R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases

Myelination is required for fast and efficient synaptic transmission in vertebrates. In the central nervous system, oligodendrocytes are responsible for creating myelin sheaths that isolate and protect axons, even throughout adulthood. However, when myelin is lost, the failure of remyelination mechanisms can cause neurodegenerative myelin-associated pathologies. From oligodendrocyte progenitor cells to mature myelinating oligodendrocytes, myelination is a highly complex process that involves many elements of cellular signaling, yet many of the mechanisms that coordinate it, remain unknown. In this review, we will focus on the three major pathways involved in myelination (PI3K/Akt/mTOR, ERK1/2-MAPK, and Wnt/β-catenin) and recent advances describing the crosstalk elements which help to regulate them. In addition, we will review the tight relation between Ras GTPases and myelination processes and discuss its potential as novel elements of crosstalk between the pathways. A better understanding of the crosstalk elements orchestrating myelination mechanisms is essential to identify new potential targets to mitigate neurodegeneration.

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Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo

Development ◽

10.1242/dev.128.10.1757 ◽

2001 ◽

Vol 128 (10) ◽

pp. 1757-1769 ◽

Cited By ~ 3

Author(s):

C. Olivier ◽

I. Cobos ◽

E.M. Perez Villegas ◽

N. Spassky ◽

B. Zalc ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Chick Embryo ◽

Embryonic Development ◽

Progenitor Cells ◽

Oligodendrocyte Progenitor Cells ◽

Chick Brain ◽

The Central Nervous System ◽

The Brain

Oligodendrocytes are the myelin-forming cells in the central nervous system. In the brain, oligodendrocyte precursors arise in multiple restricted foci, distributed along the caudorostral axis of the ventricular neuroepithelium. In chick embryonic hind-, mid- and caudal forebrain, oligodendrocytes have a basoventral origin, while in the rostral fore-brain oligodendrocytes emerge from alar territories (Perez Villegas, E. M., Olivier, C., Spassky, N., Poncet, C., Cochard, P., Zalc, B., Thomas, J. L. and Martinez, S. (1999) Dev. Biol. 216, 98–113). To investigate the respective territories colonized by oligodendrocyte progenitor cells that originate from either the basoventral or alar foci, we have created a series of quail-chick chimeras. Homotopic chimeras demonstrate clearly that, during embryonic development, oligodendrocyte progenitors that emerge from the alar anterior entopeduncular area migrate tangentially to invade the entire telencephalon, whereas those from the basal rhombomeric foci show a restricted rostrocaudal distribution and colonize only their rhombomere of origin. Heterotopic chimeras indicate that differences in the migratory properties of oligodendroglial cells do not depend on their basoventral or alar ventricular origin. Irrespective of their origin (basal or alar), oligodendrocytes migrate only short distances in the hindbrain and long distances in the prosencephalon. Furthermore, we provide evidence that, in the developing chick brain, all telencephalic oligodendrocytes originate from the anterior entopeduncular area and that the prominent role of anterior entopeduncular area in telencephalic oligodendrogenesis is conserved between birds and mammals.

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

10.1101/2022.01.04.474811 ◽

2022 ◽

Author(s):

Kristin D Dahl ◽

Hannah A Hathaway ◽

Adam R Almeida ◽

Jennifer Bourne ◽

Tanya L Brown ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Corpus Callosum ◽

Signaling Pathways ◽

Progenitor Cells ◽

Myelin Proteins ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

The Central Nervous System

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.

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Schwann cell remyelination of the central nervous system: why does it happen and what are the benefits?

Open Biology ◽

10.1098/rsob.200352 ◽

2021 ◽

Vol 11 (1) ◽

pp. 200352

Author(s):

Civia Z. Chen ◽

Björn Neumann ◽

Sarah Förster ◽

Robin J. M. Franklin

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Current Knowledge ◽

Oligodendrocyte Progenitor Cells ◽

Neuronal Function ◽

Lesion Area ◽

Myelin Sheaths ◽

The Central Nervous System ◽

Review Current ◽

Surprising Finding

Myelin sheaths, by supporting axonal integrity and allowing rapid saltatory impulse conduction, are of fundamental importance for neuronal function. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) migrate to the lesion area, proliferate and differentiate into new oligodendrocytes that make new myelin sheaths. This process is termed remyelination. Under specific conditions, demyelinated axons in the CNS can also be remyelinated by Schwann cells (SCs), the myelinating cell of the peripheral nervous system. OPCs can be a major source of these CNS-resident SCs—a surprising finding given the distinct embryonic origins, and physiological compartmentalization of the peripheral and central nervous system. Although the mechanisms and cues governing OPC-to-SC differentiation remain largely undiscovered, it might nevertheless be an attractive target for promoting endogenous remyelination. This article will (i) review current knowledge on the origins of SCs in the CNS, with a particular focus on OPC to SC differentiation, (ii) discuss the necessary criteria for SC myelination in the CNS and (iii) highlight the potential of using SCs for myelin regeneration in the CNS.

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Glial Patchwork: Oligodendrocyte Progenitor Cells and Astrocytes Blanket the Central Nervous System

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.803057 ◽

2022 ◽

Vol 15 ◽

Author(s):

Heather M. Barber ◽

Maria F. Ali ◽

Sarah Kucenas

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Progenitor Cells ◽

Developmental Process ◽

Emergent Behavior ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

Cellular Behaviors ◽

The Central Nervous System ◽

Impact Injury

Tiling is a developmental process where cell populations become evenly distributed throughout a tissue. In this review, we discuss the developmental cellular tiling behaviors of the two major glial populations in the central nervous system (CNS)—oligodendrocyte progenitor cells (OPCs) and astrocytes. First, we discuss OPC tiling in the spinal cord, which is comprised of the three cellular behaviors of migration, proliferation, and contact-mediated repulsion (CMR). These cellular behaviors occur simultaneously during OPC development and converge to produce the emergent behavior of tiling which results in OPCs being evenly dispersed and occupying non-overlapping domains throughout the CNS. We next discuss astrocyte tiling in the cortex and hippocampus, where astrocytes migrate, proliferate, then ultimately determine their exclusive domains by gradual removal of overlap rather than sustained CMR. This results in domains that slightly overlap, allowing for both exclusive control of “synaptic islands” and astrocyte-astrocyte communication. We finally discuss the similarities and differences in the tiling behaviors of these glial populations and what remains unknown regarding glial tiling and how perturbations to this process may impact injury and disease.

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Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

International Journal of Molecular Sciences ◽

10.3390/ijms22105192 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5192

Author(s):

Ulises Gómez-Pinedo ◽

Yolanda García-Ávila ◽

Lucía Gallego-Villarejo ◽

Jordi A. Matías-Guiu ◽

María Soledad Benito-Martín ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Progenitor Cells ◽

Neuromyelitis Optica ◽

Subventricular Zone ◽

Precursor Cells ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

Differentiation Capacity ◽

The Central Nervous System

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

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Biology of the repair of central nervous system demyelinated lesions: an appraisal

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1996000200026 ◽

1996 ◽

Vol 54 (2) ◽

pp. 331-334 ◽

Cited By ~ 3

Author(s):

L. A. V Peireira ◽

M. A. Cruz-Höfling ◽

M. S. J. Dertkigil ◽

D. L. Graça

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Schwann Cells ◽

Demyelinating Disease ◽

Experimental Models ◽

Primitive Cell ◽

Marked Influence ◽

Myelin Sheaths ◽

Human Material ◽

The Central Nervous System

The integrity of myelin sheaths is maintained by oligodendrocytes and Schwann cells respectively in the central nervous system (CNS) and in the peripheral nervous system. The process of demyelination consisting of the withdrawal of myelin sheaths from their axons is a characteristic feature of multiple sclerosis, the most common human demyelinating disease. Many experimental models have been designed to study the biology of demyelination and remyelination (repair of the lost myelin) in the CNS, due to the difficulties in studying human material. In the ethidium bromide (an intercalating gliotoxic drug) model of demyelination, CNS remyelination may be carried out by surviving oligodendrocytes and/or by cells differentiated from the primitive cell lines or either by Schwann cells that invade the CNS. However, some factors such as the age of the experimental animals, intensity and time of exposure to the intercalating chemical and the topography of the lesions have marked influence on the repair of the tissue.

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Central Nervous System Cell-Derived Exosomes in Neurodegenerative Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9965564 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yang Tian ◽

Chen Fu ◽

Yifan Wu ◽

Yao Lu ◽

Xuemei Liu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodegenerative Diseases ◽

Extracellular Vesicles ◽

Mammalian Cells ◽

Glia Cells ◽

Central Nervous System Cell ◽

The Central Nervous System ◽

System Cell ◽

Almost All

Exosomes are a type of extracellular vesicles secreted by almost all kinds of mammalian cells that shuttle “cargo” from one cell to another, indicative of its role in cell-to-cell transportation. Interestingly, exosomes are known to undergo alterations or serve as a pathway in multiple diseases, including neurodegenerative diseases. In the central nervous system (CNS), exosomes originating from neurons or glia cells contribute to or inhibit the progression of CNS-related diseases in special ways. In lieu of this, the current study investigated the effect of CNS cell-derived exosomes on different neurodegenerative diseases.

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