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Molecular composition of domains at the node of Ranvier. Components of the nodes include neurofascin-186, NrCAM and voltagegated Na + channels, which are tethered to a complex containing ankyrin G and IV-spectrin. The paranodes contain a complex of Caspr, contactin and 4.1B at the axonal membrane, which binds to neurofascin-155 on the paranodal loop. The multiprotein complex in the juxtaparanode contains a cis complex of Caspr2 and TAG-1, which interact with 4.1B and a PDZ-domain-containing protein associated with the two shaker-type K + channels, K v 1.1 and 1.2. This complex is linked through a trans interaction with TAG-1 to the glial membrane.
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During the development of the central nervous system the reciprocal communication between neurons and oligodendrocytes is essential for the generation of myelin, a multilamellar insulating membrane that ensheathes the axons. Neuron-derived signalling molecules regulate the proliferation, differentiation and survival of oligodendrocytes. Furthermore...
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Context 1
... the myelinating glia. These paranodal loops form septate-like junctions with the axonal membrane. The juxtaparanodal domain lies just under the compact myelin sheath next to the paranodes. Each of these domains consists of distinct multiprotein complexes, containing different cell-adhesion molecules, cytoplasmic adaptor proteins and ion channels (Fig. 3). Below we discuss briefly how these domains are generated, focusing on the intercellular interactions that direct their assembly. For a more comprehensive coverage, we refer readers to previous reviews of this topic ( Pedraza et al., 2001; Components of the nodes include neurofascin-186, NrCAM and voltage- gated Na + channels, which ...
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Central nervous system myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid impulse propagation. However, the underlying mechanisms of myelin wrapping have remained unclear. Using an integrative approach of live imaging, electron microscopy, and genetics, we show that new myelin membranes are incorporated adjacent to the...
Citations
... Neuron-derived signaling molecules regulate the proliferation, differentiation, and survival of oligodendrocytes. In turn, signals from oligodendrocytes to neurons direct the assembly of specific subdomains in neurons at the node of Ranvier [17]. Therefore, further elucidation of which cell types communicate with one another and how they communicate may help us better understand how AD occurs and progresses. ...
Background
Alzheimer’s disease (AD) is a complicated neurodegenerative disease. Neuron-glial cell interactions are an important but not fully understood process in the progression of AD. We used bioinformatic methods to analyze single-nucleus RNA sequencing (snRNA-seq) data to investigate the cellular and molecular biological processes of AD.
Method
snRNA-seq data were downloaded from Gene Expression Omnibus (GEO) datasets and reprocessed to identify 240,804 single nuclei from healthy controls and patients with AD. The cellular composition of AD was further explored using Uniform Manifold Approximation and Projection (UMAP). Enrichment analysis for the functions of the DEGs was conducted and cell development trajectory analyses were used to reveal underlying cell fate decisions. iTALK was performed to identify ligand-receptor pairs among various cell types in the pathological ecological microenvironment of AD.
Results
Six cell types and multiple subclusters were identified based on the snRNA-seq data. A subcluster of neuron and glial cells co-expressing lncRNA-SNHG14, myocardin-related transcription factor A (MRTFA), and MRTFB was found to be more abundant in the AD group. This subcluster was enriched in mitogen-activated protein kinase (MAPK)-, immune-, and apoptosis-related pathways. Through molecular docking, we found that lncRNA-SNHG14 may bind MRTFA and MRTFB, resulting in an interaction between neurons and glial cells.
Conclusions
The findings of this study describe a regulatory relationship between lncRNA-SNHG14, MRTFA, and MRTFB in the six main cell types of AD. This relationship may contribute to microenvironment remodeling in AD and provide a theoretical basis for a more in-depth analysis of AD.
... Gray matter primarily comprises neuronal cell bodies and glial cells; while, white matter contains axons that connect neurons and glial support cells. Most of these axons, especially those of larger diameter (Simons and Trajkovic 2006), are wrapped in myelin sheaths. In addition to their critical physiological functions, myelin content is correlated with increased tissue stiffness (Weickenmeier et al. 2017), suggesting that they may act as reinforcing fibers within the brain. ...
Traumatic brain injury is a major cause of morbidity in civilian as well as military populations. Computational simulations of injurious events are an important tool to understanding the biomechanics of brain injury and evaluating injury criteria and safety measures. However, these computational models are highly dependent on the material parameters used to represent the brain tissue. Reported material properties of tissue from the cerebrum and cerebellum remain poorly defined at high rates and with respect to anisotropy. In this work, brain tissue from the cerebrum and cerebellum of male Göttingen minipigs was tested in one of three directions relative to axon fibers in oscillatory simple shear over a large range of strain rates from 0.025 to 250 s⁻¹. Brain tissue showed significant direction dependence in both regions, each with a single preferred loading direction. The tissue also showed strong rate dependence over the full range of rates considered. Transversely isotropic hyper-viscoelastic constitutive models were fit to experimental data using dynamic inverse finite element models to account for wave propagation observed at high strain rates. The fit constitutive models predicted the response in all directions well at rates below 100 s⁻¹, after which they adequately predicted the initial two loading cycles, with the exception of the 250 s⁻¹ rate, where models performed poorly. These constitutive models can be readily implemented in finite element packages and are suitable for simulation of both conventional and blast injury in porcine, especially Göttingen minipig, models.
... Glial cells contribute to the formation of the blood-brain barrier, the impermeable lining of the brain capillaries and venules, that prevents toxic substances in the blood from entering the brain. Regarding the specific contributions of the different glial cells, oligodendrocytes support myelination by wrapping themselves around axons to form myelin sheaths which are the most susceptible structures to brain damage (McLaurin and Yong, 1995;Diemel et al., 1998;Simons and Trajkovic, 2006;Barres, 2008). Interestingly, myelination in humans mainly occurs postnatally when neuronal migration has ended and lasts for decades, whereas in rodents, myelination starts from neurogenesis and takes only a few weeks. ...
Lamin B1 is an essential protein of the nuclear lamina that plays a crucial role in nuclear function and organization. It has been demonstrated that lamin B1 is essential for organogenesis and particularly brain development. The important role of lamin B1 in physiological brain development and aging has only recently been at the epicenter of attention and is yet to be fully elucidated. Regarding the development of brain, glial cells that have long been considered as supporting cells to neurons have overturned this representation and current findings have displayed their active roles in neurogenesis and cerebral development. Although lamin B1 has increased levels during the differentiation of the brain cells, during aging these levels drop leading to senescent phenotypes and inciting neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. On the other hand, overexpression of lamin B1 leads to the adult-onset neurodegenerative disease known as Autosomal Dominant Leukodystrophy. This review aims at highlighting the importance of balancing lamin B1 levels in glial cells and neurons from brain development to aging.
... This paper reviews the fundamental importance of myelin and correct CNS myelination for its development, functional adaptations, and permanent reshuffling. During aging in the human patient, sporadic AD [175]). The differentiated oligodendrocytes of OPCs migrate to different axons via positive chemotactism [216]. ...
Alzheimer’s disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals’ accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.
... (c) Gene expression dot plot showing the relative expression of cell-type marker genes (x-axis) across all clusters (y-axis). The colour intensity of dots represents the average expression level (standardized to a Z-score), the size of dots the proportion ( glial cells provide neuronal and immunological support (Simons & Trajkovic, 2006). Transcriptomics at the cellular level (in this context, both single-cell and -nucleus RNA-sequencing) enables systematic characterization of cellular diversity in the brain, allowing a paradigm shift in neuroscience from the historical emphasis on cellular anatomy to the molecular classification of cell types Zeisel et al., 2015;Zhu et al., 2021). ...
Cetaceans (dolphins, whales, and porpoises) have large and anatomically sophisticated brains. To expand our understanding of the cellular makeup of cetacean brains and the similarities and divergence between the brains of cetaceans and terrestrial mammals, we here report a short-finned pilot whale (Globicephala macrorhynchus) single-nucleus transcriptome atlas. To achieve this goal, we assembled a chromosome-scale reference genome spanning 2.25 Gb on 22 chromosomes and profiled the gene expression of five major anatomical cortical regions of the short-finned pilot whale by single-nucleus RNA-sequencing (snRNA-seq). We identified six major cell lineages in the cerebral cortex (excitatory neurons, inhibitory neurons, oligodendrocytes, oligodendrocyte precursor cells, astrocytes, and endothelial cells), eight molecularly distinct subclusters of excitatory neurons, and four subclusters of inhibitory neurons. Finally, a comparison of snRNA-seq data from the short-finned pilot whale, human, and rhesus macaque revealed a broadly conserved cellular makeup of brain cell types. Our study provides genomic resources and molecular insights into cetacean brain evolution.
... Neurons and OLs share a reciprocal signaling relationship, whereby neurons send signals to OPCs and OLs to direct their proliferation, differentiation and myelination. Reciprocally, OLs shape neuronal axon structure and conduction as OLs extend multiple processes that ensheath nearby axons in layers of myelin to support proper brain development and function [104][105][106]. ...
Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer–promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type–specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.
... In young rats, following feeding with purified diet of various iron levels, showing impact on hemoglobin, cytochrome C and muscle myoglobin (Dallman, 1986). During neuronal and glial cell differentiation, a large amount of metabolic energy is required for migration processes, formation of myelin sheath, synapses formation and prolongation of neuritic process particularly in rapidly developing brain regions Simons & Trajkovic, 2006;Xiaoli Zhang et al., 2017). Iron is mainly present in oligodendrocytes and microglia and is essential for several metabolic activities including maturation of oligodendrocyte, and activation of microglial (Bishop et al., 2011;X. ...
... This result indicates that myelinmembrane growth is not affected in Dyrk1a +/− mutants and that compaction of the growing myelin sheaths would appear to be delayed. As axon diameter is a determinant factor for myelination 50,51 , hypomyelination of the Dyrk1a +/− mutant's CC could result from dysfunctional axon development. ...
... Dyrk1a +/− mutants have abnormal nodes of Ranvier. Deficient axon-oligodendroglia communication can affect myelin biogenesis and the formation and maintenance of the nodes of Ranvier, events that are crucial for the rapid propagation of the APs through saltatory conduction 50,51 . Therefore, the organization of the nodes and the flanking paranodes was examined in the CC of Dyrk1a +/− mice by immunostaining for NAV1.6 (voltage-gated sodium channel Na v 1.6), the major sodium channel in the node region 52 , and for the CASPR (contactin-associated protein) that concentrates in the paranodal region 53 . ...
... OPC differentiation depends on a cell-intrinsic timer that defines the number of divisions before the cells exit the cell cycle and undergo differentiation 72 . Recent evidence indicates that this OPC timer is controlled by the interplay of several intrinsic factors with extracellular signalling molecules, and by neuronal activity 50,73 . Thus, the delay in oligodendroglial development in the Dyrk1a +/− mouse is likely to be the result of the early deficit in OPC production as well as changes to the extrinsic cues provided by neurons and astrocytes. ...
The correct development and activity of neurons and glial cells is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase involved in the neuropathology associated with Down syndrome that influences neurogenesis and the morphological differentiation of neurons. DYRK1A loss-of-function mutations in heterozygosity cause a well-recognizable syndrome of intellectual disability and autism spectrum disorder. In this study, we analysed the developmental trajectories of macroglial cells and the properties of the corpus callosum, the major white matter tract of the brain, in Dyrk1a+/− mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome. We found that Dyrk1a+/− haploinsufficient mutants present an increase in astrogliogenesis in the neocortex and a delay in the production of cortical oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a+/− mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a+/− mutants. All these alterations are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions. These alterations highlight the relevance of glial cell abnormalities in neurodevelopmental disorders.
... The major function of oligodendrocytes and Schwann cells is the formation of myelin (Emery 2010;Franklin and Ffrench-Constant 2008;Nave 2010;Nave and Trapp 2008;Sherman and Brophy 2005;Simons and Trajkovic 2006). Myelin acts as an insulator of axonal segments and is a prerequisite for the high velocity of nerve conduction of up to 200 m/s. ...
In the human brain glial cells are as abundant as neurons. The relative number of glial cells has increased with increasing complexity of the central nervous system (CNS) during evolution. In vertebrates three types of glial cells can be distinguished in the CNS, namely, astrocytes, oligodendrocytes, and microglia. In the peripheral nervous system glial cells are represented by Schwann cells, satellite glial cells, enteric glial cells (EGCs), and olfactory ensheathing cells. Astroglia are a heterogeneous cell population that fulfill different supportive and homeostatic tasks such as providing guiding structures during development, controlling homeostasis of the extracellular space, providing energy substrate for neurons, controlling blood flow, and modulating synaptic transmission. Oligodendrocytes in the central and Schwann cells in the peripheral nervous system form myelin and thereby enable a high conduction velocity within the axons. Microglial cells are the immune competent cells of the brain and are activated during any pathologic process. The activated microglial cells can release many factors which influence the pathologic process. Taken together brain function is only possible by a concerted action of neurons and glial cells.
... This result indicates that myelin-membrane growth is not affected in Dyrk1a +/− mutants and that compaction of the growing myelin sheaths would appear to be delayed. As axon diameter is a determinant factor for myelination [50,51], hypomyelination of the Dyrk1a +/− mutant's CC could result from dysfunctional axon development. ...
... De cient axon-oligodendroglia communication can affect myelin biogenesis, and the formation and maintenance of the nodes of Ranvier, events that are crucial for the rapid propagation of the APs through saltatory conduction [50,51]. Therefore, the organization of the nodes and the anking paranodes was examined in the CC of Dyrk1a +/mice by immunostaining for NAV1.6 (voltage-gated sodium channel Na v 1.6), the major sodium channel in the node region [52], and for the CASPR (contactin-associated protein) that concentrates in the paranodal region [53]. ...
... OPC differentiation depends on a cell-intrinsic timer that de nes the number of divisions before the cells exit the cell cycle and undergo differentiation [72]. Recent evidence indicates that this OPC timer is controlled by the interplay of several intrinsic factors with extracellular signalling molecules, and by neuronal activity [50,73]. Thus, the delay in oligodendroglial development in the Dyrk1a +/mouse is likely to be the result of the early de cit in OPC production as well as changes to the extrinsic cues provided by neurons and astrocytes. ...
The correct development and activity of neurons and glial cells is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase involved in the neuropathology associated with Down syndrome that influences neurogenesis and the morphological differentiation of neurons. DYRK1A loss-of-function mutations in heterozygosity cause a well-recognizable syndrome of intellectual disability and autism spectrum disorder. In this study, we analysed the developmental trajectories of macroglial cells and the properties of the corpus callosum , the major white matter tract of the brain, in Dyrk1a +/− mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome. We found that Dyrk1a +/− haploinsufficient mutants present an increase in astrogliogenesis in the neocortex and a delay in the production of cortical oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a +/− mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a +/− mutants. All these alterations are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions. These alterations highlight the relevance of glial cell abnormalities in neurodevelopmental disorders.
