Heterogeneity in oligodendroglia: Is it relevant to mouse models and human disease?

Ornelas, Isis M.; McLane, Lauren E.; Saliu, Aminat; Evangelou, Angelina V.; Khandker, Luipa; Wood, Teresa L.

doi:10.1002/jnr.23900

Cited by 19 publications

(17 citation statements)

References 142 publications

(154 reference statements)

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“…Comparison of the findings for BLA (EC, BLA, IC, CeA) and CeA (IC, CeA) suggests that CeA oligodendrocytes are more sensitive to CSS; the IC white matter tract, which contains axon projections to GABA neurons in medial intercalated cell masses, might be particularly stress sensitive. This variation between ROIs concurs with the proposal that oligodendrocyte function, including gene expression levels, varies between brain regions …”

Section: Discussionsupporting

confidence: 90%

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Cathomas

Azzinnari

Bergamini

et al. 2018

Genes Brain and Behavior

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Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1 ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1 mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1 and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.

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Section: Discussionsupporting

confidence: 90%

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Cathomas

Azzinnari

Bergamini

et al. 2018

Genes Brain and Behavior

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“…The lack of a strong phenotype in Polr3a KI/KI and KI/KO mice could potentially be explained by the much higher proportion of white matter in the human brain (more than 50%) compared to other species (around 10% in mouse) [41–43]. This might make the human brain more vulnerable than the mouse brain to mutations in genes important for myelination.…”

Section: Discussionmentioning

confidence: 99%

Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

et al. 2017

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Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0294-y) contains supplementary material, which is available to authorized users.

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“…As described in Section 2, during development, OPCs arise from different brain areas. This raises the question whether OPCs from different origins represent specific OPC subpopulations with distinct functional features (Ornelas et al, ). Kessaris et al () revealed that OPCs derived from the three successive waves depicted in Figure are characterized by different transcription factors.…”

Section: Opc Heterogeneitymentioning

confidence: 99%

Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

Tilborg

Theije

Hal

et al. 2017

Glia

201

184

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Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients.

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Heterogeneity in oligodendroglia: Is it relevant to mouse models and human disease?

Cited by 19 publications

References 142 publications

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

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