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1.
Cell ; 187(8): 1990-2009.e19, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38513664

ABSTRACT

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Spinal Cord , Animals , Humans , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Spinal Cord/metabolism , Spinal Cord/pathology , Mice , Single-Cell Gene Expression Analysis , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Neuroglia/metabolism , Neuroglia/pathology
2.
Cell ; 186(7): 1309-1327, 2023 03 30.
Article in English | MEDLINE | ID: mdl-37001498

ABSTRACT

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets.


Subject(s)
Multiple Sclerosis , Humans , Multiple Sclerosis/drug therapy , Central Nervous System , Neuroglia , Cell Physiological Phenomena , Inflammation/pathology
3.
Cell ; 186(13): 2823-2838.e20, 2023 06 22.
Article in English | MEDLINE | ID: mdl-37236193

ABSTRACT

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.


Subject(s)
Enteric Nervous System , Inflammatory Bowel Diseases , Humans , Glucocorticoids/pharmacology , Inflammation , Enteric Nervous System/physiology , Stress, Psychological
4.
Cell ; 186(6): 1179-1194.e15, 2023 03 16.
Article in English | MEDLINE | ID: mdl-36931245

ABSTRACT

The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.


Subject(s)
Neural Stem Cells , Mice , Animals , Humans , Neural Stem Cells/metabolism , Neurons , Cell Differentiation/physiology , Neuroglia/metabolism , Brain , Astrocytes
5.
Cell ; 184(15): 4048-4063.e32, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34233165

ABSTRACT

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.


Subject(s)
Microglia/metabolism , Neural Inhibition/physiology , gamma-Aminobutyric Acid/metabolism , Animals , Animals, Newborn , Behavior, Animal , Gene Expression Regulation , HEK293 Cells , Humans , Mice , Parvalbumins/metabolism , Phenotype , Receptors, GABA-B/metabolism , Synapses/physiology , Transcription, Genetic
6.
Cell ; 180(2): 323-339.e19, 2020 01 23.
Article in English | MEDLINE | ID: mdl-31928845

ABSTRACT

Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.


Subject(s)
Nerve Tissue Proteins/ultrastructure , Receptors, Peptide/metabolism , Tenascin/metabolism , Animals , Cell Adhesion/physiology , Crystallography, X-Ray/methods , HEK293 Cells , Humans , K562 Cells , Leucine-Rich Repeat Proteins , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/ultrastructure , Membrane Proteins/metabolism , Membrane Proteins/ultrastructure , Mice , Mice, Inbred C57BL/embryology , Nerve Tissue Proteins/metabolism , Neurites/metabolism , Neurogenesis/physiology , Neurons/metabolism , Platelet Glycoprotein GPIb-IX Complex/metabolism , Platelet Glycoprotein GPIb-IX Complex/ultrastructure , Protein Binding/physiology , Proteins/metabolism , Proteins/ultrastructure , Receptors, Cell Surface/metabolism , Receptors, Peptide/ultrastructure , Synapses/metabolism , Tenascin/ultrastructure
7.
Cell ; 176(4): 743-756.e17, 2019 02 07.
Article in English | MEDLINE | ID: mdl-30735633

ABSTRACT

Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.


Subject(s)
Cerebral Cortex/cytology , Organoids/metabolism , Animals , Biological Evolution , Brain/cytology , Cell Culture Techniques/methods , Cell Differentiation/genetics , Cerebral Cortex/metabolism , Gene Regulatory Networks/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Macaca , Neurogenesis/genetics , Organoids/growth & development , Pan troglodytes , Pluripotent Stem Cells/cytology , Single-Cell Analysis , Species Specificity , Transcriptome/genetics
8.
Cell ; 176(3): 581-596.e18, 2019 01 24.
Article in English | MEDLINE | ID: mdl-30661753

ABSTRACT

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.


Subject(s)
Astrocytes/metabolism , Central Nervous System/metabolism , Animals , Central Nervous System/immunology , Computational Biology/methods , Encephalomyelitis, Autoimmune, Experimental/immunology , Endoribonucleases/metabolism , Environment , Environmental Exposure/adverse effects , Genome , Genomics , Humans , Inflammation/metabolism , Linuron/adverse effects , Mice , Mice, Inbred C57BL , Multiple Sclerosis/immunology , Protein Serine-Threonine Kinases/metabolism , Receptors, sigma/drug effects , Receptors, sigma/metabolism , Signal Transduction , X-Box Binding Protein 1/metabolism , Zebrafish
9.
Cell ; 178(1): 27-43.e19, 2019 06 27.
Article in English | MEDLINE | ID: mdl-31230713

ABSTRACT

When a behavior repeatedly fails to achieve its goal, animals often give up and become passive, which can be strategic for preserving energy or regrouping between attempts. It is unknown how the brain identifies behavioral failures and mediates this behavioral-state switch. In larval zebrafish swimming in virtual reality, visual feedback can be withheld so that swim attempts fail to trigger expected visual flow. After tens of seconds of such motor futility, animals became passive for similar durations. Whole-brain calcium imaging revealed noradrenergic neurons that responded specifically to failed swim attempts and radial astrocytes whose calcium levels accumulated with increasing numbers of failed attempts. Using cell ablation and optogenetic or chemogenetic activation, we found that noradrenergic neurons progressively activated brainstem radial astrocytes, which then suppressed swimming. Thus, radial astrocytes perform a computation critical for behavior: they accumulate evidence that current actions are ineffective and consequently drive changes in behavioral states. VIDEO ABSTRACT.


Subject(s)
Astrocytes/metabolism , Behavior, Animal/physiology , Larva/physiology , Zebrafish/physiology , Adrenergic Neurons/metabolism , Animals , Animals, Genetically Modified/physiology , Astrocytes/cytology , Brain/diagnostic imaging , Brain/physiology , Brain Mapping , Calcium/metabolism , Cell Communication/physiology , Feedback, Sensory/physiology , GABAergic Neurons/metabolism , Membrane Potentials/physiology , Optogenetics , Swimming/physiology
10.
Cell ; 173(1): 130-139.e10, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29526461

ABSTRACT

Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila "blood"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends on a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions. Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.


Subject(s)
Blood-Brain Barrier/metabolism , Circadian Clocks , Drosophila/metabolism , Rhodamines/metabolism , Xenobiotics/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Blood-Brain Barrier/drug effects , Brain/metabolism , Circadian Clocks/drug effects , Connexins/metabolism , Drosophila Proteins/metabolism , Female , Gap Junctions/metabolism , Magnesium/metabolism , Neuroglia/metabolism , Phenytoin/pharmacology , Phenytoin/therapeutic use , Seizures/drug therapy , Seizures/pathology , Seizures/veterinary
11.
Cell ; 174(3): 590-606.e21, 2018 07 26.
Article in English | MEDLINE | ID: mdl-29961574

ABSTRACT

Cerebral cortex size differs dramatically between reptiles, birds, and mammals, owing to developmental differences in neuron production. In mammals, signaling pathways regulating neurogenesis have been identified, but genetic differences behind their evolution across amniotes remain unknown. We show that direct neurogenesis from radial glia cells, with limited neuron production, dominates the avian, reptilian, and mammalian paleocortex, whereas in the evolutionarily recent mammalian neocortex, most neurogenesis is indirect via basal progenitors. Gain- and loss-of-function experiments in mouse, chick, and snake embryos and in human cerebral organoids demonstrate that high Slit/Robo and low Dll1 signaling, via Jag1 and Jag2, are necessary and sufficient to drive direct neurogenesis. Attenuating Robo signaling and enhancing Dll1 in snakes and birds recapitulates the formation of basal progenitors and promotes indirect neurogenesis. Our study identifies modulation in activity levels of conserved signaling pathways as a primary mechanism driving the expansion and increased complexity of the mammalian neocortex during amniote evolution.


Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurogenesis/genetics , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Animals , Calcium-Binding Proteins , Cerebral Cortex/metabolism , Chick Embryo , Gene Expression Regulation, Developmental/genetics , Homeodomain Proteins , Humans , Intercellular Signaling Peptides and Proteins/genetics , Jagged-1 Protein , Jagged-2 Protein , Mammals/embryology , Mice , Mice, Inbred C57BL , Neocortex/physiology , Neural Stem Cells , Neurogenesis/physiology , Neuroglia/physiology , Neurons , PAX6 Transcription Factor/metabolism , Repressor Proteins , Signal Transduction , Snakes/embryology , Roundabout Proteins
12.
Annu Rev Cell Dev Biol ; 35: 615-635, 2019 10 06.
Article in English | MEDLINE | ID: mdl-31590587

ABSTRACT

Molecular cross talk between the nervous and vascular systems is necessary to maintain the correct coupling of organ structure and function. Molecular pathways shared by both systems are emerging as major players in the communication of the neuronal compartment with the endothelium. Here we review different aspects of this cross talk and how vessels influence the development and homeostasis of the nervous system. Beyond the classical role of the vasculature as a conduit to deliver oxygen and metabolites needed for the energy-demanding neuronal compartment, vessels emerge as powerful signaling systems that control and instruct a variety of cellular processes during the development of neurons and glia, such as migration, differentiation, and structural connectivity. Moreover, a broad spectrum of mild to severe vascular dysfunctions occur in various pathologies of the nervous system, suggesting that mild structural and functional changes at the neurovascular interface may underlie cognitive decline in many of these pathological conditions.


Subject(s)
Central Nervous System/blood supply , Neuroglia/cytology , Neurons/cytology , Neurovascular Coupling/physiology , Peripheral Nervous System/blood supply , Animals , Blood Vessels/cytology , Blood Vessels/metabolism , Blood Vessels/pathology , Cell Differentiation , Cell Movement , Central Nervous System/cytology , Central Nervous System/embryology , Central Nervous System/metabolism , Homeostasis/physiology , Humans , Nervous System Diseases/genetics , Nervous System Diseases/metabolism , Neuroglia/physiology , Neurons/physiology , Peripheral Nervous System/cytology , Peripheral Nervous System/embryology , Peripheral Nervous System/metabolism
13.
Cell ; 171(4): 877-889.e17, 2017 Nov 02.
Article in English | MEDLINE | ID: mdl-28965759

ABSTRACT

N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.


Subject(s)
Neurogenesis , Prosencephalon/embryology , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , Animals , Cell Cycle , Gene Expression Regulation , Gene Expression Regulation, Developmental , Gene Knockdown Techniques , Humans , Methylation , Methyltransferases/genetics , Methyltransferases/metabolism , Mice , Mice, Knockout , Neural Stem Cells/metabolism , Organoids/metabolism , Prosencephalon/cytology , Prosencephalon/metabolism , RNA Stability
14.
Annu Rev Neurosci ; 46: 1-15, 2023 07 10.
Article in English | MEDLINE | ID: mdl-36750409

ABSTRACT

A holy grail of regenerative medicine is to replenish the cells that are lost due to disease. The adult mammalian central nervous system (CNS) has, however, largely lost such a regenerative ability. An emerging strategy for the generation of new neurons is through glia-to-neuron (GtN) conversion in vivo, mainly accomplished by the regulation of fate-determining factors. When inhibited, PTBP1, a factor involved in RNA biology, was reported to induce rapid and efficient GtN conversion in multiple regions of the adult CNS. Remarkably, PTBP1 inhibition was also claimed to greatly improve behaviors of mice with neurological diseases or aging. These phenomenal claims, if confirmed, would constitute a significant advancement in regenerative medicine. Unfortunately, neither GtN conversion nor therapeutic potential via PTBP1 inhibition was validated by the results of multiple subsequent replication studies with stringent methods. Here we review these controversial studies and conclude with recommendations for examining GtN conversion in vivo and future investigations of PTBP1.


Subject(s)
Neuroglia , Neurons , Animals , Mice , Neurons/physiology , Central Nervous System , Retina , Mammals
15.
Physiol Rev ; 103(2): 1487-1564, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36521049

ABSTRACT

Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.


Subject(s)
Enteric Nervous System , Humans , Gastrointestinal Tract , Neurons/physiology , Neuroglia , Signal Transduction/physiology
16.
Annu Rev Neurosci ; 44: 49-67, 2021 07 08.
Article in English | MEDLINE | ID: mdl-33406370

ABSTRACT

Animal behavior was classically considered to be determined exclusively by neuronal activity, whereas surrounding glial cells such as astrocytes played only supportive roles. However, astrocytes are as numerous as neurons in the mammalian brain, and current findings indicate a chemically based dialog between astrocytes and neurons. Activation of astrocytes by synaptically released neurotransmitters converges on regulating intracellular Ca2+ in astrocytes, which then can regulate the efficacy of near and distant tripartite synapses at diverse timescales through gliotransmitter release. Here, we discuss recent evidence on how diverse behaviors are impacted by this dialog. These recent findings support a paradigm shift in neuroscience, in which animal behavior does not result exclusively from neuronal activity but from the coordinated activity of both astrocytes and neurons. Decoding how astrocytes and neurons interact with each other in various brain circuits will be fundamental to fully understanding how behaviors originate and become dysregulated in disease.


Subject(s)
Astrocytes , Synaptic Transmission , Animals , Neuroglia , Neurons , Synapses
17.
Annu Rev Neurosci ; 44: 197-219, 2021 07 08.
Article in English | MEDLINE | ID: mdl-33722070

ABSTRACT

Myelination of axons provides the structural basis for rapid saltatory impulse propagation along vertebrate fiber tracts, a well-established neurophysiological concept. However, myelinating oligodendrocytes and Schwann cells serve additional functions in neuronal energy metabolism that are remarkably similar to those of axon-ensheathing glial cells in unmyelinated invertebrates. Here we discuss myelin evolution and physiological glial functions, beginning with the role of ensheathing glia in preventing ephaptic coupling, axoglial metabolic support, and eliminating oxidative radicals. In both vertebrates and invertebrates, axoglial interactions are bidirectional, serving to regulate cell fate, nerve conduction, and behavioral performance. One key step in the evolution of compact myelin in the vertebrate lineage was the emergence of the open reading frame for myelin basic protein within another gene. Several other proteins were neofunctionalized as myelin constituents and help maintain a healthy nervous system. Myelination in vertebrates became a major prerequisite of inhabiting new ecological niches.


Subject(s)
Axons , Myelin Sheath , Animals , Neuroglia , Neurons , Oligodendroglia
18.
Annu Rev Genet ; 55: 93-113, 2021 11 23.
Article in English | MEDLINE | ID: mdl-34351802

ABSTRACT

Significant advances have been made in recent years in identifying the genetic components of Wallerian degeneration, the process that brings the progressive destruction and removal of injured axons. It has now been accepted that Wallerian degeneration is an active and dynamic cellular process that is well regulated at molecular and cellular levels. In this review, we describe our current understanding of Wallerian degeneration, focusing on the molecular players and mechanisms that mediate the injury response, activate the degenerative program, transduce the death signal, execute the destruction order, and finally, clear away the debris. By highlighting the starring roles and sketching out the molecular script of Wallerian degeneration, we hope to provide a useful framework to understand Wallerian and Wallerian-like degeneration and to lay a foundation for developing new therapeutic strategies to treat axon degeneration in neural injury as well as in neurodegenerative disease.


Subject(s)
Neurodegenerative Diseases , Wallerian Degeneration , Axons/pathology , Axons/physiology , Humans , Neurodegenerative Diseases/pathology , Wallerian Degeneration/genetics , Wallerian Degeneration/pathology
19.
Annu Rev Cell Dev Biol ; 31: 647-67, 2015.
Article in English | MEDLINE | ID: mdl-26566119

ABSTRACT

Myelinated axons are divided into polarized subdomains including axon initial segments and nodes of Ranvier. These domains initiate and propagate action potentials and regulate the trafficking and localization of somatodendritic and axonal proteins. Formation of axon initial segments and nodes of Ranvier depends on intrinsic (neuronal) and extrinsic (glial) interactions. Several levels of redundancy in both mechanisms and molecules also exist to ensure efficient node formation. Furthermore, the establishment of polarized domains at and near nodes of Ranvier reflects the intrinsic polarity of the myelinating glia responsible for node assembly. Here, we discuss the various polarized domains of myelinated axons, how they are established by both intrinsic and extrinsic interactions, and the polarity of myelinating glia.


Subject(s)
Axons/physiology , Cell Polarity/physiology , Action Potentials/physiology , Animals , Humans , Myelin Sheath/physiology , Neuroglia/physiology , Neurons/physiology
20.
Genes Dev ; 35(3-4): 180-198, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33526585

ABSTRACT

Oligodendrocyte precursor cells (OPCs) are not merely a transitory progenitor cell type, but rather a distinct and heterogeneous population of glia with various functions in the developing and adult central nervous system. In this review, we discuss the fate and function of OPCs in the brain beyond their contribution to myelination. OPCs are electrically sensitive, form synapses with neurons, support blood-brain barrier integrity, and mediate neuroinflammation. We explore how sex and age may influence OPC activity, and we review how OPC dysfunction may play a primary role in numerous neurological and neuropsychiatric diseases. Finally, we highlight areas of future research.


Subject(s)
Brain/cytology , Oligodendrocyte Precursor Cells/cytology , Oligodendrocyte Precursor Cells/immunology , Age Factors , Animals , Brain/embryology , Brain/immunology , Brain/metabolism , Electrical Synapses/physiology , Humans , Mental Disorders/pathology , Nervous System Diseases/pathology , Oligodendrocyte Precursor Cells/pathology , Oligodendrocyte Precursor Cells/physiology , Sex Factors
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