Cholesterol Biosynthesis Defines Oligodendrocyte Precursor Heterogeneity between Brain and Spinal Cord

Khandker, Luipa; Jeffries, Marisa A.; Chang, Yun‐Juan; Mather, Marie L.; Bourne, Jennifer N.; Tafreshi, Azadeh K.; Ornelas, Isis M.; Bozdagi-Gunal, Ozlem; Macklin, Wendy B.; Wood, Teresa L.

doi:10.2139/ssrn.3817000

Cited by 2 publications

(3 citation statements)

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“…Using longitudinal two‐photon imaging, recent work has shown that myelin sheaths are extremely stable and that oligodendrogenesis and myelination are dynamic processes, with over half of the final amount of OLs in the mouse somatosensory cortex being generated after 4 months of age (Hughes et al, 2018). Differences in sheath thickness and length between brain and spinal cord OLs in the mouse CNS have been previously established (Bechler et al, 2015; Khandker et al, 2022). In addition, labeling studies using stage‐specific fluorescent‐tagged mice have demonstrated major differences in the survival of myelinating OLs between the brain and spinal cord throughout life.…”

Section: Origin and Timing Of Oligodendrocyte Developmentmentioning

confidence: 91%

“…Recent single‐cell RNA sequencing in mice combined with functional and biochemical studies revealed key differences in OPCs in the brain and spinal cord during development. Interestingly, spinal cord OPCs were found to have higher levels of cholesterol biosynthesis and uptake enzymes and differential dependence on mTOR signaling (Khandker et al, 2022). This reveals region‐specific and functional heterogeneity in the OPC population, but the underlying mechanisms leading to these differences remain to be uncovered.…”

Section: Origin and Timing Of Oligodendrocyte Developmentmentioning

confidence: 99%

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Development of myelinating glia: An overview

Cristobal

Lee

2022

Glia

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Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in the central and peripheral nervous systems respectively and follow different developmental paths. OLs are neural stem-cell derived and follow an intrinsic developmental program resulting in a largely irreversible differentiation state. During embryonic development, OL precursor cells (OPCs) are produced in distinct waves originating from different locations in the central nervous system, with a subset developing into myelinating OLs. OPCs remain evenly distributed throughout life, providing a population of responsive, multifunctional cells with the capacity to remyelinate after injury. SCs derive from the neural crest, are highly dependent on extrinsic signals, and have plastic differentiation states. SC precursors (SCPs) are produced in early embryonic nerve structures and differentiate into multipotent immature SCs (iSCs), which initiate radial sorting and differentiate into myelinating and non-myelinating SCs. Differentiated SCs retain the capacity to radically change phenotypes in response to external signals, including becoming repair SCs, which drive peripheral regeneration. While several

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Section: Origin and Timing Of Oligodendrocyte Developmentmentioning

confidence: 91%

Section: Origin and Timing Of Oligodendrocyte Developmentmentioning

confidence: 99%

Development of myelinating glia: An overview

Cristobal

Lee

2022

Glia

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“…However, increasing recognition of regional specialization means that an approach in one CNS region is unlikely to be generally applicable. In particular, populations of cells in the spinal cord with the ability to proliferate are transcriptionally distinct from their namesakes in the brain, including oligodendrocytes (Khandker et al, 2022), astrocytes (Tsai et al, 2012) and ependymal cells (MacDonald et al, 2021). Proliferation of cells in the adult spinal cord may have positive and negative effects on spinal cord health.…”

Section: Introductionmentioning

confidence: 99%

GABAergic regulation of cell proliferation within the adult mouse spinal cord

New

Yanagawa

McConkey

et al. 2022

Preprint

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Manipulation of neural stem cell proliferation and differentiation in the postnatal CNS is receiving significant attention due to therapeutic potential. In the spinal cord, such manipulations may promote repair in conditions such as multiple sclerosis or spinal cord injury, but may also limit excessive cell proliferation contributing to tumours such as ependymomas. Here we show that when ambient GABA is increased in vigabatrin-treated or decreased in glutamic acid decarboxylase67-green fluorescent protein (GAD67-GFP) mice, the numbers of proliferating cells respectively decreased or increased. Thus, intrinsic spinal cord GABA levels are correlated with the extent of cell proliferation, providing important evidence for the possibility of manipulating these levels. Diazepam binding inhibitor, an endogenous protein that interacts with GABA receptors and its breakdown product, octadecaneuropeptide, which preferentially activates central benzodiazepine (CBR) sites, were highly expressed in the spinal cord, especially in ependymal cells surrounding the central canal. Furthermore, animals with reduced CBR activation via treatment with flumazenil or Ro15-4513, or with a G2F77I mutation in the CBR binding site had greater numbers of Ethynyl-2’-deoxyuridine positive cells compared to control, which maintained their stem cell status since the proportion of newly proliferated cells becoming oligodendrocytes or astrocytes was significantly lower. Altering endogenous GABA levels or modulating GABAergic signaling through specific sites on the GABA receptors therefore influences NSC proliferation in the adult spinal cord. These findings provide a basis for further study into how GABAergic signaling could be manipulated to enable spinal cord self-regeneration and recovery or limit pathological proliferative activity.

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Cholesterol Biosynthesis Defines Oligodendrocyte Precursor Heterogeneity between Brain and Spinal Cord

Cited by 2 publications

References 0 publications

Development of myelinating glia: An overview

Development of myelinating glia: An overview

GABAergic regulation of cell proliferation within the adult mouse spinal cord

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