurons, astrocytes, microglia, and premyelinating oligodendrocytes. Additionally, we will discuss similarities between the maturation of newly generated neurons and premyelinating oligodendrocytes. Finally, we will consider how increasing survival and integration of preOLs has the potential to increase remyelination in multiple sclerosis. Deepening our understanding of premyelinating oligodendrocyte biology may open the door for new treatments for demyelinating disease and will help paint a clearer picture of how new oligodendrocytes are produced throughout life to facilitate brain function.

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“…Our recently published study demonstrated that mTOR signaling normally downregulates the bone morphogenetic pathway to promote the transition from the early OPC to immature oligodendrocyte (Ornelas et al, 2020). To determine whether mTOR signaling is required for KIF1B maintenance following the initial transition of the early bipolar OPCs to late progenitor cells, we used a modified in vitro differentiation paradigm where we allowed OPCs to differentiate normally for 48 h prior to inhibiting mTOR with rapamycin (Tyler et al, 2009;Fig.…”

Section: Mtor Promotes Kif1b Expression In Oligodendrocytes In the Spmentioning

confidence: 99%

Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination

et al. 2020

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During differentiation, oligodendrocyte precursor cells (OPCs) extend a network of processes that make contact with axons and initiate myelination. Recent studies revealed that actin polymerization is required for initiation of myelination whereas actin depolymerization promotes myelin wrapping. Here, we used primary OPCs in culture isolated from neonatal rat cortices of both sexes and young male and female mice with oligodendrocyte-specific deletion of mechanistic target of rapamycin (mTOR) to demonstrate that mTOR regulates expression of specific cytoskeletal targets and actin reorganization in oligodendrocytes during developmental myelination. Loss or inhibition of mTOR reduced expression of profilin2 and ARPC3, actin polymerizing factors, and elevated levels of active cofilin, which mediates actin depolymerization. The deficits in actin polymerization were revealed in reduced phalloidin and deficits in oligodendrocyte cellular branching complexity at the peak of morphologic differentiation and a delay in initiation of myelination. We further show a critical role for mTOR in expression and localization of myelin basic protein (Mbp) mRNA and MBP protein to the cellular processes where it is necessary at the myelin membrane for axon wrapping. Mbp mRNA transport deficits were confirmed by single molecule RNA FISH. Moreover, expression of the kinesin family member 1B, an Mbp mRNA transport protein, was reduced in CC11 cells in the mTOR cKO and in mTOR inhibited oligodendrocytes undergoing differentiation in vitro. These data support the conclusion that mTOR regulates both initiation of myelination and axon wrapping by targeting cytoskeletal reorganization and MBP localization to oligodendrocyte processes.

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The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation

Cited by 26 publications

References 62 publications

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Premyelinating Oligodendrocytes: Mechanisms Underlying Cell Survival and Integration

Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination

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