scholarly journals Synaptic proteins expressed by oligodendrocytes mediate CNS myelination

2018 ◽  
Author(s):  
Alexandria N. Hughes ◽  
Bruce Appel
Keyword(s):  
Myelin Sheath ◽  
Synaptic Vesicles ◽  
Synapse Formation ◽  
Synaptic Proteins ◽  
Site Location ◽  
Zebrafish Larvae ◽  
Myelin Sheaths ◽  
Vesicular Release ◽  
Sense And Respond ◽  
Cns Myelination

ABSTRACTOligodendrocytes ensheath neuronal axons with myelin, a proteolipid-rich membrane that increases conduction velocity and provides trophic support. Our lab and others have provided evidence that vesicular release from neurons promotes myelin sheath growth. Complementarily, transcriptomic and proteomic approaches have revealed that oligodendrocytes express many proteins that allow dendrites to sense and respond to vesicular release at synapses. Do axon-myelin contacts use similar communication mechanisms as nascent synapses to form myelin sheaths on axons? To test this, we used fusion proteins to track synaptic vesicle localization and membrane fusion within spinal cord axons of zebrafish larvae during developmental myelination. Additionally, we used a CRISPR/Cas9-mediated GAL4 enhancer trap and genetically-encoded intrabody to detect expression and localization of PSD-95, a component of dendritic postsynaptic complexes, within oligodendrocytes. We found that synaptic vesicles accumulate at ensheathment sites over time and are exocytosed with variable patterning underneath myelin sheaths. Accordingly, we also found that most, but not all sheaths localized PSD-95 with patterning similar to exocytosis site location within the axon. By querying published transcriptome databases, we found that oligodendrocytes express numerous transsynaptic adhesion molecules that function across synapses to promote synapse formation and maturation. Disruption of candidate PDZ-binding transsynaptic adhesion proteins in oligodendrocytes revealed that these proteins have variable effects on sheath length and number. We focused on one candidate, Cadm1b (SynCAM1), and demonstrated that it localized to myelin sheaths where both its PDZ binding and extracellular adhesion to axons are required for myelin sheath growth. Our work reveals shared mechanisms of synaptic and myelin plasticity and provides new targets for mechanistic unraveling of activity-regulated myelination.

scholarly journals Oligodendrocytes express synaptic proteins that modulate myelin sheath formation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexandria N. Hughes ◽  
Bruce Appel
Keyword(s):  
Membrane Fusion ◽  
Myelin Sheath ◽  
Synaptic Vesicles ◽  
Fusion Proteins ◽  
Synaptic Proteins ◽  
Synaptic Protein ◽  
Site Location ◽  
Myelin Sheaths ◽  
Vesicular Release ◽  
Sheath Formation

Abstract Vesicular release from neurons promotes myelin sheath growth on axons. Oligodendrocytes express proteins that allow dendrites to respond to vesicular release at synapses, suggesting that axon-myelin contacts use similar communication mechanisms as synapses to form myelin sheaths. To test this, we used fusion proteins to track synaptic vesicle localization and membrane fusion in zebrafish during developmental myelination and investigated expression and localization of PSD95, a dendritic post-synaptic protein, within oligodendrocytes. Synaptic vesicles accumulate and exocytose at ensheathment sites with variable patterning and most sheaths localize PSD95 with patterning similar to exocytosis site location. Disruption of candidate PDZ-binding transsynaptic adhesion proteins in oligodendrocytes cause variable effects on sheath length and number. One candidate, Cadm1b, localizes to myelin sheaths where both PDZ binding and extracellular adhesion to axons mediate sheath growth. Our work raises the possibility that axon-glial communication contributes to myelin plasticity, providing new targets for mechanistic unraveling of developmental myelination.

scholarly journals The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

2019 ◽  
Author(s):  
Caleb A. Doll ◽  
Katie M. Yergert ◽  
Bruce H. Appel
Keyword(s):  
Myelin Sheath ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Synaptic Proteins ◽  
Local Synthesis ◽  
Functional Changes ◽  
Myelin Sheaths

SummaryDuring development, oligodendrocytes in the central nervous system extend a multitude of processes that wrap axons with myelin. The highly polarized oligodendrocytes generate myelin sheaths on many different axons, which are far removed from the cell body. Neurons use RNA binding proteins to transport, stabilize, and locally translate mRNA in distal domains of neurons. Local synthesis of synaptic proteins during neurodevelopment facilitates the rapid structural and functional changes underlying neural plasticity and avoids extensive protein transport. We hypothesize that RNA binding proteins also regulate local mRNA regulation in oligodendrocytes to promote myelin sheath growth. Fragile X mental retardation protein (FMRP), an RNA binding protein that plays essential roles in the growth and maturation of neurons, is also expressed in oligodendrocytes. To determine whether oligodendrocytes require FMRP for myelin sheath development, we examinedfmr1-/-mutant zebrafish and droveFMR1expression specifically in oligodendrocytes. We found oligodendrocytes infmr1-/-mutants developed myelin sheaths of diminished length, a phenotype that can be autonomously rescued in oligodendrocytes withFMR1expression. Myelin basic protein (Mbp), an essential myelin protein, was reduced in myelin tracts offmr1-/-mutants, but loss of FMRP function did not impact the localization ofmbpatranscript in myelin. Finally, expression of FMR1-I304N, a missense allele that abrogates FMRP association with ribosomes, failed to rescuefmr1-/-mutant sheath growth and induced short myelin sheaths in oligodendrocytes of wild-type larvae. Taken together, these data suggest that FMRP promotes sheath growth through local regulation of translation.

scholarly journals BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin–β-catenin interactions

2006 ◽  
Vol 174 (2) ◽  
pp. 289-299 ◽  
Author(s):  
Shernaz X. Bamji ◽  
Beatriz Rico ◽  
Nikole Kimes ◽  
Louis F. Reichardt
Keyword(s):  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Time Lapse ◽  
Synapse Density ◽  
Vesicle Mobility ◽  
Small Clusters ◽  
Vertebrate Central Nervous System

Neurons of the vertebrate central nervous system have the capacity to modify synapse number, morphology, and efficacy in response to activity. Some of these functions can be attributed to activity-induced synthesis and secretion of the neurotrophin brain-derived neurotrophic factor (BDNF); however, the molecular mechanisms by which BDNF mediates these events are still not well understood. Using time-lapse confocal analysis, we show that BDNF mobilizes synaptic vesicles at existing synapses, resulting in small clusters of synaptic vesicles “splitting” away from synaptic sites. We demonstrate that BDNF's ability to mobilize synaptic vesicle clusters depends on the dissociation of cadherin–β-catenin adhesion complexes that occurs after tyrosine phosphorylation of β-catenin. Artificially maintaining cadherin–β-catenin complexes in the presence of BDNF abolishes the BDNF-mediated enhancement of synaptic vesicle mobility, as well as the longer-term BDNF-mediated increase in synapse number. Together, this data demonstrates that the disruption of cadherin–β-catenin complexes is an important molecular event through which BDNF increases synapse density in cultured hippocampal neurons.

scholarly journals The Impact of Oxytocin on Neurite Outgrowth and Synaptic Proteins in Magel2-Deficient Mice

2020 ◽  
Author(s):  
Alexandra Reichova ◽  
Fabienne Schaller ◽  
Stanislava Bukatova ◽  
Zuzana Bacova ◽  
Françoise Muscatelli ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Primary Cultures ◽  
Synaptic Proteins ◽  
Neuronal Maturation ◽  
Glutamatergic Synapses ◽  
Associated Proteins ◽  
The Impact ◽  
Deficient Mice

AbstractOxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could therefore affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin, but not retinoic acid, reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect in development that should be considered for certain neuropsychiatric conditions in infancy.

scholarly journals The CHD Protein, Kismet, is Important for the Recycling of Synaptic Vesicles during Endocytosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nina K. Latcheva ◽  
Taylor L. Delaney ◽  
Jennifer M. Viveiros ◽  
Rachel A. Smith ◽  
Kelsey M. Bernard ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Chromatin Remodeling ◽  
Neurodevelopmental Disorders ◽  
Synaptic Vesicles ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Critical Feature ◽  
Synaptic Localization ◽  
Transcription Start Sites ◽  
Mature Neurons

AbstractChromatin remodeling proteins of the chromodomain DNA-binding protein family, CHD7 and CHD8, mediate early neurodevelopmental events including neural migration and differentiation. As such, mutations in either protein can lead to neurodevelopmental disorders. How chromatin remodeling proteins influence the activity of mature synapses, however, is relatively unexplored. A critical feature of mature neurons is well-regulated endocytosis, which is vital for synaptic function to recycle membrane and synaptic proteins enabling the continued release of synaptic vesicles. Here we show that Kismet, the Drosophila homolog of CHD7 and CHD8, regulates endocytosis. Kismet positively influenced transcript levels and bound to dap160 and endophilin B transcription start sites and promoters in whole nervous systems and influenced the synaptic localization of Dynamin/Shibire. In addition, kismet mutants exhibit reduced VGLUT, a synaptic vesicle marker, at stimulated but not resting synapses and reduced levels of synaptic Rab11. Endocytosis is restored at kismet mutant synapses by pharmacologically inhibiting the function of histone deacetyltransferases (HDACs). These data suggest that HDAC activity may oppose Kismet to promote synaptic vesicle endocytosis. A deeper understanding of how CHD proteins regulate the function of mature neurons will help better understand neurodevelopmental disorders.

scholarly journals A STRUCTURAL ANALYSIS OF THE MYELIN SHEATH IN THE CENTRAL NERVOUS SYSTEM

1967 ◽  
Vol 34 (2) ◽  
pp. 555-567 ◽  
Author(s):  
Asao Hirano ◽  
Herbert M. Dembitzer
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Electron Microscope ◽  
Myelin Sheath ◽  
Cerebral White Matter ◽  
Experimental Conditions ◽  
Myelin Sheaths ◽  
Basic Theme ◽  
Cell Processes ◽  
The Central Nervous System

The cerebral white matter of rats subjected to a variety of noxious experimental conditions was examined in the electron microscope. Several unusual configurations of the myelin sheath are identified in addition to the usual configuration. These variations include the presence of (a) formed organelles within the inner and outer loops, (b) isolated islands of cytoplasm in unfused portions of the major dense lines, (c) apparently unconnected cell processes between the sheath and the axon, and (d) concentric, double myelin sheaths. A generalized model of the myelin sheath based on a hypothetical unrolling of the sheath is described. It consists of a shovel-shaped myelin sheet surrounded by a continuous thickened rim of cytoplasm. Most of the unusual myelin configurations are explained as simple variations on this basic theme. With the help of this model, an explanation of the formation of the myelin sheath is offered. This explanation involves the concept that myelin formation can occur at all cytoplasmic areas adjacent to the myelin proper and that adjacent myelin lamellae can move in relation to each other.

scholarly journals Myelin sheath survival after guanethidine-induced axonal degeneration.

1992 ◽  
Vol 116 (2) ◽  
pp. 395-403 ◽  
Author(s):  
G J Kidd ◽  
J W Heath ◽  
B D Trapp ◽  
P R Dunkley
Keyword(s):  
Schwann Cells ◽  
Superior Cervical Ganglion ◽  
Myelin Sheath ◽  
Axonal Regeneration ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Serial Sections ◽  
Myelin Sheaths ◽  
Cervical Ganglion ◽  
Contrast Analysis

Membrane-membrane interactions between axons and Schwann cells are required for initial myelin formation in the peripheral nervous system. However, recent studies of double myelination in sympathetic nerve have indicated that myelin sheaths continue to exist after complete loss of axonal contact (Kidd, G. J., and J. W. Heath. 1988. J. Neurocytol. 17:245-261). This suggests that myelin maintenance may be regulated either by diffusible axonal factors or by nonaxonal mechanisms. To test these hypotheses, axons involved in double myelination in the rat superior cervical ganglion were destroyed by chronic guanethidine treatment. Guanethidine-induced sympathectomy resulted in a Wallerian-like pattern of myelin degeneration within 10 d. In doubly myelinated configurations the axon, inner myelin sheath (which lies in contact with the axon), and approximately 75% of outer myelin sheaths broke down by this time. Degenerating outer sheaths were not found at later periods. It is probably that outer sheaths that degenerated were only partially displaced from the axon at the commencement of guanethidine treatment. In contrast, analysis of serial sections showed that completely displaced outer internodes remained ultrastructurally intact. These internodes survived degeneration of the axon and inner sheath, and during the later time points (2-6 wk) they enclosed only connective tissue elements and reorganized Schwann cells/processes. Axonal regeneration was not observed within surviving outer internodes. We therefore conclude that myelin maintenance in the superior cervical ganglion is not dependent on direct axonal contact or diffusible axonal factors. In addition, physical association of Schwann cells with the degenerating axon may be an important factor in precipitating myelin breakdown during Wallerian degeneration.

scholarly journals Developmental myelination is modified by microglial pruning

2019 ◽  
Author(s):  
Alexandria N. Hughes ◽  
Bruce Appel
Keyword(s):  
Botulinum Toxin ◽  
Neuronal Activity ◽  
Immune Cells ◽  
Myelin Sheath ◽  
Myelin Sheaths

AbstractDuring development, oligodendrocytes contact and wrap neuronal axons with myelin. Similar to neurons and synapses, excess myelin sheaths are produced and selectively eliminated. However, unlike these other structures, almost nothing is known about myelin sheath elimination. Microglia, the resident immune cells of the CNS, refine the developing CNS by engulfing surplus neurons and synapses. To determine if microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. Silencing neuronal activity with botulinum toxin (BoNT/B) increased myelin engulfment by microglia. Furthermore, oligodendrocytes maintained excessive myelin sheaths following microglial ablation. Our work reveals a neuronal activity-regulated role for microglia in regulating myelination by oligodendrocytes.

scholarly journals The Akt-mTOR pathway drives myelin sheath growth by regulating cap-dependent translation

2021 ◽  
Author(s):  
Karlie N Fedder-Semmes ◽  
Bruce Appel
Keyword(s):  
Myelin Sheath ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Loss Of Function ◽  
Myelin Sheaths ◽  
Transduction Mechanisms ◽  
Myelin Deficits

In the vertebrate central nervous system, oligodendrocytes produce myelin, a specialized proteolipid rich membrane, to insulate and support axons. Individual oligodendrocytes wrap multiple axons with myelin sheaths of variable lengths and thicknesses. Myelin grows at the distal ends of oligodendrocyte processes and multiple lines of work have provided evidence that mRNAs and RNA binding proteins localize to myelin, together supporting a model where local translation controls myelin sheath growth. What signal transduction mechanisms could control this? One strong candidate is the Akt-mTOR pathway, a major cellular signaling hub that coordinates transcription, translation, metabolism, and cytoskeletal organization. Here, using zebrafish as a model system, we found that Akt-mTOR signaling promotes myelin sheath growth and stability during development. Through cell-specific manipulations to oligodendrocytes, we show that the Akt-mTOR pathway drives cap-dependent translation to promote myelination and that restoration of cap-dependent translation is sufficient to rescue myelin deficits in mTOR loss-of-function animals. Moreover, an mTOR-dependent translational regulator co-localized with mRNA encoding a canonically myelin-translated protein in vivo and bioinformatic investigation revealed numerous putative translational targets in the myelin transcriptome. Together, these data raise the possibility that Akt-mTOR signaling in nascent myelin sheaths promotes sheath growth via translation of myelin-resident mRNAs during development.

Schwann Cell Reactions in Acute and Chronic Segmental Demyelinating Neuropathies

1968 ◽  
Vol 26 ◽  
pp. 108-109
Author(s):  
Roy O. Weller
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Myelin Sheath ◽  
Wallerian Degeneration ◽  
Demyelinating Disease ◽  
Segmental Demyelination ◽  
Recovery Stage ◽  
Myelin Sheaths ◽  
Demyelinating Neuropathies

The length of axon that each Schwann cell myelinates in a normal peripheral nerve is approximately proportional to the diameter of the axon and the thickness of the myelin sheath produced. When segmental demyelination occurs, individual segments, represented by the length of axon covered by one Schwann cell, lose their myelin sheaths but the axons are preserved. This differs from Wallerian degeneration where myelin destruction occurs along the length of a nerve fibre following death of the axon.In experimental diphtheritic neuropathy, an acute segmental demyelinating disease, lysosomes accumulate within the Schwann cells prior to disruption of the myelin sheath; furthermore, the site of initial myelin breakdown appears to be closely related to the collections of lysosomes. The Schwann cell starts to form a new myelin sheath around the axon probably within a few hours of the destruction of the original myelin sheath, and while the latter is being catabolised within lysosomal vacuoles This stage of remyelination follows a similar course to primary myelination, so that the recovery stage is characterised by normal axons with either no myelin, or surrounded by sheaths that are very thin relative to the diameter of the axon.

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