Developmental pruning of early-stage myelin segments during CNS myelination in vivo.
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ABSTRACT:
SUBMITTER: Liu P
PROVIDER: S-EPMC3698634 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
Publications
Developmental pruning of early-stage myelin segments during CNS myelination in vivo.
Liu Peng P Du Jiu-Lin JL He Cheng C
Cell research 20130507 7
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Project description:During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similarly to neurons and synapses, excess myelin sheaths are produced and selectively eliminated, but how elimination occurs is unknown. Microglia, the resident immune cells of the central nervous system, engulf surplus neurons and synapses. To determine whether microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. By using a combination of optical, genetic, chemogenetic, and behavioral approaches, we reveal that neuronal activity bidirectionally balances microglial association with neuronal cell bodies and myelin phagocytosis in the optic tectum. Furthermore, multiple strategies to deplete microglia resulted in oligodendrocytes maintaining excessive and ectopic myelin. Our work reveals a neuronal activity-regulated role for microglia in modifying developmental myelin targeting by oligodendrocytes.
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Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.
2017-08-01 | GSE60276 | GEO
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.
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Project description:Oligodendrocytes in the central nervous system (CNS) produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. beta1 integrins regulate the myelination of peripheral nerves, but their function during the myelination of axonal tracts in the CNS is unclear. Here we show that genetically modified mice lacking beta1 integrins in the CNS present a deficit in myelination but no defects in the development of the oligodendroglial lineage. Instead, in vitro data show that beta1 integrins regulate the outgrowth of myelin sheaths. Oligodendrocytes derived from mutant mice are unable to efficiently extend myelin sheets and fail to activate AKT (also known as AKT1), a kinase that is crucial for axonal ensheathment. The inhibition of PTEN, a negative regulator of AKT, or the expression of a constitutively active form of AKT restores myelin outgrowth in cultured beta1-deficient oligodendrocytes. Our data suggest that beta1 integrins play an instructive role in CNS myelination by promoting myelin wrapping in a process that depends on AKT.
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Project description:A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
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Project description:Development of myelin, a fatty sheath that insulates nerve fibers, is critical for brain function. Myelination during infancy has been studied with histology, but postmortem data cannot evaluate the longitudinal trajectory of white matter development. Here, we obtained longitudinal diffusion MRI and quantitative MRI measures of longitudinal relaxation rate (R1) of white matter in 0, 3 and 6 months-old human infants, and developed an automated method to identify white matter bundles and quantify their properties in each infant's brain. We find that R1 increases from newborns to 6-months-olds in all bundles. R1 development is nonuniform: there is faster development in white matter that is less mature in newborns, and development rate increases along inferior-to-superior as well as anterior-to-posterior spatial gradients. As R1 is linearly related to myelin fraction in white matter bundles, these findings open new avenues to elucidate typical and atypical white matter myelination in early infancy.
| S-EPMC8863985 | biostudies-literature
Project description:The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.
| S-EPMC9324160 | biostudies-literature
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named Myelin-gene Regulatory Factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. We used microarrays to compare cultured oligodendrocytes (differentiated in vitro for 4 days) from MRF conditional knockouts and control litteramates to look at the effects of MRF deficiency on myelin gene expression. Mouse OPCs grown in vitro in the presence of PDGF serve as a baseline for gene expression prior to differentiation. Mouse OPCs from MRF conditional knockout (MRF fl/fl, Olig2 wt/cre) mice and control littermates (MRF wt/fl; Olig2 wt/cre) were isolated from enzymatically dissociated P7 mouse brains as previously described (Cahoy et al., 2008), positively immunopanning for PDGFR-alpha following a depletion of microglia with BSL1. Cells were grown in defined serum-free media as previously described (Dugas et al., 2006), but with the addition of 2% B-27 (Invitrogen). Cells were proliferated for several days in the presence of PDGF-AA (10 ng/ml, PeproTech) and then differentiation induced by withdrawal of PDGF-AA and addition of triiodothyronine (T3) (40 ng/ml; Sigma). RNA was isolated from cells 4 days after induction of differentiation; OPCs maintained in PDGF-AA serve as a baseline of OPC gene expression. Total RNA was isolated from cells with the RNeasy micro kit (Qiagen, Valencia, CA) using Qiagen on-column DNase treatment to remove any contaminating genomic DNA. The integrity of RNA was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies) and RNA concentration was determined using a NanoDrop ND-1000 spectrophotometer (NanoDrop, Rockland, DE). Biotinylated cRNAs for hybridization to Affymetrix 3'-arrays were prepared from 1ug total RNA using the Affymetrix two-cycle target labeling assay with spike in controls (Affymetrix Inc., Santa Clara, CA, 900494). Labeled-cRNA was fragmented and hybridized to Mouse Genome 430 2.0 Arrays (3'-arrays, Affymetrix, 900495) following the manufacturer's protocols. Raw image files were processed using Affymetrix GCOS 1.3 software to calculate individual probe cell intensity data and generate CEL data files. Using GCOS and the MAS 5.0 algorithm, intensity data was normalized per chip to a target intensity TGT value of 500 and expression data and present/absent calls for individual probe sets calculated. Gene symbols and names for data analyzed with the MAS 5.0 algorithm were from the Affymetrix Netaffx Mouse430_2 annotations file (http://www.affymetrix.com/support/technical/byproduct.affx?product=moe430-20). Quality control was performed by examining raw DAT image files for anomalies, confirming each GeneChip array had a background value less than 100, monitoring that the percencelle present calls was appropriate for the cell type, and inspecting the poly(A) spike in controls, housekeeping genes, and hybridization controls to confirm labeling and hybridization consistency.
2009-05-31 | E-GEOD-15303 | biostudies-arrayexpress
Project description:Δ9 -Tetrahydrocannabinol (THC), the main bioactive compound found in the plant Cannabis sativa, exerts its effects by activating cannabinoid receptors present in many neural cells. Cannabinoid receptors are also physiologically engaged by endogenous cannabinoid compounds, the so-called endocannabinoids. Specifically, the endocannabinoid 2-arachidonoylglycerol has been highlighted as an important modulator of oligodendrocyte (OL) development at embryonic stages and in animal models of demyelination. However, the potential impact of THC exposure on OL lineage progression during the critical periods of postnatal myelination has never been explored. Here, we show that acute THC administration at early postnatal ages in mice enhanced OL development and CNS myelination in the subcortical white matter by promoting oligodendrocyte precursor cell cycle exit and differentiation. Mechanistically, THC-induced-myelination was mediated by CB1 and CB2 cannabinoid receptors, as demonstrated by the blockade of THC actions by selective receptor antagonists. Moreover, the THC-mediated modulation of oligodendroglial differentiation relied on the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, as mTORC1 pharmacological inhibition prevented the THC effects. Our study identifies THC as an effective pharmacological strategy to enhance oligodendrogenesis and CNS myelination in vivo.
| S-EPMC7821226 | biostudies-literature
Project description:BackgroundTherapeutic agents stimulating the process of myelination could be beneficial for the treatment of demyelinating diseases, such as multiple sclerosis. The efficient translation of compounds promoting myelination in vitro to efficacy in vivo is inherently time-consuming and expensive. Thyroid hormones accelerate the differentiation and maturation of oligodendrocytes, thereby promoting myelination. Systemic administration of the thyroid hormone thyroxine (T4) accelerates brain maturation, including myelination, during early postnatal development. The objective of this study was to validate an animal model for rapid testing of promyelinating therapeutic candidates for their effects on early postnatal development by using T4 as a reference compound.MethodsDaily subcutaneous injections of T4 were given to Sprague Dawley rat pups from postnatal day (PND) 2 to PND10. Changes in white matter were determined at PND10 using diffusion tensor magnetic resonance imaging (DTI). Temporal changes in myelination from PND3 to PND11 were also assessed by quantifying myelin basic protein (MBP) expression levels in the brain using the resonance Raman spectroscopy/enzyme-linked immunosorbent assay (RRS-ELISA) and quantitative immunohistochemistry.ResultsDTI of white matter tracts showed significantly higher fractional anisotropy in the internal capsule of T4-treated rat pups. The distribution of total FA values in the forebrain was significantly shifted towards higher values in the T4-treated group, suggesting increased myelination. In vivo imaging data were supported by in vitro observations, as T4 administration significantly potentiated the developmental increase in MBP levels in brain lysates starting from PND8. MBP levels in the brain of animals that received treatment for 9 days correlated with the FA metric determined in the same pups in vivo a day earlier. Furthermore, accelerated developmental myelination following T4 administration was confirmed by immunohistochemical staining for MBP in coronal brain sections of treated rat pups.ConclusionsT4-treated rat pups had increased MBP expression levels and higher MRI fractional anisotropy values, both indications of accelerated myelination. This simple developmental myelination model affords a rapid test of promyelinating activity in vivo within several days, which could facilitate in vivo prescreening of candidate therapeutic compounds for developmental hypomyelinating diseases. Further research will be necessary to assess the utility of this platform for screening promyelination compounds in more complex demyelination disease models, such us multiple sclerosis.
| S-EPMC9134688 | biostudies-literature