ORCID Profile
0000-0002-9132-3045
Current Organisations
Oregon Health & Science University
,
University of Aveiro
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Central Nervous System | Neurosciences
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Psychology and Cognitive Sciences |
Publisher: Society for Neuroscience
Date: 05-09-2012
DOI: 10.1523/JNEUROSCI.1069-12.2012
Abstract: Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.CELL.2008.10.031
Abstract: A major challenge to understanding how cells work together in the central nervous system (CNS) is the heterogeneous cellular composition of the brain. In this issue, Heiman et al. (2008) and Doyle et al. (2008) introduce a new strategy (TRAP) that enables the profiling of translated mRNAs in specific CNS cell populations without the need for purifying cells to homogeneity.
Publisher: American Society for Clinical Investigation
Date: 16-04-2018
DOI: 10.1172/JCI94158
Publisher: Cambridge University Press (CUP)
Date: 12-2007
DOI: 10.1017/S0025315407058183
Abstract: The ribosome is the location of protein translation and therefore a pivotal macromolecular complex for all organisms. The RNA molecules involved in the formation and functioning of the ribosome (rRNA) are partially single-stranded (loops) and partially double-stranded (helices or stems) as a result of pairing of complementary regions in either their own or other rRNA subunits. This pattern provides the rRNA with a secondary structure crucial for its functionality. The stability of these secondary structures is mediated by their base compositions: a helix rich in G-C pairs possesses a higher thermodynamic stability than an A-T rich counterpart. However, the base composition of these structures is neither homogeneous throughout the molecule nor throughout the demosponge taxa. Here, we present patterns of biased nucleotide composition in demosponge 28S rDNA. We analyse their correlation in respect to environment and taxonomy. We find significantly higher G+C contents in haplosclerid demosponges compared to other orders and investigate evidence for an association between water temperature and rRNA base composition in demosponges.
Publisher: Wiley
Date: 14-05-2015
DOI: 10.1002/GLIA.22855
Publisher: Public Library of Science (PLoS)
Date: 13-08-2013
Publisher: Cold Spring Harbor Laboratory
Date: 27-01-2021
DOI: 10.1101/2021.01.25.428149
Abstract: Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2020
DOI: 10.1038/S41597-019-0344-7
Abstract: The use of functional information in the form of species traits plays an important role in explaining bio ersity patterns and responses to environmental changes. Although relationships between species composition, their traits, and the environment have been extensively studied on a case-by-case basis, results are variable, and it remains unclear how generalizable these relationships are across ecosystems, taxa and spatial scales. To address this gap, we collated 80 datasets from trait-based studies into a global database for metaCommunity Ecology: Species, Traits, Environment and Space “CESTES”. Each dataset includes four matrices: species community abundances or presences/absences across multiple sites, species trait information, environmental variables and spatial coordinates of the s ling sites. The CESTES database is a live database: it will be maintained and expanded in the future as new datasets become available. By its harmonized structure, and the ersity of ecosystem types, taxonomic groups, and spatial scales it covers, the CESTES database provides an important opportunity for synthetic trait-based research in community ecology.
Publisher: Wiley
Date: 30-04-2019
DOI: 10.1002/GLIA.23629
Abstract: Myelin is a critical component of the vertebrate nervous system, both increasing the conduction velocity of myelinated axons and allowing for metabolic coupling between the myelinating cells and axons. An increasing number of studies demonstrate that myelination is not simply a developmentally hardwired program, but rather that new myelinating oligodendrocytes can be generated throughout life. The generation of these oligodendrocytes and the formation of myelin are influenced both during development and adulthood by experience and levels of neuronal activity. This led to the concept of adaptive myelination, where ongoing activity-dependent changes to myelin represent a form of neural plasticity, refining neuronal functioning, and circuitry. Although human neuroimaging experiments support the concept of dynamic changes within specific white matter tracts relevant to in idual tasks, animal studies have only just begun to probe the extent to which neuronal activity may alter myelination at the level of in idual circuits and axons. Uncovering the role of adaptive myelination requires a detailed understanding of the localized interactions that occur between active axons and myelinating cells. In this review, we focus on recent animal studies that have begun to investigate the interactions between active axons and myelinating cells and review the evidence for-and against-the ability of neuronal activity to alter myelination at an axon-specific level.
Publisher: Cold Spring Harbor Laboratory
Date: 09-2013
Abstract: Oligodendrocytes are the myelinating cells of the vertebrate central nervous system, responsible for generating the myelin sheath necessary for saltatory conduction. The use of increasingly sophisticated genetic tools, particularly in mice, has vastly increased our understanding of the molecular mechanisms that regulate development of the oligodendrocyte lineage. This increased reliance on the mouse as a genetic model has led to a need for the development of culture methods to allow the use of mouse cells in vitro as well as in vivo. Here, we present a protocol for the isolation of different stages of the oligodendrocyte lineage, oligodendrocyte precursor cells (OPCs) and/or postmitotic oligodendrocytes, from the postnatal mouse cortex using immunopanning. This protocol allows for the subsequent culture or biochemical analysis of these cells.
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41467-017-02719-2
Abstract: Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the in idual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of in idual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.MCN.2006.01.005
Abstract: Cytokines that signal through the LIFRbeta/gp130 receptor complex, including LIF and CNTF, promote the self-renewal of embryonic and adult neural precursor cells (NPCs). In non-CNS tissues, the protein suppressor of cytokine signaling-3 (SOCS3) negatively regulates signaling through gp130. Here, we analyze the role of SOCS3 in inhibiting LIF signaling in NPCs in vitro. SOCS3 is rapidly expressed by NPCs in response to LIF stimulation, with this expression largely dependent on recruitment of STAT proteins to the activated gp130 receptor. Proliferating NPC cultures can be generated from SOCS3 knockout (SOCS3KO/KO) embryos and display prolonged STAT3 phosphorylation and induction of the GFAP gene in response to LIF. In comparison with SOCS3 wild-type (SOCS3WT/WT) NPCs, SOCS3KO/KO cultures display enhanced self-renewal capacity. However, the clonal potential of SOCS3WT/WT but not SOCS3KO/KO NPCs is enhanced by exogenous LIF. Thus, SOCS3 acts as a negative regulator of LIF signaling in NPCs.
Publisher: Elsevier BV
Date: 05-2001
DOI: 10.1016/S0925-4773(01)00350-1
Abstract: Over recent years the secreted guidance cue, netrin-1, and its receptor, DCC, have been shown to be an essential guidance system driving axon pathfinding within the developing vertebrate central nervous system (CNS). Mice lacking DCC exhibit severe defects in commissural axon extension towards the floor plate demonstrating that the DCC-netrin guidance system is largely responsible for directing axonal projections toward the ventral midline in the developing spinal cord (Fazeli et al., Nature 386 (1997) 796). In addition, these mutants lack several major commissures within the forebrain, including the corpus callosum and the hippoc al commissure. In contrast to the CNS, the role of the DCC guidance receptor in the development of the mammalian peripheral and enteric nervous systems (PNS and ENS) has not been investigated. Here we demonstrate using immunohistochemical analysis that the DCC receptor is present in the developing mouse PNS where it is found on spinal, segmental, and sciatic nerves, and in developing sensory ganglia and their associated axonal projections. In addition, DCC is present in the ENS throughout the early developmental phase.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2020
DOI: 10.1007/S00248-019-01465-W
Abstract: In the present study, we assessed prokaryotic communities of demosponges, a calcareous sponge, octocorals, sediment and seawater in coral reef habitat of the central Red Sea, including endemic species and species new to science. Goals of the study were to compare the prokaryotic communities of demosponges with the calcareous sponge and octocorals and to assign preliminary high microbial abundance (HMA) or low microbial abundance (LMA) status to the sponge species based on compositional trait data. Based on the compositional data, we were able to assign preliminary LMA or HMA status to all sponge species. Certain species, however, had traits of both LMA and HMA species. For ex le, the sponge Ectyoplasia coccinea, which appeared to be a LMA species, had traits, including a relatively high abundance of Chloroflexi members, that were more typical of HMA species. This included dominant OTUs assigned to two different classes within the Chloroflexi. The calcareous sponge clustered together with seawater, the known LMA sponge Stylissa carteri and other presumable LMA species. The two dominant OTUs of this species were assigned to the Deltaproteobacteria and had no close relatives in the GenBank database. The octocoral species in the present study had prokaryotic communities that were distinct from sediment, seawater and all sponge species. These were characterised by OTUs assigned to the orders Rhodospirillales, Cellvibrionales, Spirochaetales and the genus Endozoicomonas, which were rare or absent in s les from other biotopes.
Publisher: Cold Spring Harbor Laboratory
Date: 08-2013
Abstract: This protocol describes how to purify oligodendrocyte precursor cells (OPCs) from postnatal rodent brains. The method utilizes an immunopanning technique to first remove unwanted cells by negative selection and then purify OPCs by positive selection and subsequent enzymatic release from the final panning plate. Included are modifications that allow for purification and culturing of OPCs from mouse instead of rat tissue and for use of optic nerves instead of whole brains. The method for isolating OPCs from whole brain can be used for isolating OPCs from any specific region of the brain, provided that the area can be dissected away from the rest of the tissue. Suggested culture media for maintaining proliferating OPCs or inducing oligodendrocyte (OL) differentiation are also described.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.PNEUROBIO.2017.03.009
Abstract: Poor white matter development in intrauterine growth restricted (IUGR) babies remains a major, untreated problem in neonatology. New therapies, guided by an understanding of the mechanisms that underlie normal and abnormal oligodendrocyte development and myelin formation, are required. Much of our knowledge of the mechanisms that underlie impaired myelination come from studies in adult demyelinating disease, preterm brain injury, or experimental models of hypoxia-ischemia. However, relatively less is known for IUGR which is surprising because IUGR is a leading cause of perinatal mortality and morbidity, second only to premature birth. IUGR is also a significant risk factor for the later development of cerebral palsy, and is a greater risk compared to some of the more traditionally researched antecedents - asphyxia and inflammation. Recent evidence suggests that the white matter injury and reduced myelination in the brains of some preterm babies is due to impaired maturation of oligodendrocytes thereby resulting in the reduced capacity to synthesize myelin. Therefore, it is not surprising that the hypomyelination observable in the central nervous system of IUGR infants has similarly lead to investigations identifying a delay or blockade in the progress of maturation of oligodendrocytes in these infants. This review will discuss current ideas thought to account for the poor myelination often present in the neonate's brain following IUGR, and discuss novel interventions that are promising as treatments that promote oligodendrocyte maturation, and thereby repair the myelination deficits that otherwise persist into infancy and childhood and lead to neurodevelopmental abnormalities.
Publisher: Inter-Research Science Center
Date: 31-03-2014
DOI: 10.3354/MEPS10678
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2010
DOI: 10.1101/GAD.1864510
Abstract: The controlling factors that prompt mature oligodendrocytes to myelinate axons are largely undetermined. In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 ( Zfp191 ), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein–protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function. Therefore, this study demonstrates that ZFP191 is required for the myelinating function of differentiated oligodendrocytes.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.NEUROSCIENCE.2005.09.022
Abstract: Multiple sclerosis is an autoimmune disease of the CNS that results in the death of oligodendrocytes, the myelinating cells of the CNS. Previous studies have indicated that the cytokine leukemia inhibitory factor prevents the cytotoxic effects of interferon-gamma on oligodendrocytes in vitro, and the death of oligodendrocytes in an animal model of multiple sclerosis. Members of a recently characterized family of proteins, the suppressors of cytokine signaling, have been demonstrated to mediate negative cross-talk between cytokines, with induction of suppressors of cytokine signaling proteins by one cytokine inhibiting the activity of a second. Here, we assess whether induction of members of the suppressors of cytokine signaling family could explain the antagonistic biological effects of leukemia inhibitory factor and interferon-gamma upon oligodendrocytes. It is found that leukemia inhibitory factor rapidly and strongly induces the expression of suppressors of cytokine signaling-3 in cultured rat oligodendrocytes, whereas interferon-gamma weakly induces the expression of both suppressor of cytokine signaling-1 and 3. Pre-treatment of oligodendrocytes with leukemia inhibitory factor does not prevent the subsequent phosphorylation of signal transducer and activator of transcription-1 by interferon-gamma indicating that the leukemia inhibitory factor inhibition of interferon-gamma toxicity in oligodendrocytes is mediated by a suppressor of cytokine signaling-3 independent mechanism.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2022
DOI: 10.1038/S42003-022-03470-1
Abstract: Oligodendrocyte progenitor cells (OPCs) express protocadherin 15 (Pcdh15), a member of the cadherin superfamily of transmembrane proteins. Little is known about the function of Pcdh15 in the central nervous system (CNS), however, Pcdh15 expression can predict glioma aggression and promote the separation of embryonic human OPCs immediately following a cell ision. Herein, we show that Pcdh15 knockdown significantly increases extracellular signal-related kinase (ERK) phosphorylation and activation to enhance OPC proliferation in vitro. Furthermore, Pcdh15 knockdown elevates Cdc42-Arp2/3 signalling and impairs actin kinetics, reducing the frequency of lamellipodial extrusion and slowing filopodial withdrawal. Pcdh15 knockdown also reduces the number of processes supported by each OPC and new process generation. Our data indicate that Pcdh15 is a critical regulator of OPC proliferation and process motility, behaviours that characterise the function of these cells in the healthy CNS, and provide mechanistic insight into the role that Pcdh15 might play in glioma progression.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2017
DOI: 10.1007/S00401-017-1741-7
Abstract: Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase π positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. In idual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure.
Publisher: Informa UK Limited
Date: 22-07-2016
DOI: 10.1080/17588928.2016.1206070
Abstract: Voelker and colleagues propose that we may illuminate learning-associated phenomena such as generalization by considering white matter plasticity. Consistent with this idea, human neuroimaging studies reveal learning-induced changes in adult white matter. Animal studies reveal that some forms of learning induce, and are dependent on, generation of new oligodendrocytes. Nevertheless, it remains unclear which alterations to myelin structure are most relevant to learning, and humans and rodents may profoundly differ in their capacity for oligodendrogenesis in adulthood. A full understanding of these issues will be critical to appreciating the role of adaptive myelination in human neuroplasticity.
Publisher: Society for Neuroscience
Date: 02-01-2008
DOI: 10.1523/JNEUROSCI.4178-07.2008
Abstract: Understanding the cell–cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100β promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of ,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin α v β 5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a “glial” cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.CELREP.2020.108641
Abstract: Central nervous system myelination increases action potential conduction velocity. However, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supported by mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitude in the spatial learning task was found to correlate with action potential conduction velocity in the fimbria-fornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in the adult mouse brain.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1186/S13064-021-00156-Y
Abstract: Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Establishing the proper pattern of myelin in neural circuits requires communicative axo-glial interactions, however, the molecular interactions that occur between oligodendrocytes and axons during developmental myelination and myelin maintenance remain to be fully elucidated. Our previous work identified G protein-coupled receptor 62 (Gpr62), an uncharacterized orphan g-protein coupled receptor, as being selectively expressed by mature oligodendrocytes within the CNS, suggesting a potential role in myelination or axoglial interactions. However, no studies to date have assessed the functional requirement for Gpr62 in oligodendrocyte development or CNS myelination. To address this, we generated a knockout mouse strain lacking the Gpr62 gene. We assessed CNS myelination during both postnatal development and adulthood using immunohistochemistry, electron microscopy and western blot. In addition, we utilized AAV-mediated expression of a tagged Gpr62 in oligodendrocytes to determine the subcellular localization of the protein in vivo. We find that virally expressed Gpr62 protein is selectively expressed on the adaxonal myelin layer, suggestive of a potential role for Gpr62 in axo-myelinic signaling. Nevertheless, Gpr62 knockout mice display normal oligodendrocyte numbers and apparently normal myelination within the CNS during both postnatal development and adulthood. We conclude that in spite of being well-placed to mediate neuronal-oligodendrocyte communications, Gpr62 is overall dispensable for CNS myelination.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Frontiers Media SA
Date: 08-03-2021
DOI: 10.3389/FCELL.2021.653101
Abstract: The myelination of axons by oligodendrocytes is a highly complex cell-to-cell interaction. Oligodendrocytes and axons have a reciprocal signaling relationship in which oligodendrocytes receive cues from axons that direct their myelination, and oligodendrocytes subsequently shape axonal structure and conduction. Oligodendrocytes are necessary for the maturation of excitatory domains on the axon including nodes of Ranvier, help buffer potassium, and support neuronal energy metabolism. Disruption of the oligodendrocyte-axon unit in traumatic injuries, Alzheimer’s disease and demyelinating diseases such as multiple sclerosis results in axonal dysfunction and can culminate in neurodegeneration. In this review, we discuss the mechanisms by which demyelination and loss of oligodendrocytes compromise axons. We highlight the intra-axonal cascades initiated by demyelination that can result in irreversible axonal damage. Both the restoration of oligodendrocyte myelination or neuroprotective therapies targeting these intra-axonal cascades are likely to have therapeutic potential in disorders in which oligodendrocyte support of axons is disrupted.
Publisher: Elsevier BV
Date: 07-2009
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Publisher: American Society for Clinical Investigation
Date: 18-04-2019
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
DOI: 10.1038/S41597-020-0420-Z
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Wiley
Date: 23-02-2006
DOI: 10.1002/GLIA.20321
Abstract: Autoimmune injury to oligodendrocytes evokes an endogenous response in the central nervous system, which initially limits the acute injury to oligodendrocytes and myelin, and subsequently promotes remyelination. The key molecular and cellular events responsible for this beneficial outcome are incompletely understood. In this article, we utilize murine autoimmune encephalomyelitis (EAE) to focus on the effect of endogenously produced leukemia inhibitory factor (LIF) upon mature oligodendrocyte survival after demyelinating injury. We show that the mRNA for LIF is markedly upregulated in the spinal cord in the context of acute inflammatory demyelination. After clinical disease onset, administration of neutralizing anti-LIF antibodies over a four day period significantly worsens disease severity in two different murine EAE models. We also show that administration of neutralizing antibodies results in reduced activation of the cognate LIF receptor components in the spinal cord. Histologically, anti-LIF antibody administration increases the extent of acute demyelination (P < 0.01) and doubles the oligodendrocyte loss already induced by EAE (P < 0.05), without altering the extent of inflammatory infiltration into the spinal cord. Although acute EAE induces a rapid, three-fold increase in the proliferation of NG2 positive oligodendrocyte progenitors (P < 0.001), this response is not diminished by antagonism of endogenous LIF. We conclude that endogenous LIF is induced in response to autoimmune demyelination in the spinal cord and protects mature oligodendrocytes from demyelinating injury and cell death, thereby resulting in attenuation of clinical disease severity.
Publisher: Elsevier BV
Date: 11-2008
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-11-2010
Abstract: Despite the importance of myelin for the rapid conduction of action potentials, the molecular bases of oligodendrocyte differentiation and central nervous system (CNS) myelination are still incompletely understood. Recent results have greatly advanced this understanding, identifying new transcriptional regulators of myelin gene expression, elucidating vital roles for microRNAs in controlling myelination, and clarifying the extracellular signaling mechanisms that orchestrate the development of myelin. Studies have also demonstrated an unexpected level of plasticity of myelin in the adult CNS. These recent advances provide new insight into how remyelination may be stimulated in demyelinating disorders such as multiple sclerosis.
Publisher: Springer Netherlands
Date: 2013
DOI: 10.1007/978-94-007-6621-1_8
Abstract: With the discovery two decades ago that the adult brain contains neural stem cells (NSCs) capable of producing new neurons, a great deal of research has been undertaken to manipulate these cells to repair the damaged nervous system. Much progress has been made in understanding what regulates adult neural stem cell specification, proliferation and differentiation but much remains to be determined. Lessons can be learned from understanding how embryonic neural stem cells produce the exquisitely complicated organ that is the adult mammalian nervous system. This review will highlight the role of transcriptional regulation of mammalian neural stem cells during embryonic development and compare these to the adult neural stem cell/neural precursor cell (NPC) niches of the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippoc al dentate gyrus. Normal physiological NSC/NPC regulation will be explored, as well as their regulation and responses following neural injury and disease. Finally, transcriptional regulation of the endogenous NSC/NPCs will be compared and contrasted with embryonic stem/induced pluripotent stem (ES/iPS) cell-derived NSC/NPCs. Recapitulation of the embryonic sequence of transcriptional events in neural stem cell development into specific neuronal or glial lineages improves directed differentiation of ES/iPS cells and may be useful for activation and specification of endogenous adult neural stem cells for therapeutic purposes.
Publisher: Informa UK Limited
Date: 09-2004
Abstract: Immune-mediated therapies can reduce the relapse rate in multiple sclerosis. However, there is no clear-cut evidence that any of these therapies substantially alter the long-term outcome for patients with progressive multiple sclerosis. The neurological disability that all too frequently accompanies multiple sclerosis is ultimately due to injury to target cells, principally oligodendroglia, within the nervous system. Recent data suggest that activation of leukemia inhibitory factor-receptor signaling is an important component of a neurobiological response that serves to limit the extent of immune-mediated injury. Therefore, inactivation of this pathway could provide a novel approach to the treatment of demyelinating disease.
Publisher: Cold Spring Harbor Laboratory
Date: 09-2013
Abstract: Oligodendrocytes are the cells of the vertebrate central nervous system responsible for forming myelin sheaths, which are essential for the rapid propagation of action potential. The formation of oligodendrocytes and myelin sheaths is tightly regulated, both temporally and spatially, by a number of extracellular and intracellular factors. For ex le, notch ligands, thyroid hormones, and mitogens such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) can all interact with oligodendrocyte precursor cell–expressed receptors to impact proliferation, differentiation, and myelin gene expression. To facilitate oligodendrocyte biology research, we have developed a technique using immunopanning to isolate different stages of the oligodendrocyte lineage, oligodendrocyte precursor cells and/or postmitotic oligodendrocytes, from postnatal rat or mouse brains. These cells can be cultured in defined, serum-free media in conditions that either promote differentiation into mature oligodendrocytes or continued proliferation as immature oligodendrocyte precursors. These cells represent an ideal system in which to study the regulation of oligodendrocyte proliferation, migration, differentiation, myelin gene expression, or other fundamental aspects of oligodendrocyte biology.
Publisher: Wiley
Date: 08-07-2022
DOI: 10.1111/BRV.12876
Abstract: Disturbances alter bio ersity via their specific characteristics, including severity and extent in the landscape, which act at different temporal and spatial scales. Bio ersity response to disturbance also depends on the community characteristics and habitat requirements of species. Untangling the mechanistic interplay of these factors has guided disturbance ecology for decades, generating mixed scientific evidence of bio ersity responses to disturbance. Understanding the impact of natural disturbances on bio ersity is increasingly important due to human‐induced changes in natural disturbance regimes. In many areas, major natural forest disturbances, such as wildfires, windstorms, and insect outbreaks, are becoming more frequent, intense, severe, and widespread due to climate change and land‐use change. Conversely, the suppression of natural disturbances threatens disturbance‐dependent biota. Using a meta‐analytic approach, we analysed a global data set (with most s ling concentrated in temperate and boreal secondary forests) of species assemblages of 26 taxonomic groups, including plants, animals, and fungi collected from forests affected by wildfires, windstorms, and insect outbreaks. The overall effect of natural disturbances on α‐ ersity did not differ significantly from zero, but some taxonomic groups responded positively to disturbance, while others tended to respond negatively. Disturbance was beneficial for taxonomic groups preferring conditions associated with open canopies (e.g. hymenopterans and hoverflies), whereas ground‐dwelling groups and/or groups typically associated with shady conditions (e.g. epigeic lichens and mycorrhizal fungi) were more likely to be negatively impacted by disturbance. Across all taxonomic groups, the highest α‐ ersity in disturbed forest patches occurred under moderate disturbance severity, i.e. with approximately 55% of trees killed by disturbance. We further extended our meta‐analysis by applying a unified ersity concept based on Hill numbers to estimate α‐ ersity changes in different taxonomic groups across a gradient of disturbance severity measured at the stand scale and incorporating other disturbance features. We found that disturbance severity negatively affected ersity for Hill number q = 0 but not for q = 1 and q = 2, indicating that ersity–disturbance relationships are shaped by species relative abundances. Our synthesis of α‐ ersity was extended by a synthesis of disturbance‐induced change in species assemblages, and revealed that disturbance changes the β‐ ersity of multiple taxonomic groups, including some groups that were not affected at the α‐ ersity level (birds and woody plants). Finally, we used mixed rarefaction/extrapolation to estimate bio ersity change as a function of the proportion of forests that were disturbed, i.e. the disturbance extent measured at the landscape scale. The comparison of intact and naturally disturbed forests revealed that both types of forests provide habitat for unique species assemblages, whereas species ersity in the mixture of disturbed and undisturbed forests peaked at intermediate values of disturbance extent in the simulated landscape. Hence, the relationship between α‐ ersity and disturbance severity in disturbed forest stands was strikingly similar to the relationship between species richness and disturbance extent in a landscape consisting of both disturbed and undisturbed forest habitats. This result suggests that both moderate disturbance severity and moderate disturbance extent support the highest levels of bio ersity in contemporary forest landscapes.
Publisher: Elsevier BV
Date: 03-2010
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.CONB.2010.05.005
Abstract: The successful transduction of action potentials along vertebrate axons is highly reliant on myelin, the concentric layers of membrane surrounding most large diameter axons. Within the central nervous system myelin is produced by oligodendrocytes. Developmentally, the oligodendrocyte linage arises from subventricular zone progenitors that give rise to oligodendrocyte progenitor cells (OPCs), which ide and migrate throughout the CNS before terminally differentiating to generate mature oligodendrocytes which myelinate receptive axons. Each step of progression along the lineage is under tight transcriptional control, elucidation of this control is vital for understanding developmental myelination and for developing strategies to promote repair in demyelinating diseases. Recent studies have identified a number of new transcriptional regulators and microRNAs as having key roles in CNS myelination.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
DOI: 10.1038/NN.4351
Publisher: Cold Spring Harbor Laboratory
Date: 07-2015
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.NEUROSCIENCE.2013.11.029
Abstract: Oligodendrocytes and the myelin they produce are a remarkable vertebrate specialization that enables rapid and efficient nerve conduction within the central nervous system. The generation of myelin during development involves a finely-tuned pathway of oligodendrocyte precursor specification, proliferation and migration followed by differentiation and the subsequent myelination of appropriate axons. In this review we summarize the molecular mechanisms known to regulate each of these processes, including the extracellular ligands that promote or inhibit development of the oligodendrocyte lineage, the intracellular pathways they signal through and the key transcription factors that mediate their effects. Many of these regulatory mechanisms have recurring roles in regulating several transitions during oligodendrocyte development, highlighting their importance. It is also highly likely that many of these developmental mechanisms will also be involved in myelin repair in human neurological disease.
Publisher: Public Library of Science (PLoS)
Date: 02-05-2019
Publisher: Wiley
Date: 02-12-2018
DOI: 10.1002/GLIA.23561
Abstract: The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.
Location: Australia
Location: United States of America
Start Date: 07-2018
End Date: 12-2021
Amount: $487,460.00
Funder: Australian Research Council
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